FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Freeman, S Bhatt, A Pedamallu, C King, S Duke, F Jung, J Lawton, M Anderson, E Fuhlbrigge, RC Kenna, M Licameli, G Meyerson, M Dedeoglu, F AF Freeman, Samuel Bhatt, Ami Pedamallu, Chandra King, Sandra Duke, Fujiko Jung, Joonil Lawton, Maranda Anderson, Edwin Fuhlbrigge, Robert C. Kenna, Margaret Licameli, Greg Meyerson, Matthew Dedeoglu, Fatma TI In Search of Infectious Triggers of Periodic Fever, Aphthous Stomatitis, Pharyngitis and Adenitis Syndrome SO ARTHRITIS & RHEUMATOLOGY LA English DT Meeting Abstract C1 [Freeman, Samuel; Bhatt, Ami; Pedamallu, Chandra; Duke, Fujiko; Jung, Joonil] Broad Inst, Cambridge, MA USA. [King, Sandra] Brigham & Womens Hosp, Boston, MA 02115 USA. [Lawton, Maranda; Fuhlbrigge, Robert C.] Childrens Hosp, Boston, MA 02115 USA. [Anderson, Edwin; Dedeoglu, Fatma] Boston Childrens Hosp, Boston, MA USA. [Kenna, Margaret; Licameli, Greg] Harvard Univ, Sch Med, Boston, MA USA. [Meyerson, Matthew] Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 4 Z9 4 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2326-5191 EI 2326-5205 J9 ARTHRITIS RHEUMATOL JI Arthritis Rheumatol. PD MAR PY 2014 VL 66 SU 3 SI SI MA A121 BP S158 EP S158 DI 10.1002/art.38542 PG 1 WC Rheumatology SC Rheumatology GA CB9KQ UT WOS:000349950900123 ER PT J AU Eapen, M Richardson, P Prentice, G Ehrhardt, M Korman, S Horowitz, MM AF Eapen, M. Richardson, P. Prentice, G. Ehrhardt, M. Korman, S. Horowitz, M. M. TI DATA FROM AN INDEPENDENT REGISTRY CORROBORATES RESULTS OF A PREVIOUS STUDY CONFIRMING THE EFFECTIVENESS OF DEFIBROTIDE IN THE TREATMENT OF SEVERE VENO-OCCLUSIVE DISEASE SO BONE MARROW TRANSPLANTATION LA English DT Meeting Abstract CT 40th Annual Meeting of the European-Group-for-Blood-and-Marrow-Transplantation CY MAR 30-APR 02, 2014 CL Milan, ITALY SP European Grp Blood & Marrow Transplantat C1 [Eapen, M.; Ehrhardt, M.; Korman, S.; Horowitz, M. M.] Med Coll Wisconsin, Milwaukee, WI 53226 USA. [Richardson, P.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Prentice, G.] Pharmion Corp, London, England. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0268-3369 EI 1476-5365 J9 BONE MARROW TRANSPL JI Bone Marrow Transplant. PD MAR PY 2014 VL 49 SU 1 MA PH-P332 BP S258 EP S259 PG 2 WC Biophysics; Oncology; Hematology; Immunology; Transplantation SC Biophysics; Oncology; Hematology; Immunology; Transplantation GA CP5RP UT WOS:000359941901332 ER PT J AU Levine, JE Braun, TM Harris, AC Holler, E Taylor, A Miller, H Magenau, J Weisdorf, DJ Ho, VT Bolanos-Meade, J Alousi, AM Ferrara, JLM AF Levine, J. E. Braun, T. M. Harris, A. C. Holler, E. Taylor, A. Miller, H. Magenau, J. Weisdorf, D. J. Ho, V. T. Bolanos-Meade, J. Alousi, A. M. Ferrara, J. L. M. CA Blood Marrow Transplant Clinical TI A NEW ANN ARBOR GRADING SYSTEM USES BIOMARKERS TO RISK STRATIFY PATIENTS FOR NON RELAPSE MORTALITY AT THE ONSET OF ACUTE GRAFT VERSUS HOST DISEASE SO BONE MARROW TRANSPLANTATION LA English DT Meeting Abstract CT 40th Annual Meeting of the European-Group-for-Blood-and-Marrow-Transplantation CY MAR 30-APR 02, 2014 CL Milan, ITALY SP European Grp Blood & Marrow Transplantat C1 [Levine, J. E.; Harris, A. C.; Taylor, A.; Miller, H.; Magenau, J.; Ferrara, J. L. M.] Univ Michigan, Blood & Marrow Transplant Program, Ann Arbor, MI 48109 USA. [Braun, T. M.] Univ Michigan, Sch Publ Hlth, Ann Arbor, MI 48109 USA. [Holler, E.] Univ Regensburg, Hematol & Oncol, D-93053 Regensburg, Germany. [Weisdorf, D. J.] Univ Minnesota, Blood & Marrow Transplant Program, Minneapolis, MN USA. [Ho, V. T.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Bolanos-Meade, J.] Johns Hopkins Sch Med, Dept Hematol Malignancies, Baltimore, MD USA. [Alousi, A. M.] Univ Texas MD Anderson Canc Ctr, Dept Stem Cell Transplantat, Houston, TX 77030 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0268-3369 EI 1476-5365 J9 BONE MARROW TRANSPL JI Bone Marrow Transplant. PD MAR PY 2014 VL 49 SU 1 MA PH-O005 BP S3 EP S3 PG 1 WC Biophysics; Oncology; Hematology; Immunology; Transplantation SC Biophysics; Oncology; Hematology; Immunology; Transplantation GA CP5RP UT WOS:000359941900006 ER PT J AU Manzo, T Buchan, S Flutter, B Zhang, L Bennett, C Freeman, GJ Croft, M Sykes, M Al-Shamkhani, A Chakraverty, R AF Manzo, T. Buchan, S. Flutter, B. Zhang, L. Bennett, C. Freeman, G. J. Croft, M. Sykes, M. Al-Shamkhani, A. Chakraverty, R. TI AGONISTIC CO-STIMULATION SYNERGIZES WITH CO-INHIBITORY BLOCKADE TO REVERSE EXHAUSTION OF HELPLESS CD8 T CELLS SO BONE MARROW TRANSPLANTATION LA English DT Meeting Abstract CT 40th Annual Meeting of the European-Group-for-Blood-and-Marrow-Transplantation CY MAR 30-APR 02, 2014 CL Milan, ITALY SP European Grp Blood & Marrow Transplantat C1 [Manzo, T.; Flutter, B.; Bennett, C.; Chakraverty, R.] UCL, Canc Inst, London, England. [Buchan, S.] Canc Sci Unit, Southampton, Hants, England. [Zhang, L.] Inst Canc Res, London, England. [Freeman, G. J.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Croft, M.] Inst Allergy & Immunol, San Diego, CA USA. [Sykes, M.] Columbia Univ, Med Ctr, New York, NY USA. [Al-Shamkhani, A.] Univ Southampton, Canc Sci Unit, Southampton, Hants, England. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0268-3369 EI 1476-5365 J9 BONE MARROW TRANSPL JI Bone Marrow Transplant. PD MAR PY 2014 VL 49 SU 1 MA PH-O042 BP S23 EP S23 PG 1 WC Biophysics; Oncology; Hematology; Immunology; Transplantation SC Biophysics; Oncology; Hematology; Immunology; Transplantation GA CP5RP UT WOS:000359941900043 ER PT J AU Trlen, J Ringden, O Le-Rademacher, J Battiwalla, M Chen, J Ho, VT Kebriaei, P Keever-Taylor, CA Kindwall-Keller, TL Lazarus, HM Laughlin, M Lill, MC Brien, TO Perales, MA Rocha, V Savani, BN Szwajcer, D Valcarcel, D Eapen, M AF Trlen, J. Ringden, O. Le-Rademacher, J. Battiwalla, M. Chen, J. Ho, V. T. Kebriaei, P. Keever-Taylor, C. A. Kindwall-Keller, T. L. Lazarus, H. M. Laughlin, M. Lill, M. C. Brien, T. O' Perales, M. -A. Rocha, V. Savani, B. N. Szwajcer, D. Valcarcel, D. Eapen, M. CA Ctr Int Blood Marrow Transplant TI LOW CD34 CELL DOSE IS ASSOCIATED WITH HIGHER NON-RELAPSE AND OVERALL MORTALITY AFTER REDUCED INTENSITY CONDITIONING HEMATOPOIETIC STEM CELL TRANSPLANTATION FOR ACUTE MYELOID LEUKEMIA AND MYELODYSPLASTIC SYNDROME SO BONE MARROW TRANSPLANTATION LA English DT Meeting Abstract CT 40th Annual Meeting of the European-Group-for-Blood-and-Marrow-Transplantation CY MAR 30-APR 02, 2014 CL Milan, ITALY SP European Grp Blood & Marrow Transplantat C1 [Trlen, J.] Karolinska Univ Hosp, Ctr Allogene Stem Cell Transplantat, Stockholm, Sweden. [Ringden, O.] Karolinska Inst, Div Therapeut Immunol, Stockholm, Sweden. [Le-Rademacher, J.] Med Coll Wisconsin, Ctr Int Blood & Marrow Transplantat Res, Milwaukee, WI 53226 USA. [Battiwalla, M.] NIH, Heart Lung & Blood Inst, Hematol Branch, Bethesda, MD 20892 USA. [Chen, J.; Eapen, M.] Med Coll Wisconsin, Ctr Int Blood & Marrow Transplant Res, Milwaukee, WI 53226 USA. [Ho, V. T.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Kebriaei, P.] Univ Texas MD Anderson Canc Ctr, Dept Stem Cell Transplantat & Cellular Therapy, Houston, TX 77030 USA. [Keever-Taylor, C. A.] Med Coll Wisconsin, Div Hematol & Oncol, Milwaukee, WI 53226 USA. [Kindwall-Keller, T. L.] Univ Virginia, Med Ctr, Charlottesville, VA USA. [Lazarus, H. M.] Univ Hosp Case Med Ctr, Seidman Canc Ctr, Cleveland, OH USA. [Laughlin, M.] Cleveland Cord Blood Ctr, Cleveland, OH USA. [Lill, M. C.] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. [Brien, T. O'] Sydney Childrens Hosp, Ctr Childrens Canc & Blood Disorders, Sydney, NSW, Australia. [Perales, M. -A.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Rocha, V.] Churchill Hosp, Canc & Haematol Ctr, Oxford OX3 7LJ, England. [Savani, B. N.] Vanderbilt Univ, Med Ctr, Nashville, TN USA. [Szwajcer, D.] Univ Manitoba, CancerCare Manitoba, Winnipeg, MB, Canada. [Valcarcel, D.] Hosp Infantil Vall dHebron, Barcelona, Spain. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0268-3369 EI 1476-5365 J9 BONE MARROW TRANSPL JI Bone Marrow Transplant. PD MAR PY 2014 VL 49 SU 1 MA PH-P269 BP S229 EP S230 PG 2 WC Biophysics; Oncology; Hematology; Immunology; Transplantation SC Biophysics; Oncology; Hematology; Immunology; Transplantation GA CP5RP UT WOS:000359941901269 ER PT J AU Ackroyd, SA Wexler, DJ AF Ackroyd, Sarah A. Wexler, Deborah J. TI Effectiveness of Diabetes Interventions in the Patient-Centered Medical Home SO CURRENT DIABETES REPORTS LA English DT Review DE Diabetes; Interventions; Patient-centered medical home; Quality improvement; Cost-effectiveness ID RANDOMIZED CONTROLLED-TRIAL; PRIMARY-CARE EVIDENCE; PRACTICE TRANSFORMATION; CLINICAL-OUTCOMES; MANAGEMENT; PHARMACIST; QUALITY; DEPRESSION; METAANALYSIS; IMPACT AB The patient-centered medical home (PCMH) is an innovative care model for the provision of primary care that is being rapidly adopted in the U.S. with the support of federal agencies and professional organizations. Its goal is to provide comprehensive, patient-centered care with increased access, quality, and efficiency. Diabetes, as a common, costly, chronic disease that requires ongoing management by patients and providers, is a condition that is frequently monitored as a test case in PCMH implementations. While in theory a PCMH care model that supports patient engagement and between-visit care may help improve diabetes care delivery and outcomes, the success of this approach may depend largely upon the specific strategies used and implementation approach. The cost-effectiveness of diabetes care in the PCMH model is not yet clear. Interventions have been most effective and most cost-effective for those with the poorest diabetes management at baseline. C1 [Ackroyd, Sarah A.] Univ Rochester, Sch Med & Dent, Rochester, NY 14642 USA. [Wexler, Deborah J.] Massachusetts Gen Hosp, Ctr Diabet, Boston, MA 02114 USA. [Wexler, Deborah J.] Harvard Univ, Sch Med, Boston, MA USA. RP Wexler, DJ (reprint author), Massachusetts Gen Hosp, Ctr Diabet, 50 Staniford St, Boston, MA 02114 USA. EM dwexler@partners.org FU Boston Area Diabetes Endocrinology Research Center [5P30DK057521] FX Sarah A. Ackroyd was supported by the Boston Area Diabetes Endocrinology Research Center 5P30DK057521. NR 57 TC 8 Z9 8 U1 2 U2 9 PU CURRENT MEDICINE GROUP PI PHILADELPHIA PA 400 MARKET STREET, STE 700, PHILADELPHIA, PA 19106 USA SN 1534-4827 EI 1539-0829 J9 CURR DIABETES REP JI Curr. Diabetes Rep. PD MAR PY 2014 VL 14 IS 3 AR 471 DI 10.1007/s11892-013-0471-z PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CY1QB UT WOS:000366181400007 PM 24477830 ER PT J AU Antai-Otong, D AF Antai-Otong, Deborah TI Vitamin D: An Anti-Inflammatory Treatment Option for Depression? SO ISSUES IN MENTAL HEALTH NURSING LA English DT Editorial Material ID D DEFICIENCY ALTERS; C-REACTIVE PROTEIN; MAJOR DEPRESSION; 1,25-DIHYDROXYVITAMIN D-3; COGNITIVE THERAPY; ADULT-RAT; BRAIN; INFLAMMATION; METAANALYSIS; CYTOKINES C1 US Dept Vet Affairs, Med Ctr, Dallas, TX 75216 USA. RP Antai-Otong, D (reprint author), US Dept Vet Affairs, Med Ctr, Dallas, TX 75216 USA. EM Deborah.Antai-Otong@va.gov NR 74 TC 1 Z9 1 U1 1 U2 7 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 0161-2840 EI 1096-4673 J9 ISSUES MENT HEALTH N JI Issues Ment. Health Nurs. PD MAR PY 2014 VL 35 IS 3 BP 227 EP 234 DI 10.3109/01612840.2013.875086 PG 8 WC Nursing; Psychiatry SC Nursing; Psychiatry GA CG3XL UT WOS:000353212800012 PM 24597590 ER PT J AU Matthews, DD Blosnich, JR Farmer, GW Adams, BJ AF Matthews, Derrick D. Blosnich, John R. Farmer, Grant W. Adams, Brian J. TI Operational Definitions of Sexual Orientation and Estimates of Adolescent Health Risk Behaviors SO LGBT HEALTH LA English DT Article DE adolescents; data analysis; health behavior; measurement; sexual orientation ID UNITED-STATES; SUBSTANCE USE; COLLEGE-STUDENTS; MINORITY; IDENTITY; GAY; SURVEILLANCE; YOUTH; MEN AB Purpose: Increasing attention to the health of lesbian, gay, and bisexual (LGB) populations comes with requisite circumspection about measuring sexual orientation in surveys. However, operationalizing these variables also requires considerable thought. This research sought to document the consequences of different operational definitions of sexual orientation by examining variation in health risk behaviors. Methods: Using Massachusetts Youth Risk Behavior Survey data, we examined how operational definitions of sexual behavior and sexual identity influenced differences among three health behaviors known to disparately affect LGB populations: smoking, suicide risk, and methamphetamine use. Sexual behavior and sexual identity were also examined together to explore if they captured unique sources of variability in behavior. Results: Estimates of health disparities changed as a result of using either sexual behavior or sexual identity. Youth who reported their sexual identity as "not sure'' also had increased odds of health risk behavior. Disaggregating bisexual identity and behavior from same-sex identity and behavior frequently resulted in the attenuation or elimination of health disparities that would have otherwise been attributable to exclusively same-sex sexual minorities. Finally, sexual behavior and sexual identity explained unique and significant sources of variability in all three health behaviors. Conclusion: Researchers using different operational definitions of sexual orientation could draw different conclusions, even when analyzing the same data, depending upon how they chose to represent sexual orientation in analyses. We discuss implications that these manipulations have on data interpretation and provide specific recommendations for best-practices when analyzing sexual orientation data collected from adolescent populations. C1 [Matthews, Derrick D.; Adams, Brian J.] Univ N Carolina, Gillings Sch Global Publ Hlth, Dept Hlth Behav, Chapel Hill, NC 27599 USA. [Blosnich, John R.] Univ Rochester, Rochester, NY USA. [Blosnich, John R.] US Dept Vet Affairs, VISN Ctr Excellence Suicide Prevent 2, Canandaigua, NY USA. [Farmer, Grant W.] St Louis Univ, Dept Epidemiol, Coll Publ Hlth & Social Justice, St Louis, MO 63103 USA. RP Matthews, DD (reprint author), Univ N Carolina, Gillings Sch Global Publ Hlth, Dept Hlth Behav, Campus Box 7440, Chapel Hill, NC 27599 USA. EM derrick.matthews@unc.edu FU Summer Institute in LGBT Population Health; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) [R25HD064426]; National Institute of Mental Health [5T32MH020061] FX This research project was partially supported by a training fellowship from the Summer Institute in LGBT Population Health to D.D.M., J.R.B., and G.W.F. under award number R25HD064426 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). The project was also supported by a post-doctoral fellowship to J.R.B. in an Institutional National Research Service Award from the National Institute of Mental Health (5T32MH020061). NR 37 TC 19 Z9 19 U1 6 U2 14 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 2325-8292 EI 2325-8306 J9 LGBT HEALTH JI LGBT Health PD MAR PY 2014 VL 1 IS 1 BP 42 EP 49 DI 10.1089/lgbt.2013.0002 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CR9PQ UT WOS:000361689300009 PM 25110718 ER PT J AU Mattocks, KM Kauth, MR Sandfort, T Matza, AR Sullivan, JC Shipherd, JC AF Mattocks, Kristin M. Kauth, Michael R. Sandfort, Theo Matza, Alexis R. Sullivan, J. Cherry Shipherd, Jillian C. TI Understanding Health-Care Needs of Sexual and Gender Minority Veterans: How Targeted Research and Policy Can Improve Health SO LGBT HEALTH LA English DT Article DE biology and sexual/gender minority status; gender identity; gender variance; LGBT; mental health needs veteran ID MENTAL-HEALTH; TRANSGENDER PATIENTS; UNITED-STATES; SUBSTANCE USE; GAY; AFFAIRS; PREVALENCE; BEHAVIOR; RISK; VICTIMIZATION AB Given the size of the patient population of the Veterans Health Administration (VHA), it is likely the largest single provider of health care for sexual and gender minority (SGM) individuals in the United States, including lesbian, gay, bisexual, and transgender persons. However, current VHA demographic data-collection strategies limit the understanding of how many SGM veterans there are, thereby making a population-based understanding of the health needs of SGM veterans receiving care in VHA difficult. In this article, we summarize the emergent research findings about SGM veterans and the first initiatives that have been implemented by VHA to promote quality care. Though the research on SGM veterans is in its infancy, it suggests that SGM veterans share some of the health risks noted in veterans generally and also risks associated with SGM status. Some promising resiliency factors have also been identified. These findings have implications for both VHA and non-VHA systems in the treatment of SGM veterans. However, more research on the unique needs of SGM veterans is needed to fully understand their health risks and resiliencies in addition to health-care utilization patterns. C1 [Mattocks, Kristin M.; Sullivan, J. Cherry] VA Cent Western Massachusetts Hlthcare Syst, Leeds, MA 01053 USA. [Mattocks, Kristin M.] Univ Massachusetts, Sch Med, Worcester, MA 01605 USA. [Kauth, Michael R.; Shipherd, Jillian C.] VA Patient Care Serv, LGBT Program, Washington, DC USA. [Kauth, Michael R.] VA South Cent Mental Illness Res Educ & Clin Ctr, Houston, TX USA. [Kauth, Michael R.] Michael E DeBakey VA Med Ctr, Houston VA HSR&D Ctr Excellence, Houston, TX USA. [Kauth, Michael R.] Baylor Coll Med, Houston, TX 77030 USA. [Sandfort, Theo] Columbia Univ, Dept Psychiat, Div Gender Sexual & Hlth, New York, NY USA. [Sandfort, Theo] New York State Psychiat Inst & Hosp, New York, NY 10032 USA. [Matza, Alexis R.; Shipherd, Jillian C.] VA Boston Healthcare Syst, Boston, MA USA. [Matza, Alexis R.; Shipherd, Jillian C.] Natl Ctr PTSD, Womens Hlth Sci Div, Boston, MA USA. [Matza, Alexis R.; Shipherd, Jillian C.] Boston Univ, Sch Med, Boston, MA 02118 USA. RP Mattocks, KM (reprint author), VA Cent Western Massachusetts Hlthcare Syst, Leeds, MA 01053 USA. FU VA HSRD [SDR 10-012]; Houston VA Health Services Research and Development Center of Excellence [HFP90-020] FX This work was partly supported by VA HSR&D-funded Women's Health Research Network (Project # SDR 10-012) and the Houston VA Health Services Research and Development Center of Excellence (HFP90-020). NR 62 TC 11 Z9 11 U1 4 U2 6 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 2325-8292 EI 2325-8306 J9 LGBT HEALTH JI LGBT Health PD MAR PY 2014 VL 1 IS 1 BP 50 EP 57 DI 10.1089/lgbt.2013.0003 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CR9PQ UT WOS:000361689300010 PM 26789509 ER PT J AU Molina, RL Palazuelos, D AF Molina, Rose Leonard Palazuelos, Daniel TI Navigating and Circumventing a Fragmented Health System: The Patient's Pathway in the Sierra Madre Region of Chiapas, Mexico SO MEDICAL ANTHROPOLOGY QUARTERLY LA English DT Article DE health care reform; access to care; insurance; trust; Seguro Popular ID REFORM; INSURANCE; COVERAGE; POLICY AB Mexico has implemented several important reforms in how health care for its poorest is financed and delivered. Seguro Popular, in particular, a recently implemented social insurance program, aims to provide new funds for a previously underfunded state-based safety net system. Through in-depth ethnographic structured interviews with impoverished farmers in the state of Chiapas, this article presents an analysis of Seguro Popular from the perspective of a highly underserved beneficiary group. Specific points of tension among the various stakeholders-the government system (including public clinics, hospitals, and vertical programs), community members, private doctors, and pharmacies-are highlighted and discussed. Ethnographic data presented in this article expose distinct gaps between national health policy rhetoric and the reality of access to health services at the community level in a highly marginalized municipality in one of Mexico's poorest states. These insights have important implications for the structure and implementation of on-going reforms. C1 [Molina, Rose Leonard] Brigham & Womens Hosp, Dept Obstet & Gynecol, Boston, MA 02115 USA. [Molina, Rose Leonard] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Palazuelos, Daniel] Brigham & Womens Hosp, Div Global Hlth Equ, Boston, MA 02115 USA. [Palazuelos, Daniel] Harvard Univ, Sch Med, Dept Global Hlth & Social Med, Boston, MA USA. [Palazuelos, Daniel] PIH, Companeros En Salud Mexico CES, Boston, MA USA. RP Molina, RL (reprint author), Brigham & Womens Hosp, Dept Obstet & Gynecol, 75 Francis St, Boston, MA 02115 USA. NR 31 TC 4 Z9 4 U1 0 U2 3 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0745-5194 EI 1548-1387 J9 MED ANTHROPOL Q JI Med. Anthropol. Q. PD MAR PY 2014 VL 28 IS 1 BP 23 EP 43 DI 10.1111/maq.12071 PG 21 WC Anthropology; Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Anthropology; Public, Environmental & Occupational Health; Biomedical Social Sciences GA AD7EN UT WOS:000333425000011 ER PT J AU Benson, LA Healy, BC Gorman, MP Baruch, NF Gholipour, T Musallam, A Chitnis, T AF Benson, L. A. Healy, B. C. Gorman, M. P. Baruch, N. F. Gholipour, T. Musallam, A. Chitnis, T. TI Elevated relapse rates in pediatric compared to adult MS persist for at least 6 years SO MULTIPLE SCLEROSIS AND RELATED DISORDERS LA English DT Article DE Multiple sclerosis; Pediatric; Relapse; Demyelination; Attack; Disability ID ONSET MULTIPLE-SCLEROSIS; NATURAL-HISTORY; CLINICAL CHARACTERISTICS; PSYCHOSOCIAL FEATURES; JUVENILE MS; FOLLOW-UP; CHILDHOOD; PROGNOSIS; DISABILITY; DISEASE AB Objective: To compare relapse rates in pediatric-onset multiple sclerosis (POMS) and adult-onset multiple sclerosis (AOMS) over the first 6-years of disease. Methods: Patients with relapsing-remitting disease onset were identified from the Partners Pediatric MS Center, Massachusetts General Hospital and Partners MS Center, Brigham and Women's Hospital. 84 POMS and 258 AOMS patients were included. Annualized relapse rates (ARR) for each individual year from year 1 to year 6, after first attack were compared using Poisson regression, as was expanded disability status scale (EDSS) score at the visit closest to each year interval. Results: ARR was significantly higher in POMS compared to AOMS at individual years (except year 4), and was not significantly affected by adjustment for gender, race and proportion of time on treatment. Despite a 2.30 times higher relapse rate over 6-years, EDSS between groups did not differ. ARR in years 1-5 did not impact year 5 disability measured by EDSS in POMS. Conclusions: Our findings demonstrate that higher ARR in POMS relative to AOMS is sustained over 6-years, suggesting a more inflammatory nature and potential disconnect between relapses and disability measured by EDSS early in POMS. This data may be useful when designing clinical trials for POMS. (C) 2013 Elsevier B.V. All rights reserved. C1 [Benson, L. A.; Baruch, N. F.; Chitnis, T.] Massachusetts Gen Hosp, Partners Pediat Multiple Sclerosis Ctr, Boston, MA 02114 USA. [Benson, L. A.; Healy, B. C.; Baruch, N. F.; Gholipour, T.; Musallam, A.; Chitnis, T.] Brigham & Womens Hosp, Partners Multiple Sclerosis Ctr, Boston, MA 02115 USA. [Benson, L. A.; Gorman, M. P.; Baruch, N. F.] Boston Childrens Hosp, Dept Neurol, Boston, MA USA. RP Chitnis, T (reprint author), Brigham & Womens Hosp, Partners Multiple Sclerosis Ctr, 1 Brookline Pl, Boston, MA 02115 USA. EM leslie.benson@childrens.harvard.edu; bchealy@parterns.org; mark.gorman@childrens.harvard.edu; nbaruch@partners.org; tgholipour@partners.org; amusallam@partners.org; tchitnis@rics.bwh.harvard.edu FU National Multiple Sclerosis Society [TC-RG-4256A4/2/]; Pediatric MS Regional Centers of Excellence Grant from the National MS Society FX Supported by the National Multiple Sclerosis Society (TC-RG-4256A4/2/) and the Pediatric MS Regional Centers of Excellence Grant from the National MS Society (TC). NR 37 TC 12 Z9 12 U1 0 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 2211-0348 EI 2211-0356 J9 MULT SCLER RELAT DIS JI Mult. Scler. Relat. Disord. PD MAR PY 2014 VL 3 IS 2 BP 186 EP 193 DI 10.1016/j.msard.2013.06.004 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA CB5KA UT WOS:000349664700008 PM 25878006 ER PT J AU Sperling, R Mormino, E Schultz, A Rentz, D Aisen, P Johnson, K AF Sperling, Reisa Mormino, E. Schultz, A. Rentz, D. Aisen, P. Johnson, K. TI THE AGING BRAIN - DOES AMYLOID MATTER? SO NEUROBIOLOGY OF AGING LA English DT Meeting Abstract CT 13th International Geneva/Springfield Symposium on Advances in Alzheimer Therapy CY MAR 26-29, 2014 CL Geneva, SWITZERLAND DE Preclinical Alzheimer's disease; Amyloid imaging; Prevention trials C1 [Sperling, Reisa; Rentz, D.] Harvard Univ, Brigham & Womens Hosp, Massachusetts Gen Hosp, Sch Med, Boston, MA 02115 USA. [Mormino, E.; Schultz, A.; Johnson, K.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Aisen, P.] Alzheimers Dis Cooperat Study, San Diego, CA USA. EM reisa@rics.bwh.harvard.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-4580 EI 1558-1497 J9 NEUROBIOL AGING JI Neurobiol. Aging PD MAR PY 2014 VL 35 SU 1 BP S21 EP S21 PG 1 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA CP6PW UT WOS:000360011100079 ER PT J AU Tanzi, RE AF Tanzi, Rudolph E. TI DECODING ALZHEIMER'S IN THE AGE OF GENOME-WIDE ANALYSES SO NEUROBIOLOGY OF AGING LA English DT Meeting Abstract CT 13th International Geneva/Springfield Symposium on Advances in Alzheimer Therapy CY MAR 26-29, 2014 CL Geneva, SWITZERLAND DE Genes; CD33; Sequencing C1 [Tanzi, Rudolph E.] Harvard Univ, Sch Med, Mass Gen Hosp, Boston, MA USA. EM rtanzi@gmail.com NR 0 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-4580 EI 1558-1497 J9 NEUROBIOL AGING JI Neurobiol. Aging PD MAR PY 2014 VL 35 SU 1 BP S22 EP S22 PG 1 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA CP6PW UT WOS:000360011100082 ER PT J AU Cummings, BM Noviski, N AF Cummings, Brian M. Noviski, Natan TI Pediatric Extubation Readiness: Faith-Based Practice or Amenable to Standardization? SO RESPIRATORY CARE LA English DT Editorial Material ID RANDOMIZED CONTROLLED-TRIAL; AIR LEAK TEST; ENDOTRACHEAL-TUBE; CHILDREN; OUTCOMES; INFANTS C1 [Cummings, Brian M.; Noviski, Natan] Massachusetts Gen Hosp, Div Pediat Crit Care Med, Boston, MA 02114 USA. RP Noviski, N (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, 175 Cambridge St,CPZS-524, Boston, MA 02114 USA. EM nnoviski@partners.org NR 8 TC 1 Z9 1 U1 0 U2 0 PU DAEDALUS ENTERPRISES INC PI IRVING PA 9425 N MAC ARTHUR BLVD, STE 100, IRVING, TX 75063-4706 USA SN 0020-1324 EI 1943-3654 J9 RESP CARE JI Respir. Care PD MAR PY 2014 VL 59 IS 3 BP 445 EP 446 DI 10.4187/respcare.03103 PG 2 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA CA8VQ UT WOS:000349199400019 PM 24587483 ER PT J AU Gunn, AJ Gervais, DA AF Gunn, Andrew J. Gervais, Debra A. TI Percutaneous Ablation of the Small Renal Mass-Techniques and Outcomes SO SEMINARS IN INTERVENTIONAL RADIOLOGY LA English DT Article DE renal mass; percutaneous ablation; radiofrequency ablation; cryoablation; interventional radiology ID GUIDED RADIOFREQUENCY ABLATION; RADIO-FREQUENCY ABLATION; CELL CARCINOMA; ONCOLOGIC OUTCOMES; TISSUE ABLATION; TUMOR ABLATION; PARTIAL NEPHRECTOMY; PRACTICE PATTERNS; FOLLOW-UP; CRYOABLATION AB An increasing number of T1a renal cell carcinomas are being diagnosed in recent years, in part due to incidental detection from the increased use of cross-sectional imaging. Although partial nephrectomy is still considered the primary treatment for these small renal masses, percutaneous ablation is now being performed as a standard therapeutic, nephron-sparing approach in patients who are poor surgical candidates. Clinical studies to date have demonstrated that percutaneous ablation is an effective therapy with acceptable outcomes and low risk in the appropriate clinical settings. This article will review various clinical aspects regarding the percutaneous ablation of small renal masses, including patient selection, preprocedural preparations, and the procedural considerations of commonly employed ablative technologies. Specific techniques such as radiofrequency ablation, cryoablation, microwave ablation, irreversible electroporation, and high-intensity focused ultrasound will be addressed in detail. In addition, the technical and oncologic outcomes of percutaneous ablation will be discussed and referenced to that of partial nephrectomy. C1 [Gunn, Andrew J.] Harvard Univ, Sch Med, Dept Radiol, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Gervais, Debra A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Abdominal Imaging & Intervent, Boston, MA USA. RP Gervais, DA (reprint author), Massachusetts Gen Hosp, Dept Radiol, Div Abdominal Imaging & Intervent, 55 Fruit St, Boston, MA 02114 USA. EM dgervais@partners.org FU Covidien FX Dr. Gervais has received research support from Covidien. NR 58 TC 3 Z9 4 U1 0 U2 1 PU THIEME MEDICAL PUBL INC PI NEW YORK PA 333 SEVENTH AVE, NEW YORK, NY 10001 USA SN 0739-9529 J9 SEMIN INTERVENT RAD JI Semin. Interv. Radiol. PD MAR PY 2014 VL 31 IS 1 BP 33 EP 41 DI 10.1055/s-0033-1363841 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA CU1MW UT WOS:000363287000006 PM 24596438 ER PT J AU Guanci, MM AF Guanci, Mary McKenna TI We had a patient who underwent hypothermia after cardiac arrest and was brought back to 37 degrees C. The physicians removed the cooling device, and the patient's temperature escalated to 38 degrees C 12 hours later. What are the best methods to control temperature once the patient is back at normothermia if the device has been removed? SO THERAPEUTIC HYPOTHERMIA AND TEMPERATURE MANAGEMENT LA English DT Letter ID FEVER C1 Massachusetts Gen Hosp, Neurosci Intens Care, Boston, MA 02114 USA. RP Guanci, MM (reprint author), Massachusetts Gen Hosp, Neurosci Intens Care, Boston, MA 02114 USA. NR 5 TC 0 Z9 0 U1 1 U2 1 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 2153-7658 EI 2153-7933 J9 THER HYPOTHERMIA TEM JI Ther. Hypothermia Temp. Manag. PD MAR 1 PY 2014 VL 4 IS 1 BP 56 EP 56 PG 1 WC Critical Care Medicine SC General & Internal Medicine GA CF3UV UT WOS:000352475100011 ER PT J AU Leadholm, AKK Rothschild, AJ Nielsen, J Bech, P Ostergaard, SD AF Leadholm, Anne Katrine K. Rothschild, Anthony J. Nielsen, Jimmi Bech, Per Ostergaard, Soren D. TI Risk factors for suicide among 34,671 patients with psychotic and non-psychotic severe depression SO JOURNAL OF AFFECTIVE DISORDERS LA English DT Article DE Depressive disorder; Affective disorders; Psychotic; Suicide; Suicide prevention; Register study ID GENERAL-POPULATION; MENTAL-DISORDERS; ASSOCIATION; PREDICTORS; REGISTER; FEATURES; EPISODES; ILLNESS; PREVALENCE; ATTEMPTERS AB Background: Severe unipolar depression is associated with increased risk of suicide, but it remains unknown whether the same risk factors are present in the non-psychotic (non-PD) and psychotic (PD) subtypes respectively. Therefore, this study aimed to identify risk factors for suicide in non-PD and PD separately, and to investigate if the presence of psychotic symptoms is an independent risk factor for suicide in severe depression. Methods: This register-based, nationwide, historical prospective cohort study used logistic regression analyses to ascertain risk factors for suicide among all adults diagnosed with severe depression at Danish psychiatric hospitals between January 1,1994 and December 31, 2010. The risk for suicide was expressed as adjusted odds ratios (AOR). Results: A total of 34,671 individuals with severe depression (non-PD: n=26,106 and PD: n=12,101) were included in the study. Of these, 755 completed suicide during follow up. PD was not found to be an independent risk factor for suicide in severe depression (AOR=0.97 [0.83-1.151). Older age (non-PD AOR= 1.05 per year], PD AOR=1.04 [per yeari), male sex (non-PD AOR=1.89, PD AOR=1.98), and a previous incident of self-harm (non-PD AOR=5.02, PD AOR=5.17) were significant risk factors for both groups. Limitations: As the study population was comprised only of patients with contact to psychiatric hospitals, the results cannot be extrapolated to the primary care setting. Conclusion: The following risk factors for non-PD and PD were identified: older age, male gender and previous incidents of self-harm. In suicide prevention efforts, equal attention should be paid to non-PD and PD patients. (C) 2013 Elsevier B.V. All rights reserved. C1 [Leadholm, Anne Katrine K.; Ostergaard, Soren D.] Aalborg Univ Hosp, Unit Psychiat Res, Aalborg Psychiat Hosp, DK-9000 Aalborg, Denmark. [Rothschild, Anthony J.] Univ Massachusetts, Sch Med, Worcester, MA USA. [Nielsen, Jimmi] Aalborg Univ Hosp, Ctr Schizophrenia, Aalborg Psychiat Hosp, Aalborg, Denmark. [Leadholm, Anne Katrine K.; Bech, Per] Univ Copenhagen, Psychiat Res Unit, Psychiat Ctr North Zealand, Hillerod, Denmark. [Ostergaard, Soren D.] Aarhus Univ Hosp, Inst Clin Med, DK-8000 Aarhus, Denmark. [Ostergaard, Soren D.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Depress Clin & Res Program, Boston, MA USA. RP Leadholm, AKK (reprint author), Aalborg Univ Hosp, Unit Psychiat Res, Aalborg Psychiat Hosp, Molleparkvej 10, DK-9000 Aalborg, Denmark. EM a.k.leadholm@gmail.com OI Ostergaard, Soren Dinesen/0000-0002-8032-6208 FU Lundbeck Foundation FX The study was partly funded by a Grant from the Lundbeck Foundation (stipend for A.K. Leadholm). The remaining authors were funded by their respective institutions as listed under affiliations. NR 78 TC 11 Z9 13 U1 0 U2 11 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 MAR PY 2014 VL 156 BP 119 EP 125 DI 10.1016/j.jad.2013.12.003 PG 7 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 296WI UT WOS:000330215700014 PM 24388683 ER PT J AU Pedersen, ER Kaysen, DL Lindgren, KP Blayney, J Simpson, TL AF Pedersen, Eric R. Kaysen, Debra L. Lindgren, Kristen P. Blayney, Jessica Simpson, Tracy L. TI Impact of Daily Assessments on Distress and PTSD Symptoms in Trauma-Exposed Women SO JOURNAL OF INTERPERSONAL VIOLENCE LA English DT Article DE daily assessments; PTSD; women; distress ID POSTTRAUMATIC-STRESS-DISORDER; PROLONGED EXPOSURE; SEXUAL EXPERIENCES; VICTIMS; COLLEGE; PARTICIPATION; THERAPY; ASSAULT; RAPE; VICTIMIZATION AB As more advanced methodologies are developed for symptom assessment in traumatic stress studies, it is important to examine how these methodologies can exacerbate distress or contribute to symptoms among study participants. Using a sample of 202 female college students, we examined the changes in posttraumatic stress disorder (PTSD) symptoms and general psychological symptomatology among groups of trauma-exposed and non-trauma-exposed women randomly assigned to complete 30 days of daily monitoring of traumatic symptoms and substance use behaviors using personal digital assistants (PDAs). These two groups were compared with a trauma-exposed sample of women who did not complete daily monitoring assessments and only completed pre- and post-monitoring online assessments. While trauma-exposed participants in the monitoring group reported more distress from the daily assessments than those in the monitoring group with no history of trauma, this distress level was relatively low. Online surveys delivered pre- and post-monitoring showed a similar pattern. Trauma-exposed participants in monitoring and no-monitoring groups reported a decrease in general psychological symptoms over the 30 days; however, monitoring participants reported increased levels of PTSD severity over time. Closer examination revealed the observed changes were relatively moderate. Participants expressed benefits and risks regarding study participation supporting the findings that repeated assessments of traumatic symptoms using personal handheld devices may lead to small increases in distress and PTSD symptoms, but that these approaches may be generally well tolerated. C1 [Pedersen, Eric R.] RAND Corp, Santa Monica, CA 90407 USA. [Kaysen, Debra L.; Lindgren, Kristen P.; Simpson, Tracy L.] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. [Kaysen, Debra L.] Univ Washington, Dept Psychol, Seattle, WA 98195 USA. [Kaysen, Debra L.] Univ Washington, Dept Global Hlth, Seattle, WA 98195 USA. [Blayney, Jessica] Univ Washington, Ctr Hlth & Risk Behav, Seattle, WA 98195 USA. [Simpson, Tracy L.] VA Puget Sound Hlth Care Syst, Seattle, WA USA. RP Pedersen, ER (reprint author), RAND Corp, 1776 Main St, Santa Monica, CA 90407 USA. EM ericp@rand.org FU NIAAA NIH HHS [F31 AA018591, F31AA018591, R21 AA016211, R21AA016211] NR 37 TC 5 Z9 5 U1 2 U2 10 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0886-2605 EI 1552-6518 J9 J INTERPERS VIOLENCE JI J. Interpers. Violence PD MAR PY 2014 VL 29 IS 5 BP 824 EP 845 DI 10.1177/0886260513505705 PG 22 WC Criminology & Penology; Family Studies; Psychology, Applied SC Criminology & Penology; Family Studies; Psychology GA 294CK UT WOS:000330019800003 PM 24257591 ER PT J AU Rubio, DM Day, NL Conigliaro, J Hanusa, BH Larkby, C McNeil, M Cohen, E Jones, B Watt-Morse, M Gilmour, C Lancet, M Kraemer, KL AF Rubio, Doris McGartland Day, Nancy L. Conigliaro, Joseph Hanusa, Barbara H. Larkby, Cynthia McNeil, Melissa Cohen, Elan Jones, Bobby Watt-Morse, Margaret Gilmour, Carol Lancet, Michelle Kraemer, Kevin L. TI Brief motivational enhancement intervention to prevent or reduce postpartum alcohol use: A single-blinded, randomized controlled effectiveness trial SO JOURNAL OF SUBSTANCE ABUSE TREATMENT LA English DT Article DE Brief motivational enhancement; Postpartum alcohol use; Comparative effectiveness; Randomized trial ID POSTNATAL-DEPRESSION-SCALE; PREGNANT-WOMEN; PRIMARY-CARE; CONSUMPTION; DRINKING; DRINKERS; EXPOSURE AB Aims: The aim of this study is to assess the effect of brief motivational enhancement intervention postpartum alcohol use. Design: This study is a single-blinded, randomized controlled effectiveness trial in which pregnant women were assigned to receive usual care or up to 5 face-to-face brief motivational enhancement sessions lasting 10-30 minutes each and occurring at study enrollment, 4 and 8 weeks after enrollment, 32 weeks of gestation, and 6 weeks postpartum. Setting: The setting is in a large, urban, obstetrics clinic. Participants: Participants were women who were years old, <20 weeks of gestation, and consumed alcohol during pregnancy. Of 3438 women screened, 330 eligible women were assigned to usual care (n = 165) or intervention (n = 165). Due to missing data, we analyzed 125 in the intervention group and 126 in the usual care group. Measurements: The measurements were the proportion of women with any alcohol use and the number of drinks per day, reported via follow-up telephone interviews at 4 and 8 weeks after enrollment, 32 weeks of gestation, and 6 weeks, 6 months, and 12 months postpartum. Findings: In random effects models adjusted for confounders, the intervention group was less likely to use any alcohol (odds ratio 0.50; 95% confidence interval ICI], 0.23-1.09; P = 0.08) and consumed fewer drinks per day (coefficient 0.11; 95% Cl 0.23-0.01; P. = 0.07) than, the usual care group in the postpartum period but these differences were non-significant. Missing data during the prenatal period prevented us from modeling prenatal alcohol use. Conclusions: Brief motivational enhancement intervention delivered in an obstetrical outpatient setting did not conclusively decrease alcohol use during the postpartum period. (C) 2014 Elsevier Inc. All rights reserved. C1 [Rubio, Doris McGartland; McNeil, Melissa; Lancet, Michelle; Kraemer, Kevin L.] Univ Pittsburgh, Sch Med, Dept Med, Div Gen Internal Med, Pittsburgh, PA 15213 USA. [Rubio, Doris McGartland; Cohen, Elan] Univ Pittsburgh, Sch Med, Ctr Data, Ctr Res Hlth Care, Pittsburgh, PA 15213 USA. [Day, Nancy L.; Larkby, Cynthia; Jones, Bobby] Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA 15213 USA. [Conigliaro, Joseph] NYU, Dept Med, New York, NY 10016 USA. [Hanusa, Barbara H.] VA Pittsburgh Healthcare Syst, Ctr Hlth Equ Res & Promot, Pittsburgh, PA USA. [Watt-Morse, Margaret] Magee Womens Hosp, Dept Obstet & Gynecol, Pittsburgh, PA USA. [Gilmour, Carol] UPMC, Hamot Womens Hosp, Erie, PA USA. RP Rubio, DM (reprint author), Univ Pittsburgh, Sch Med, Dept Med, Ctr Res Hlth Care,Div Gen Internal Med, 200 Meyran Ave,Suite 200, Pittsburgh, PA 15213 USA. EM rubiodm@upmc.edu RI Day, Nancy/H-3171-2016 FU NCATS NIH HHS [UL1 TR000005]; NIAAA NIH HHS [R01 AA012485] NR 33 TC 3 Z9 4 U1 5 U2 15 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0740-5472 J9 J SUBST ABUSE TREAT JI J. Subst. Abus. Treat. PD MAR PY 2014 VL 46 IS 3 BP 382 EP 389 DI 10.1016/j.jsat.2013.10.009 PG 8 WC Psychology, Clinical; Substance Abuse SC Psychology; Substance Abuse GA 294XX UT WOS:000330082300014 PM 24315218 ER PT J AU Hoy, CL Ferhanoglu, O Yildirim, M Kim, KH Karajanagi, SS Chan, KMC Kobler, JB Zeitels, SM Ben-Yakar, A AF Hoy, Christopher L. Ferhanoglu, Onur Yildirim, Murat Kim, Ki Hyun Karajanagi, Sandeep S. Chan, Ka Man Carmen Kobler, James B. Zeitels, Steven M. Ben-Yakar, Adela TI Clinical Ultrafast Laser Surgery: Recent Advances and Future Directions SO IEEE JOURNAL OF SELECTED TOPICS IN QUANTUM ELECTRONICS LA English DT Article DE laser ablation; surgery; nonlinear optics; biomedical optical imaging ID POSTERIOR LAMELLAR KERATOPLASTY; NONLINEAR REFRACTIVE-INDEX; RING SEGMENT IMPLANTATION; FEMTOSECOND LASER; PENETRATING KERATOPLASTY; TISSUE ABLATION; TRANSPARENT MATERIALS; TOOTH PREPARATION; LABORATORY MODEL; CORNEAL BIOPSY AB Ultrafast pulsed lasers can be used to achieve remarkable precision during surgical ablation. Through nonlinear interactions with tissue, ultrafast lasers can provide a largely non-thermal mechanism of ablation and a unique ability to create targeted damage within bulk tissue. These advantages have made ultrafast lasers the ideal surgical tool for various novel applications in ophthalmology. Clinical adoption of ultrafast lasers in other surgical applications remains limited in part due to the lack of a means for fiber delivery of ultrafast laser pulses as a flexible, hand-held surgical endoscope. This review provides an overview of the recent advances in bringing this unique surgical tool into the clinic. We discuss fundamental mechanisms and limitations of ultrafast laser ablation, novel techniques for overcoming these limitations, the current state of clinical applications, and conclude with our recent efforts in developing fiber-coupled probes for flexible ultrafast laser surgery and imaging. C1 [Hoy, Christopher L.; Ferhanoglu, Onur; Yildirim, Murat; Kim, Ki Hyun; Ben-Yakar, Adela] Univ Texas Austin, Dept Mech Engn, Austin, TX 78712 USA. [Hoy, Christopher L.] Erasmus MC, Dept Radiat Oncol, Ctr Opt Diagnost & Therapy, Rotterdam, Netherlands. [Karajanagi, Sandeep S.; Chan, Ka Man Carmen; Kobler, James B.; Zeitels, Steven M.] Massachusetts Gen Hosp, Ctr Laryngeal Surg & Voice Rehabil, Boston, MA 02114 USA. RP Hoy, CL (reprint author), Univ Texas Austin, Dept Mech Engn, Austin, TX 78712 USA. EM c.1hoy@erasmusmc.nl; oferhanoglu@utexas.edu; yildirim@utexas.edu; kihyunkim@utexas.edu; skarajanagi@partners.org; kaman@mit.edu; James.Kobler@mgh.harvard.edu; zeitels.steven@mgh.harvard.edu; ben-yakar@mail.utexas.edu RI Ferhanoglu, Onur/I-9348-2014 OI Ferhanoglu, Onur/0000-0002-5381-533X FU National Science Foundation [BES-0548673, CBET-1014953, CBET-0846868]; University of Texas Board of Regents FX Manuscript received July 16, 2013; revised August 29, 2013; accepted August 30, 2013. This work was supported by the National Science Foundation under Grants BES-0548673, CBET-1014953, and Career Award CBET-0846868, as well as a grant from the Texas Ignition Fund by the University of Texas Board of Regents. NR 121 TC 20 Z9 20 U1 2 U2 30 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 1077-260X EI 1558-4542 J9 IEEE J SEL TOP QUANT JI IEEE J. Sel. Top. Quantum Electron. PD MAR-APR PY 2014 VL 20 IS 2 AR 7100814 DI 10.1109/JSTQE.2013.2287098 PG 14 WC Engineering, Electrical & Electronic; Optics; Physics, Applied SC Engineering; Optics; Physics GA 293TS UT WOS:000329997200028 ER PT J AU Vinegoni, C Lee, S Feruglio, PF Weissleder, R AF Vinegoni, Claudio Lee, Sungon Feruglio, Paolo Fumene Weissleder, Ralph TI Advanced Motion Compensation Methods for Intravital Optical Microscopy SO IEEE JOURNAL OF SELECTED TOPICS IN QUANTUM ELECTRONICS LA English DT Article DE Intravital microscopy; image stabilization; in vivo imaging; motion artifact and motion compensation ID MOUSE SPINAL-CORD; IN-VIVO; 2-PHOTON MICROSCOPY; HIGH-SPEED; FLUORESCENCE MICROSCOPY; CHAMBER TECHNIQUE; IMAGING WINDOW; RESOLUTION; MICE; ANIMALS AB Intravital microscopy has emerged in the recent decade as an indispensible imaging modality for the study of the microdynamics of biological processes in live animals. Technical advancements in imaging techniques and hardware components, combined with the development of novel targeted probes and new mice models, have enabled us to address long-standing questions in several biology areas such as oncology, cell biology, immunology, and neuroscience. As the instrument resolution has increased, physiological motion activities have become a major obstacle that prevents imaging live animals at resolutions analogue to the ones obtained in vitro. Motion compensation techniques aim at reducing this gap and can effectively increase the in vivo resolution. This paper provides a technical review of some of the latest developments in motion compensation methods, providing organ specific solutions. C1 [Vinegoni, Claudio; Lee, Sungon; Feruglio, Paolo Fumene; Weissleder, Ralph] Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. [Vinegoni, Claudio; Lee, Sungon; Feruglio, Paolo Fumene; Weissleder, Ralph] Harvard Univ, Sch Med, Richard B Simches Res Ctr, Boston, MA 02114 USA. [Feruglio, Paolo Fumene] Univ Verona, Dept Neurol & Movement Sci, I-37134 Verona, Italy. RP Vinegoni, C (reprint author), Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. EM cvinegoni@mgh.harvard.edu; solee@kist.re.kr; paolofumene@gmail.com; rweissleder@mgh.harvard.edu FU National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services [HHSN26820100004xC]; Institute of Biomedical Engineering [R01EB006432] FX This work was supported in part by Federal funds from the National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services under Contract HHSN26820100004xC and in part by the Institute of Biomedical Engineering under Grant R01EB006432. C. Vinegoni and S. Lee equally contributed to this paper. NR 56 TC 6 Z9 6 U1 1 U2 21 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 1077-260X EI 1558-4542 J9 IEEE J SEL TOP QUANT JI IEEE J. Sel. Top. Quantum Electron. PD MAR-APR PY 2014 VL 20 IS 2 AR 6800709 DI 10.1109/JSTQE.2013.2279314 PG 9 WC Engineering, Electrical & Electronic; Optics; Physics, Applied SC Engineering; Optics; Physics GA 293TS UT WOS:000329997200007 ER PT J AU Hagendoorn, J Yock, TI Borel, IHM Padera, TP Ebb, DH AF Hagendoorn, Jeroen Yock, Torunn I. Borel, Inne H. M. Padera, Timothy P. Ebb, David H. TI Novel Molecular Pathways in Gorham Disease: Implications for Treatment SO PEDIATRIC BLOOD & CANCER LA English DT Article DE Gorham disease; lymphangiogenesis; molecular biology; rare tumors; tumor biology; vascular malformations ID OF-THE-LITERATURE; MASSIVE OSTEOLYSIS; STOUT-SYNDROME; GROWTH-FACTOR; DISSEMINATED LYMPHANGIOMATOSIS; INTERFERON-ALPHA; DIFFUSE LYMPHANGIOMATOSIS; SUCCESSFUL MANAGEMENT; DISAPPEARING BONE; ZOLEDRONIC ACID AB Rapid advances in evidence-based treatment schedules are a hallmark of modern oncology. In rare neoplastic diseases, however, clinical expertise is hard to build and evidence based on randomized trials almost impossible to collect. Gorham disease is a rare form of lymphatic proliferation accompanied by osteolysis, which usually occurs in young adults. Despite the fact that the clinical course of Gorham disease is often devastating and occasionally fatal, insights into its biological background are sparse and standardized treatment unavailable. Interestingly, recent knowledge on the mechanisms of lymphangiogenesis may help elucidate the pathophysiology of Gorham disease and lead to novel treatment targets. Here, we discuss our current understanding of Gorham disease, discuss established and emerging therapeutic strategies, and attempt to frame a treatment rationale. Pediatr Blood Cancer 2014;61:401-406. (c) 2013 Wiley Periodicals, Inc. C1 [Hagendoorn, Jeroen; Borel, Inne H. M.] Univ Med Ctr Utrecht, Dept Surg Oncol, Utrecht, Netherlands. [Yock, Torunn I.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Yock, Torunn I.; Padera, Timothy P.; Ebb, David H.] Harvard Univ, Sch Med, Boston, MA USA. [Padera, Timothy P.] Massachusetts Gen Hosp, Edwin L Steele Lab Tumor Biol, Boston, MA 02114 USA. [Ebb, David H.] Massachusetts Gen Hosp, Dept Pediat Hematol, Boston, MA 02114 USA. RP Ebb, DH (reprint author), Massachusetts Gen Hosp, Dept Pediat Hematol & Oncol, Yawkey 8B,55 Fruit St, Boston, MA 02114 USA. EM debb@partners.org OI Padera, Timothy/0000-0002-3453-9384 FU NIH [R00CA137167, DP2OD008780] FX Grant sponsor: NIH; Grant numbers: R00CA137167; DP2OD008780 NR 63 TC 5 Z9 6 U1 1 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 MAR PY 2014 VL 61 IS 3 BP 401 EP 406 DI 10.1002/pbc.24832 PG 6 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 288AZ UT WOS:000329585300003 PM 24214028 ER PT J AU Weigel, B Malempati, S Reid, JM Voss, SD Cho, SY Chen, HX Krailo, M Villaluna, D Adamson, PC Blaney, SM AF Weigel, Brenda Malempati, Suman Reid, Joel M. Voss, Stephan D. Cho, Steven Y. Chen, Helen X. Krailo, Mark Villaluna, Doojduen Adamson, Peter C. Blaney, Susan M. TI Phase 2 Trial of Cixutumumab in Children, Adolescents, and Young Adults With Refractory Solid Tumors: A Report From the Children's Oncology Group SO PEDIATRIC BLOOD & CANCER LA English DT Article DE insulin-like growth factor-I receptor; investigational agents; monoclonal antibody; pediatric cancer ID FACTOR-I RECEPTOR; GROWTH-FACTOR RECEPTOR; MONOCLONAL-ANTIBODY; ANTITUMOR-ACTIVITY; DOWN-REGULATION; WILMS-TUMOR; INSULIN; CANCER; VIVO; PROLIFERATION AB PurposeThis phase 2 study was designed to assess the efficacy of single agent cixutumumab (IMC-A12) and gain further information about associated toxicities and pharmacodynamics in children, adolescents, and young adults with recurrent or refractory solid tumors. Patients and MethodsPatients with relapsed or refractory solid tumors were treated with 9mg/kg of cixutumumab as a 1-hour IV infusion once weekly. Strata included: osteosarcoma, Ewing sarcoma, rhabdomyosarcoma, neuroblastoma (evaluable disease), neuroblastoma (measurable disease), Wilms tumor, adrenocortical carcinoma, synovial sarcoma, hepatoblastoma, and retinoblastoma. Correlative studies in consenting patients included an assessment of c-peptide, IGFBP-3, IGF-1, IGF-2, hGH, and insulin in consenting patients. ResultsOne hundred sixteen patients with 114 eligible having a median age of 12 years (range, 2-30) were enrolled. Five patients achieved a partial response: 4/20 with neuroblastoma (evaluable only) and 1/20 with rhabdomyosarcoma. Fourteen patients had stable disease for a median of 10 cycles. Hematologic and non-hematologic toxicities were generally mild and infrequent. Serum IGF-1 and IGFBP-3 increased in response to therapy with cixutumumab. ConclusionCixutumumab is well tolerated in children with refractory solid tumors. Limited objective single-agent activity of cixutumumab was observed; however, prolonged stable disease was observed in 15% of patients. Ongoing studies are evaluating the toxicity and benefit of cixutumumab in combination with other agents that inhibit the IGF pathway. Pediatr Blood Cancer 2014;61:452-456. (c) 2013 Wiley Periodicals, Inc. C1 [Weigel, Brenda] Univ Minnesota, Minneapolis, MN 55455 USA. [Malempati, Suman] Oregon Hlth & Sci Univ, Dept Pediat, Portland, OR 97201 USA. [Reid, Joel M.] Mayo Clin & Mayo Fdn, Rochester, MN USA. [Voss, Stephan D.] Childrens Hosp, Boston, MA 02115 USA. [Voss, Stephan D.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Cho, Steven Y.] Johns Hopkins Univ Hosp, Baltimore, MD 21287 USA. [Chen, Helen X.] NCI, Rockville, MD USA. [Krailo, Mark] USC Keck Sch Med, Dept Prevent Med, Los Angeles, CA USA. [Villaluna, Doojduen] Childrens Oncol Grp Operat Ctr, Monrovia, CA USA. [Adamson, Peter C.] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Blaney, Susan M.] Baylor Coll Med, Texas Childrens Canc Ctr, Houston, TX 77030 USA. RP Weigel, B (reprint author), Univ Minnesota, Dept Pediat, Div Pediat Hematol Oncol, MMC 366,420 Delaware St SE, Minneapolis, MN 55455 USA. EM weige007@umn.edu FU National Cancer Institute [U01 CA97452, U10 CA98543]; GCRC [M01-RR00188-46] FX Grant sponsor: National Cancer Institute; Grant numbers: U01 CA97452, U10 CA98543; Grant sponsor: GCRC; Grant number: M01-RR00188-46 NR 34 TC 40 Z9 42 U1 0 U2 12 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 MAR PY 2014 VL 61 IS 3 BP 452 EP 456 DI 10.1002/pbc.24605 PG 5 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 288AZ UT WOS:000329585300011 PM 23956055 ER PT J AU Rosenberg, AR Wolfe, J Bradford, MC Shaffer, ML Yi-Frazier, JP Curtis, JR Syrjala, KL Baker, KS AF Rosenberg, Abby R. Wolfe, Joanne Bradford, Miranda C. Shaffer, Michele L. Yi-Frazier, Joyce P. Curtis, J. Randall Syrjala, Karen L. Baker, K. Scott TI Resilience and Psychosocial Outcomes in Parents of Children With Cancer SO PEDIATRIC BLOOD & CANCER LA English DT Article DE parents; pediatric cancer; psychosocial outcomes; resilience; whole patient care ID CONNOR-DAVIDSON RESILIENCE; SERIOUS MENTAL-ILLNESS; SCALE CD-RISC; CHILDHOOD-CANCER; PSYCHOLOGICAL DISTRESS; POSTTRAUMATIC STRESS; GENERAL-POPULATION; PEDIATRIC ONCOLOGY; POTENTIAL TRAUMA; SYMPTOMS AB BackgroundThe psychosocial function of parents of children with cancer can impact the well-being of the entire family. Resilience resources are likely related to psychosocial outcomes and may be amenable to intervention. We hypothesized that parents with lower resources would report worse outcomes. MethodsIn the Understanding Resilience in Parents of Children with Cancer study, comprehensive surveys were mailed to consecutive, English-speaking parents of children with cancer who were treated at Seattle Children's Hospital and completed therapy between January 1, 2009 and December 31, 2010. Resilience resources were measured by the Connor-Davidson Resilience Scale; outcome measures included psychological distress, health-related behaviors, social and family function, and perceived communication with the medical team. ResultsNinety-six parents (86% of contactable) completed the survey. Compared to population norms, enrolled parents had lower resilience resources, higher psychological distress, and more commonly reported binge drinking. Conversely, they reported higher social support and family adaptability (P<0.001-0.006). Lower resilience resources were associated with higher distress, lower social support, and lower family function (P<0.001-0.007). Parents in the lowest quartile of resilience resources had higher odds of frequent sleep difficulties (OR 5.19, 95% CI 1.74,15.45), lower health satisfaction (OR 5.71, 95% CI 2.05,15.92), and decreased ability to express worries to the medical team (OR 4.00, 95% CI 1.43,11.18). ConclusionsParents of children with cancer are at risk for poor psychosocial outcomes and those with low resilience resources may be at greater risk. Interventions directed at promoting resilience resources may provide a novel and complimentary approach toward improving outcomes for families facing pediatric cancer. (c) 2013 Wiley Periodicals, Inc. C1 [Rosenberg, Abby R.; Bradford, Miranda C.; Shaffer, Michele L.; Yi-Frazier, Joyce P.; Baker, K. Scott] Seattle Childrens Hosp, Seattle, WA 98105 USA. [Rosenberg, Abby R.; Syrjala, Karen L.; Baker, K. Scott] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Rosenberg, Abby R.; Yi-Frazier, Joyce P.; Curtis, J. Randall; Syrjala, Karen L.; Baker, K. Scott] Univ Washington, Seattle, WA 98195 USA. [Rosenberg, Abby R.] Treuman Katz Ctr Pediat Bioeth, Seattle, WA USA. [Wolfe, Joanne] Boston Childrens Hosp, Boston, MA USA. [Wolfe, Joanne] Dana Farber Canc Inst, Boston, MA 02115 USA. [Wolfe, Joanne] Harvard Univ, Sch Med, Boston, MA USA. [Curtis, J. Randall] Univ Washington, Harborview Med Ctr, Seattle, WA 98104 USA. [Curtis, J. Randall] UW Palliat Care Ctr Excellence, Seattle, WA USA. RP Rosenberg, AR (reprint author), Seattle Childrens Hosp, Div Hematol Oncol, Dept Pediat, 4800 Sand Point Way NE Mailstop MB 8-501, Seattle, WA 98105 USA. EM abby.rosenberg@seattlechildrens.org FU Conquer Cancer Foundation of ASCO; Ruth L. Kirschstein National Research Service Award [T32CA009351] FX Grant sponsor: Conquer Cancer Foundation of ASCO; Grant sponsor: Ruth L. Kirschstein National Research Service Award; Grant number: T32CA009351 NR 38 TC 16 Z9 17 U1 4 U2 42 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 MAR PY 2014 VL 61 IS 3 BP 552 EP 557 DI 10.1002/pbc.24854 PG 6 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 288AZ UT WOS:000329585300028 PM 24249426 ER PT J AU Sahni, H Kirkwood, K Kyriakides, TC Stapleton, J Brown, ST Holodniy, M AF Sahni, Harleen Kirkwood, Katherine Kyriakides, Tassos C. Stapleton, Jack Brown, Sheldon T. Holodniy, Mark CA OPTIMA Study Team TI GBV-C Viremia and Clinical Events in Advanced HIV Infection SO JOURNAL OF MEDICAL VIROLOGY LA English DT Article DE HIV; GBV-C; Veterans; antiretroviral therapy; clinical trial ID HUMAN-IMMUNODEFICIENCY-VIRUS; ANTIRETROVIRAL THERAPY; COINFECTION; PREVALENCE; INDIVIDUALS; PROGRESSION; ACTIVATION; MORTALITY; SURVIVAL; DISEASE AB GB Virus C (GBV-C) is a non-pathogenic flavivirus, commonly found in HIV infected patients. Studies suggest a survival benefit of GBV-C viremia in HIV infection. Impact of GBV-C viremia was evaluated on clinical outcome in multidrug-resistant HIV. The OPTIMA study enrolled advanced multidrug-resistant HIV patients with a CD4 count 300cells/mm(3). This study included a subset of OPTIMA patients. Primary endpoints included AIDS events or death. GBV-C status was assessed at baseline and last time point on study by real-time PCR. Cox proportional hazards models were used to determine if CD4 count (100/mm(3)), treatment assignment, presence or disappearance of GBV-C viremia, GBV-C viral load level and Hepatitis C virus antibody status were associated with outcome. Of 288 patients (98% male, baseline mean age 48 years, HIV viral load 4.67log(10)/ml, and CD4 127cells/mm(3)), 62 (21.5%) had detectable GBV-C viremia. The mortality rate for GBV-C infected subjects was lower, 19/62 (30.7%) versus 87/226 (38.5%), and time to death shorter (HR 0.67, 95% CI 0.41-1.11), but the results were not significantly different. The time to development of AIDS events was not different (HR 0.90, 95% CI 0.52-1.53). Among covariates, only CD4 count (HR 0.28, CI 0.19-0.42) had a significant survival effect. A trend in decreased mortality was seen in GBV-C+ patients with CD4 <100/mm(3) in multivariate analyses. GBV-C co-infection in multidrug-resistant HIV infected patients was associated with a trend in improved survival but not decreased AIDS events. Analysis was limited by cohort size. J. Med. Virol. 86:426-432, 2014. (c) 2013 Wiley Periodicals, Inc. C1 [Sahni, Harleen; Holodniy, Mark] VA Palo Alto Hlth Care Syst, Palo Alto, CA 94304 USA. [Kirkwood, Katherine; Kyriakides, Tassos C.] West Haven VA CSPCC, West Haven, CT USA. [Stapleton, Jack] Iowa City VAMC, Iowa City, IA USA. [Brown, Sheldon T.] James J Peters VAMC, Bronx, NY USA. RP Sahni, H (reprint author), VA Palo Alto Hlth Care Syst, 3801 Miranda Ave 132, Palo Alto, CA 94304 USA. EM harleen.sahni@gmail.com FU Office of Research and Development (Cooperative Studies Program), US Department of Veterans Affairs FX We thank Donna Klinzman at the Iowa city VA for technical assistance in conducting the assays. This work was supported by the Office of Research and Development (Cooperative Studies Program), US Department of Veterans Affairs. NR 20 TC 4 Z9 5 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0146-6615 EI 1096-9071 J9 J MED VIROL JI J. Med. Virol. PD MAR PY 2014 VL 86 IS 3 BP 426 EP 432 DI 10.1002/jmv.23845 PG 7 WC Virology SC Virology GA 286IJ UT WOS:000329461000008 PM 24249700 ER PT J AU Trask, DJ Ledoux, WR Whittaker, EC Roush, GC Sangeorzan, BJ AF Trask, Darrin J. Ledoux, William R. Whittaker, Eric C. Roush, Grant C. Sangeorzan, Bruce J. TI Second Metatarsal Osteotomies for Metatarsalgia: A Robotic Cadaveric Study of the Effect of Osteotomy Plane and Metatarsal Shortening on Plantar Pressure SO JOURNAL OF ORTHOPAEDIC RESEARCH LA English DT Article DE second metatarsal; plantar pressure; metatarsalgia; lesser metatarsal osteotomies; gait simulation ID LESSER METATARSOPHALANGEAL JOINTS; WEIL OSTEOTOMY; FOLLOW-UP; GAIT; SIMULATION; FORCE; FEET; TOE AB Symptom relief of recalcitrant metatarsalgia can be achieved through surgical shortening of the affected metatarsal, thus decreasing plantar pressure. Theoretically an oblique metatarsal osteotomy can be oriented distal to proximal (DP) or proximal to distal (PD). We characterized the relationship between the amount of second metatarsal shortening, osteotomy plane, and plantar pressure. We hypothesized that the PD osteotomy is more effective in reducing metatarsal peak pressure and pressure time integral. We performed eight DP and eight PD second metatarsal osteotomies on eight pairs of cadaveric feet. A custom designed robotic gait simulator (RGS) generated dynamic in vitro simulations of gait. Second metatarsals were incrementally shortened, with three trials for each length. We calculated regression lines for peak pressure and pressure time integral vs. metatarsal shortening. Shortening the second metatarsal using either osteotomy significantly affected the metatarsal peak pressure and pressure time integral (first and third metatarsal increased, p<0.01 and <0.05; second metatarsal decreased, p<0.01). Changes in peak pressure (p=0.0019) and pressure time integral (p=0.0046) were more sensitive to second metatarsal shortening with the PD osteotomy than the DP osteotomy. The PD osteotomy plane reduces plantar pressure more effectively than the DP osteotomy plane. Published 2013 by Wiley Periodicals, Inc. on behalf of the Orthopaedic Research Society. J Orthop Res 32:385-393, 2014. C1 [Trask, Darrin J.; Ledoux, William R.; Whittaker, Eric C.; Roush, Grant C.; Sangeorzan, Bruce J.] VA Puget Sound Hlth Care Syst, Dept Vet Affairs, RR&D Ctr Excellence Limb Loss Prevent & Prosthet, Seattle, WA 98108 USA. [Trask, Darrin J.] Univ Washington, Sch Med, Seattle, WA 98195 USA. [Ledoux, William R.; Sangeorzan, Bruce J.] Univ Washington, Dept Orthopaed & Sports Med, Seattle, WA 98195 USA. [Ledoux, William R.; Roush, Grant C.] Univ Washington, Dept Mech Engn, Seattle, WA 98195 USA. RP Ledoux, WR (reprint author), VA Puget Sound Hlth Care Syst, Dept Vet Affairs, RR&D Ctr Excellence Limb Loss Prevent & Prosthet, Seattle, WA 98108 USA. EM wrledoux@uw.edu RI Ledoux, William/K-6815-2015 OI Ledoux, William/0000-0003-4982-7714 FU Department of Veterans Affairs Rehabilitation Research and Development Service [A4843C]; University of Washington Medical Student Research Training Program FX Department of Veterans Affairs Rehabilitation Research and Development Service A4843C; Grant sponsor: University of Washington Medical Student Research Training Program. NR 33 TC 2 Z9 2 U1 0 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0736-0266 EI 1554-527X J9 J ORTHOP RES JI J. Orthop. Res. PD MAR PY 2014 VL 32 IS 3 BP 385 EP 393 DI 10.1002/jor.22524 PG 9 WC Orthopedics SC Orthopedics GA 285UW UT WOS:000329421500005 PM 24243763 ER PT J AU Salem, BE Nyamathi, A Brecht, ML Phillips, LR Mentes, JC Sarkisian, C Stein, JA AF Salem, Benissa E. Nyamathi, Adeline Brecht, Mary-Lynn Phillips, Linda R. Mentes, Janet C. Sarkisian, Catherine Stein, Judith A. TI Constructing and identifying predictors of frailty among homeless adults-A latent variable structural equations model approach SO ARCHIVES OF GERONTOLOGY AND GERIATRICS LA English DT Article DE Frailty; Homeless; SEM; Health disparities and vulnerable populations ID YOUNG-ADULTS; GERIATRIC SYNDROMES; SAN-FRANCISCO; OLDER-ADULTS; HEALTH-CARE; ORAL-HEALTH; PREVALENCE; POPULATION; INDIVIDUALS; TORONTO AB Homeless urbanites are a heterogeneous population with unique health and social service needs. The study examined situational, behavioral, health-related and resource indicators in terms of their direct impact on frailty, hypothesized as a latent variable. Using structural equation modeling (SEM), a model was tested with 150 homeless men and women, ages 40-73, from three homeless day center drop-in sites on Skid Row and one residential drug treatment (RDT) facility that works with homeless parolees and probationers. In bivariate analyses with the latent construct frailty, months homeless (p < 0.01), female gender (p < 0.05), education (p < 0.05), comorbid conditions (p < 0.001), nutrition (p < 0.001), resilience (p < 0.001), health care utilization (p < 0.01), and falls (p < 0.001) were significantly associated with frailty. In the final path model, significant predictors of frailty included educational attainment (p < 0.01), comorbid conditions (p < 0.001), nutrition (p < 0.001), resilience (p < 0.001), and falls (p < 0.01). These findings will serve as a foundation for future nurse-led, community-based initiatives that focus on key predictors of frailty among the homeless and the development of interventions. (C) 2013 Elsevier Ireland Ltd. All rights reserved. C1 [Salem, Benissa E.; Nyamathi, Adeline; Brecht, Mary-Lynn; Phillips, Linda R.; Mentes, Janet C.; Stein, Judith A.] UCLA Sch Nursing, Los Angeles, CA 90007 USA. [Sarkisian, Catherine] UCLA, Div Geriatr, VA Greater Los Angeles Healthcare Syst, GRECC, Los Angeles, CA 90073 USA. RP Salem, BE (reprint author), UCLA Sch Nursing, 700 Tiverton Ave, Los Angeles, CA 90007 USA. EM bsalem@sonnet.ucla.edu FU National Institute of Health (NIH)/Nursing Research (NINR) [T32 NR007077]; University of California Los Angeles (UCLA) Dissertation Year Fellowship Award; University of California, Los Angeles Community Academic Partnership for Research in Aging (L.A. CAPRA) Center NIH [1RC4AG038182-01] FX This work was supported by the National Institute of Health (NIH)/Nursing Research (NINR) T32 NR007077, University of California Los Angeles (UCLA) Dissertation Year Fellowship Award, and the University of California, Los Angeles Community Academic Partnership for Research in Aging (L.A. CAPRA) Center NIH Grant 1RC4AG038182-01. We acknowledge the support of Judith Stein, PhD in providing guidance with the analysis. We similarly thank the Los Angeles-based Skid Row homeless participants for their willingness to share of their time and experiences. NR 71 TC 0 Z9 0 U1 3 U2 24 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0167-4943 EI 1872-6976 J9 ARCH GERONTOL GERIAT JI Arch. Gerontol. Geriatr. PD MAR-APR PY 2014 VL 58 IS 2 BP 248 EP 256 DI 10.1016/j.archger.2013.09.005 PG 9 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 280WR UT WOS:000329062000011 PM 24505611 ER PT J AU Nahrendorf, M Swirski, FK AF Nahrendorf, Matthias Swirski, Filip K. TI Fluorescent Leukocytes Enter Plaque on the Microscope Stage SO CIRCULATION RESEARCH LA English DT Editorial Material DE Editorials; atherosclerosis; blood platelets; monocytes; neutrophils ID IN-VIVO; APOLIPOPROTEIN-E; T-CELLS; ATHEROSCLEROSIS; MICE; DEFICIENT; MONOCYTES; MIGRATION; BEHAVIOR; LESIONS C1 [Nahrendorf, Matthias; Swirski, Filip K.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Syst Biol, Boston, MA 02114 USA. RP Nahrendorf, M (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Syst Biol, Boston, MA 02114 USA. EM mnahrendorf@mgh.harvard.edu; fswirski@mgh.harvard.edu FU NHLBI NIH HHS [R01 HL114477, R01 HL095612, R01HL114477, R01HL095629, R01HL095612, R01 HL095629]; NIAID NIH HHS [R56AI104695, R56 AI104695] NR 19 TC 1 Z9 1 U1 0 U2 2 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 FEB 28 PY 2014 VL 114 IS 5 BP 740 EP 741 DI 10.1161/CIRCRESAHA.114.303520 PG 2 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA AG7GS UT WOS:000335586900001 PM 24577957 ER PT J AU Ito, K Bick, AG Flannick, J Friedman, DJ Genovese, G Parfenov, MG DePalma, SR Gupta, N Gabriel, SB Taylor, HA Fox, ER Newton-Cheh, C Kathiresan, S Hirschhorn, JN Altshuler, DM Pollak, MR Wilson, JG Seidman, JG Seidman, C AF Ito, Kaoru Bick, Alexander G. Flannick, Jason Friedman, David J. Genovese, Giulio Parfenov, Michael G. DePalma, Steven R. Gupta, Namrata Gabriel, Stacey B. Taylor, Herman A. Fox, Ervin R. Newton-Cheh, Christopher Kathiresan, Sekar Hirschhorn, Joel N. Altshuler, David M. Pollak, Martin R. Wilson, James G. Seidman, J. G. Seidman, Christine TI Increased Burden of Cardiovascular Disease in Carriers of APOL1 Genetic Variants SO CIRCULATION RESEARCH LA English DT Article DE atherosclerosis; continental population groups; epidemiology; genetics; renal insufficiency; chronic; risk factors ID KIDNEY-DISEASE; ASSOCIATION; RISK; AFRICAN; PLAQUE; ATHEROSCLEROSIS; MANAGEMENT; AMERICANS; CALCIUM; IMPACT AB Rationale: Two distinct alleles in the gene encoding apolipoprotein L1 (APOL1), a major component of high-density lipoprotein, confer protection against Trypanosoma brucei rhodesiense infection and also increase risk for chronic kidney disease. Approximately 14% of Americans with African ancestry carry 2 APOL1 risk alleles, accounting for the high chronic kidney disease burden in this population. Objective: We tested whether APOL1 risk alleles significantly increase risk for atherosclerotic cardiovascular disease (CVD) in African Americans. Methods and Results: We sequenced APOL1 in 1959 randomly selected African American participants in the Jackson Heart Study (JHS) and evaluated associations between APOL1 genotypes and renal and cardiovascular phenotypes. Previously identified association between APOL1 genotypes and chronic kidney disease was confirmed (P=2.4x10(-6)). Among JHS participants with 2 APOL1 risk alleles, we observed increased risk for CVD (50/763 events among participants without versus 37/280 events among participants with 2 risk alleles; odds ratio, 2.17; P=9.4x10(-4)). We replicated this novel association of APOL1 genotype with CVD in Women's Health Initiative (WHI) participants (66/292 events among participants without versus 37/101 events among participants with 2 risk alleles; odds ratio, 1.98; P=8.37x10(-3); JHS and WHI combined, P=8.5x10(-5); odds ratio, 2.12). The increased risk for CVD conferred by APOL1 alleles was robust to correction for both traditional CVD risk factors and chronic kidney disease. Conclusions:APOL1 variants contribute to atherosclerotic CVD risk, indicating a genetic component to cardiovascular health disparities in individuals of African ancestry. The considerable population of African Americans with 2 APOL1 risk alleles may benefit from intensive interventions to reduce CVD. C1 [Ito, Kaoru; Bick, Alexander G.; Parfenov, Michael G.; DePalma, Steven R.; Hirschhorn, Joel N.; Seidman, J. G.; Seidman, Christine] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Ito, Kaoru; Bick, Alexander G.; Flannick, Jason; Genovese, Giulio; Gupta, Namrata; Gabriel, Stacey B.; Newton-Cheh, Christopher; Kathiresan, Sekar; Hirschhorn, Joel N.; Altshuler, David M.; Pollak, Martin R.; Seidman, J. G.; Seidman, Christine] Broad Inst Harvard & Massachusetts Inst Technol, Cambridge, MA USA. [Flannick, Jason; Newton-Cheh, Christopher; Kathiresan, Sekar; Altshuler, David M.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Friedman, David J.; Genovese, Giulio; Parfenov, Michael G.] Beth Israel Deaconess Med Ctr, Dept Med, Div Nephrol, Boston, MA 02215 USA. [Friedman, David J.] Beth Israel Deaconess Med Ctr, Dept Med, Vasc Biol Res Ctr, Boston, MA 02215 USA. Harvard Univ, Sch Med, Boston, MA USA. [Taylor, Herman A.; Fox, Ervin R.] Univ Mississippi, Med Ctr, Dept Med, Jackson, MS 39216 USA. [Wilson, James G.] Univ Mississippi, Med Ctr, Dept Physiol & Biophys, Jackson, MS 39216 USA. [Taylor, Herman A.] Jackson State Univ, Jackson, MS 39217 USA. [Taylor, Herman A.] Tougaloo Coll, Jackson, MS 39174 USA. [Newton-Cheh, Christopher; Kathiresan, Sekar] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Hirschhorn, Joel N.] Childrens Hosp, Div Genet, Boston, MA 02115 USA. [Hirschhorn, Joel N.] Childrens Hosp, Div Endocrinol, Boston, MA 02115 USA. [Hirschhorn, Joel N.] Childrens Hosp, Program Genom, Boston, MA 02115 USA. [Seidman, Christine] Brigham & Womens Hosp, Howard Hughes Med Inst, Boston, MA 02115 USA. [Seidman, Christine] Brigham & Womens Hosp, Div Cardiovasc Med, Boston, MA 02115 USA. RP Seidman, C (reprint author), Harvard Univ, Sch Med, Dept Genet, NRB 256,77 Ave Louis Pasteur, Boston, MA 02115 USA. EM cseidman@genetics.med.harvard.edu FU National Human Genome Research Institute [U54 HG003067]; National Heart, Lung, and Blood Institute (NHLBI) [HL080494-05]; National Institute on Minority Health and Health Disparities [R01MD007092]; Howard Hughes Medical Institute; Banyu Fellowship Program; Uehara Research Fellowship Program; National Institutes of Health (NIH) [5T32GM007753-33]; NHLBI, the National Institute for Minority Health and Health Disparities [N01-HC-95170, N01-HC-95171, N01-HC-95172, HL-102924, RC2 HL-102925, RC2 HL-102926]; National Institute of Biomedical Imaging and Bioengineering; NIH, US Department of Health and Human Services [N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32, 44221] FX This work was supported by grants from the National Human Genome Research Institute (Medical Sequencing Program grant U54 HG003067 to the Broad Institute [to E. Lander]), the National Heart, Lung, and Blood Institute (NHLBI; HL080494-05 to C. Seidman and J.G. Seidman), the National Institute on Minority Health and Health Disparities (R01MD007092 to M. R. Pollak) and the Howard Hughes Medical Institute (to C. Seidman). K. Ito was supported by Banyu Fellowship Program and Uehara Research Fellowship Program. A. G. Bick is supported by National Institutes of Health (NIH) Medical Scientist Training Program fellowship 5T32GM007753-33. The Jackson Heart Study is supported by contracts N01-HC-95170, N01-HC-95171, and N01-HC-95172 from the NHLBI, the National Institute for Minority Health and Health Disparities, and additional support from the National Institute of Biomedical Imaging and Bioengineering. The WHI Sequencing Project is funded by the NHLBI (HL-102924) as well as the NIH, US Department of Health and Human Services through contracts N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32, and 44221. The WHI exome sequencing was performed through NHLBI grants RC2 HL-102925 (BroadGO) and RC2 HL-102926 (SeattleGO). NR 29 TC 51 Z9 52 U1 1 U2 4 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 FEB 28 PY 2014 VL 114 IS 5 BP 845 EP 850 DI 10.1161/CIRCRESAHA.114.302347 PG 6 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA AG7GS UT WOS:000335586900016 PM 24379297 ER PT J AU Blenner, MA Dong, XC Springer, TA AF Blenner, Mark A. Dong, Xianchi Springer, Timothy A. TI Structural Basis of Regulation of von Willebrand Factor Binding to Glycoprotein Ib SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article DE Directed Evolution; Immunology; Protein Folding; Structural Biology; von Willebrand Factor; Glycoprotein Ib; Yeast Display ID FACTOR A1 DOMAIN; IX-V COMPLEX; YEAST SURFACE DISPLAY; LEUCINE-RICH REPEATS; N-TERMINAL DOMAIN; CRYSTAL-STRUCTURE; ALPHA-THROMBIN; PLATELET-AGGREGATION; RISTOCETIN COFACTOR; DISEASE MUTATIONS AB Background: Force in fluid flow regulates von Willebrand factor (VWF) A1 domain binding to glycoprotein Ib (GPIb). Results: X-ray crystal structures of high affinity A1-GPIb complexes and mutations reveal interactions involving central leucine-rich repeats of GPIb. Conclusion: Structural changes are on a pathway to a force-induced super high affinity state. Significance: A1-GPIb complexes provide insight into mechanochemistry of bleeding disorders. Activation by elongational flow of von Willebrand factor (VWF) is critical for primary hemostasis. Mutations causing type 2B von Willebrand disease (VWD), platelet-type VWD (PT-VWD), and tensile force each increase affinity of the VWF A1 domain and platelet glycoprotein Ib (GPIb) for one another; however, the structural basis for these observations remains elusive. Directed evolution was used to discover a further gain-of-function mutation in A1 that shifts the long range disulfide bond by one residue. We solved multiple crystal structures of this mutant A1 and A1 containing two VWD mutations complexed with GPIb containing two PT-VWD mutations. We observed a gained interaction between A1 and the central leucine-rich repeats (LRRs) of GPIb, previously shown to be important at high shear stress, and verified its importance mutationally. These findings suggest that structural changes, including central GPIb LRR-A1 contact, contribute to VWF affinity regulation. Among the mutant complexes, variation in contacts and poor complementarity between the GPIb -finger and the region of A1 harboring VWD mutations lead us to hypothesize that the structures are on a pathway to, but have not yet reached, a force-induced super high affinity state. C1 [Springer, Timothy A.] Harvard Univ, Sch Med, Boston Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA. [Springer, Timothy A.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. RP Springer, TA (reprint author), Harvard Univ, Sch Med, Boston Childrens Hosp, Program Cellular & Mol Med, 3 Blackfan Circle, Boston, MA 02115 USA. EM timothy.springer@childrens.harvard.edu RI Dong, Xianchi/C-1393-2015 OI Dong, Xianchi/0000-0001-5121-1236 FU National Institutes of Health [HL-103526, NIH-1F32HL-099167]; American Heart Association [AHA-10POST4170043] FX This work was supported, in whole or in part, by National Institutes of Health Grant HL-103526 and Postdoctoral Fellowship NIH-1F32HL-099167 (to M. A. B.). This work was also supported by American Heart Association Postdoctoral Fellowship AHA-10POST4170043 (to M. A. B.). NR 51 TC 16 Z9 18 U1 0 U2 6 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 28 PY 2014 VL 289 IS 9 BP 5565 EP 5579 DI 10.1074/jbc.M113.511220 PG 15 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AB8BQ UT WOS:000332015500022 PM 24391089 ER PT J AU Korenic, A Boltze, J Deten, A Peters, M Andjus, P Radenovic, L AF Korenic, Andrej Boltze, Johannes Deten, Alexander Peters, Myriam Andjus, Pavle Radenovic, Lidija TI Astrocytic Mitochondrial Membrane Hyperpolarization following Extended Oxygen and Glucose Deprivation SO PLOS ONE LA English DT Article ID FOCAL CEREBRAL-ISCHEMIA; OXIDATIVE STRESS; SUBCELLULAR HETEROGENEITY; PRIMARY CULTURES; CELL-CULTURES; NITRIC-OXIDE; NEURONS; INHIBITION; INDICATOR; APOPTOSIS AB Astrocytes can tolerate longer periods of oxygen and glucose deprivation (OGD) as compared to neurons. The reasons for this reduced vulnerability are not well understood. Particularly, changes in mitochondrial membrane potential (Delta psi(m)) in astrocytes, an indicator of the cellular redox state, have not been investigated during reperfusion after extended OGD exposure. Here, we subjected primary mouse astrocytes to glucose deprivation (GD), OGD and combinations of both conditions varying in duration and sequence. Changes in Delta psi(m), visualized by change in the fluorescence of JC-1, were investigated within one hour after reconstitution of oxygen and glucose supply, intended to model in vivo reperfusion. In all experiments, astrocytes showed resilience to extended periods of OGD, which had little effect on Delta psi(m) during reperfusion, whereas GD caused a robust Delta psi(m) negativation. In case no Delta psi(m) negativation was observed after OGD, subsequent chemical oxygen deprivation (OD) induced by sodium azide caused depolarization, which, however, was significantly delayed as compared to normoxic group. When GD preceded OD for 12 h, Delta psi(m) hyperpolarization was induced by both GD and subsequent OD, but significant interaction between these conditions was not detected. However, when GD was extended to 48 h preceding OGD, hyperpolarization enhanced during reperfusion. This implicates synergistic effects of both conditions in that sequence. These findings provide novel information regarding the role of the two main substrates of electron transport chain (glucose and oxygen) and their hyperpolarizing effect on Delta psi(m) during substrate deprivation, thus shedding new light on mechanisms of astrocyte resilience to prolonged ischemic injury. C1 [Korenic, Andrej; Andjus, Pavle; Radenovic, Lidija] Univ Belgrade, Dept Physiol & Biochem, Ctr Laser Microscopy, Fac Biol, Belgrade, Serbia. [Boltze, Johannes; Deten, Alexander; Peters, Myriam] Fraunhofer Inst Cell Therapy & Immunol, Leipzig, Germany. [Boltze, Johannes] Univ Leipzig, Translat Ctr Regenerat Med, D-04109 Leipzig, Germany. [Boltze, Johannes] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Boltze, Johannes] Harvard Univ, Sch Med, Boston, MA USA. RP Korenic, A (reprint author), Univ Belgrade, Dept Physiol & Biochem, Ctr Laser Microscopy, Fac Biol, Belgrade, Serbia. EM agapije@gmail.com FU Fraunhofer Institute for Cell Therapy and Immunology (Department of Cell Therapy); DAAD (German Academic Exchange Service, Deutscher Akademischer Austauschdienst); Serbian Ministry of Education and Science [III 41005] FX This study was supported by intramural funds of the Fraunhofer Institute for Cell Therapy and Immunology (Department of Cell Therapy) and a DAAD (German Academic Exchange Service, Deutscher Akademischer Austauschdienst) short term research fellowship, as well as by the Serbian Ministry of Education and Science (III 41005). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 34 TC 8 Z9 8 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 FEB 28 PY 2014 VL 9 IS 2 AR e90697 DI 10.1371/journal.pone.0090697 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AC3DW UT WOS:000332396200246 PM 24587410 ER PT J AU Lone, AM Leidl, M McFedries, AK Horner, JW Creemers, J Saghatelian, A AF Lone, Anna Mari Leidl, Mathias McFedries, Amanda K. Horner, James W. Creemers, John Saghatelian, Alan TI Deletion of Prepl Causes Growth Impairment and Hypotonia in Mice SO PLOS ONE LA English DT Article ID CYSTINURIA SYNDROME; OLIGOPEPTIDASE; PROTEIN; FIBROBLASTS; SECRETION; RECEPTOR; PCSK9; RAT; LDL AB Genetic studies of rare diseases can identify genes of unknown function that strongly impact human physiology. Prolyl endopeptidase-like (PREPL) is an uncharacterized member of the prolyl peptidase family that was discovered because of its deletion in humans with hypotonia-cystinuria syndrome (HCS). HCS is characterized by a number of physiological changes including diminished growth and neonatal hypotonia or low muscle tone. HCS patients have deletions in other genes as well, making it difficult to tease apart the specific role of PREPL. Here, we develop a PREPL null (PREPL-/-) mouse model to address the physiological role of this enzyme. Deletion of exon 11 from the Prepl gene, which encodes key catalytic amino acids, leads to a loss of PREPL protein as well as lower Prepl mRNA levels. PREPL-/- mice have a pronounced growth phenotype, being significantly shorter and lighter than their wild type (PREPL+/+) counterparts. A righting assay revealed that PREPL-/- pups took significantly longer than PREPL+/+ pups to right themselves when placed on their backs. This deficit indicates that PREPL-/- mice suffer from neonatal hypotonia. According to these results, PREPL regulates growth and neonatal hypotonia in mice, which supports the idea that PREPL causes diminished growth and neonatal hypotonia in humans with HCS. These animals provide a valuable asset in deciphering the underlying biochemical, cellular and physiological pathways that link PREPL to HCS, and this may eventually lead to new insights in the treatment of this disease. C1 [Lone, Anna Mari; Leidl, Mathias; McFedries, Amanda K.; Saghatelian, Alan] Harvard Univ, Dept Chem & Chem Biol, Cambridge, MA 02138 USA. [Horner, James W.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Belfer Inst Appl Canc Sci, Boston, MA 02115 USA. [Horner, James W.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Horner, James W.] Univ Texas MD Anderson Canc Ctr, Inst Appl Canc Sci, Houston, TX 77030 USA. [Creemers, John] Katholieke Univ Leuven, Dept Human Genet, Biochem Neuroendocrinol Lab, Louvain, Belgium. RP Saghatelian, A (reprint author), Harvard Univ, Dept Chem & Chem Biol, Cambridge, MA 02138 USA. EM alan.saghatelian@gmail.com FU Forris Jewitt Moore Fellowship; Amherst College; National Institutes of Health [GM007598, 1DP2OD002374]; Fonds voor Wetenschappelijk Onderzoek Vlaanderen; Searle Scholar Award; Burroughs Wellcome Fund Career Award in the Biomedical Sciences FX This work was supported by a Forris Jewitt Moore Fellowship sponsored by Amherst College (A. M. L.), an National Institutes of Health training grant (GM007598) (A. M. L), Fonds voor Wetenschappelijk Onderzoek Vlaanderen (J.C.), Searle Scholar Award (A. S.), Burroughs Wellcome Fund Career Award in the Biomedical Sciences (A. S.), National Institutes of Health Grants 1DP2OD002374 (A. S.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 29 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 FEB 28 PY 2014 VL 9 IS 2 AR e89160 DI 10.1371/journal.pone.0089160 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AC3DW UT WOS:000332396200038 PM 24586561 ER PT J AU Beissner, F Baudrexel, S AF Beissner, Florian Baudrexel, Simon TI Investigating the human brainstem with structural and functional MRI SO FRONTIERS IN HUMAN NEUROSCIENCE LA English DT Editorial Material DE brainstem; fMRI; MRI; physiological noise; autonomic nervous system; neuromodulatory systems; pain modulation; reticular formation C1 [Beissner, Florian] Hannover Med Sch, Dept Neuroradiol Somatosensory & Autonom Therapy, Hannover, Germany. [Beissner, Florian] Massachusetts Gen Hosp, Dept Radiol, Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Baudrexel, Simon] Goethe Univ Frankfurt, Univ Hosp, Dept Neurol, D-60054 Frankfurt, Germany. RP Beissner, F (reprint author), Hannover Med Sch, Dept Neuroradiol Somatosensory & Autonom Therapy, Hannover, Germany. EM coffeefellow@gmail.com NR 9 TC 4 Z9 4 U1 0 U2 10 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1662-5161 J9 FRONT HUM NEUROSCI JI Front. Hum. Neurosci. PD FEB 28 PY 2014 VL 8 AR 116 DI 10.3389/fnhum.2014.00116 PG 2 WC Neurosciences; Psychology SC Neurosciences & Neurology; Psychology GA AB9YC UT WOS:000332150600002 PM 24616692 ER PT J AU Schmidt, D Schachter, SC AF Schmidt, Dieter Schachter, Steven C. TI Drug treatment of epilepsy in adults SO BMJ-BRITISH MEDICAL JOURNAL LA English DT Review ID RANDOMIZED CONTROLLED-TRIAL; CHILDHOOD-ONSET EPILEPSY; NEWLY-DIAGNOSED EPILEPSY; CONTROLLED-RELEASE CARBAMAZEPINE; SEIZURE-FREE PATIENTS; CURRENT CLINICAL-EXPERIENCE; LONG-TERM OUTCOMES; ANTIEPILEPTIC DRUGS; DOUBLE-BLIND; REFRACTORY EPILEPSY AB Epilepsy is a serious, potentially life shortening brain disorder, the symptoms of which can be successfully treated in most patients with one or more antiepileptic drug. About two in three adults with new onset epilepsy will achieve lasting seizure remission on or off these drugs, although around half will experience mild to moderately severe adverse effects. Patients with epilepsy, especially the 20-30% whose seizures are not fully controlled with available drugs (drug resistant epilepsy), have a significantly increased risk of death, as well as psychiatric and somatic comorbidities, and adverse effects from antiepileptic drugs. Newer drugs have brought more treatment options, and some such as levetiracetam cause fewer drug interactions and less hypersensitivity than older ones. However, they do not reduce the prevalence of drug resistant epilepsy or prevent the development of epilepsy in patients at high risk, such as those with a traumatic brain injury. The development of antiepileptic drugs urgently needs to be revitalized so that we can discover more effective antiseizure drugs for the treatment of drug resistant epilepsy, including catastrophic forms. Antiepileptogenic agents to prevent epilepsy before the first seizure in at risk patients and disease modifying agents to control ongoing severe epilepsy associated with progressive underlying disease are also needed. C1 [Schmidt, Dieter] Epilepsy Res Grp, D-14163 Berlin, Germany. [Schachter, Steven C.] Massachusetts Gen Hosp, Dept Neurol, Beth Israel Deaconess Med Ctr, Boston, MA 02114 USA. [Schachter, Steven C.] Harvard Univ, Sch Med, Boston, MA USA. RP Schmidt, D (reprint author), Epilepsy Res Grp, Goethestr 5, D-14163 Berlin, Germany. EM dbschmidt@t-online.de FU Eisai; Sun; UCB; Viropharma FX We have read and understood the BMJ Group policy on declaration of interests and declare the following interests: DS has received hospitality and consulting fees in the past two years from Eisai, Sun, UCB, and Viropharma. None of the companies has had any input to the manuscript. SCS: none declared. NR 135 TC 47 Z9 48 U1 2 U2 16 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1756-1833 J9 BMJ-BRIT MED J JI BMJ-British Medical Journal PD FEB 28 PY 2014 VL 348 AR g2546 DI 10.1136/bmj.g254 PG 18 WC Medicine, General & Internal SC General & Internal Medicine GA AC0UX UT WOS:000332212100008 PM 24583319 ER PT J AU Fan, FJ Tonon, G Bashari, MH Vallet, S Antonini, E Goldschmidt, H Schulze-Bergkamen, H Opferman, JT Sattler, M Anderson, KC Jager, D Podar, K AF Fan, Fengjuan Tonon, Giovanni Bashari, Muhammad Hasan Vallet, Sonia Antonini, Elena Goldschmidt, Hartmut Schulze-Bergkamen, Henning Opferman, Joseph T. Sattler, Martin Anderson, Kenneth C. Jaeger, Dirk Podar, Klaus TI Targeting Mcl-1 for multiple myeloma (MM) therapy: Drug-induced generation of Mcl-1 fragment Mcl-1(128-350) triggers MM cell death via c-Jun upregulation SO CANCER LETTERS LA English DT Article DE MCl-1; c-Jun; Multiple myeloma; Apoptosis; MEFs; Glioblastoma ID ANTI-APOPTOTIC MCL-1; SURVIVAL; PROTEIN; EXPRESSION; CLEAVAGE; BORTEZOMIB; PATHWAY; NOXA; DIFFERENTIATION; DEGRADATION AB Myeloid cell leukemia-1 (Mcl-1, HGNC: 6943), a pro-survival member of the Bcl-2 family, plays a crucial role in Multiple Myeloma (MM) pathogenesis and drug resistance, thus representing a promising therapeutic target in MM. A novel strategy to inhibit Mcl-1 activity is the induction of ubiquitin-independent Mcl-1 degradation. Our own and other previous studies have demonstrated, caspase-dependent generation of a 28 kDa Mcl-1 fragment, Mcl-1(128-350) which inhibits MM cell proliferation and survival. Here, we show that similar to bortezomib, the novel proteasome inhibitors carfilzomib and ixazomib, as well as staurosporine and adaphostin, induce the generation of Mcl-1(128-350) in MM cells. Next, the molecular sequelae downstream of Mcl-1(128-350), which mediate its pro-apoptotic activity, were delineated. Surprisingly, we observed nuclear accumulation of drug-induced or exogenously overexpressed Mcl-1(128-350), followed by elevated mRNA and protein levels of c-Jun, as well as enhanced AP-1 reporter activity. Moreover, drug-induced AP-1 activity was blocked after introducing a point mutation into the highly conserved Mcl-1 caspase-cleavage site Asp127, but not Asp157. Consequently, drug-triggered cell death was significantly decreased in MM cells transfected with Mcl-1 D127A, but not with Mcl-1 D157A. Consistent with these data, treatment with bortezomib triggered c-Jun upregulation followed by apoptosis in Mcl-1(wt/wt), but not Mcl-1(Delta/null) murine embryonic fibroblasts (MEFs). Transfection of a plasmid carrying Mcl-1(wt) into Mcl-1(Delta/null) MEFs restored bortezomib-induced Mcl-1 fragmentation, c-Jun upregulation and AP-1 reporter activity. Finally, our data indicate that drug-induced generation of a pro-apoptotic Mcl-1 fragment followed by c-Jun upregulation may also be a novel therapeutic approach in other tumor entities. (C) 2013 Elsevier Ireland Ltd. All rights reserved. C1 [Fan, Fengjuan; Bashari, Muhammad Hasan; Vallet, Sonia; Schulze-Bergkamen, Henning; Jaeger, Dirk; Podar, Klaus] Heidelberg Univ, Natl Ctr Tumor Dis NCT, D-69120 Heidelberg, Germany. [Fan, Fengjuan; Bashari, Muhammad Hasan; Vallet, Sonia; Schulze-Bergkamen, Henning; Jaeger, Dirk; Podar, Klaus] German Canc Res Ctr, Heidelberg, Germany. [Tonon, Giovanni; Antonini, Elena] Ist Sci San Raffaele, Div Mol Oncol, Funct Genom Canc Unit, I-20132 Milan, Italy. [Sattler, Martin; Anderson, Kenneth C.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Goldschmidt, Hartmut] Heidelberg Univ, Natl Ctr Tumor Dis NCT, Sect Multiple Myeloma, Dept Internal Med 5, D-69120 Heidelberg, Germany. [Opferman, Joseph T.] St Jude Childrens Res Hosp, Memphis, TN 38105 USA. RP Podar, K (reprint author), Heidelberg Univ, Natl Ctr Tumor Dis NCT, Neuenheimer Feld 460, D-69120 Heidelberg, Germany. EM klaus.podar@nct-heidelberg.de RI Bashari, Muhammad Hasan/H-7079-2016 OI Bashari, Muhammad Hasan/0000-0001-7298-0317 FU B. Braun Stiftungs-Grant FX We thank Dr. G. Packham (University of Southampton School of Medicine, Southampton General Hospital, Southampton, UK) for kindly providing Mcl-1128-350 plasmid; and Drs. M. Trier and D. Bohmann for kindly providing c-Jun plasmid. K. Podar is a recipient of a B. Braun Stiftungs-Grant. NR 48 TC 8 Z9 8 U1 1 U2 11 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3835 EI 1872-7980 J9 CANCER LETT JI Cancer Lett. PD FEB 28 PY 2014 VL 343 IS 2 BP 286 EP 294 DI 10.1016/j.canlet.2013.09.042 PG 9 WC Oncology SC Oncology GA AB1YK UT WOS:000331589600017 PM 24120758 ER PT J AU Sung, YJ Lue, N Hamza, B Martel, J Irimia, D Dasari, RR Choi, W Yaqoob, Z So, P AF Sung, Yongjin Lue, Niyom Hamza, Bashar Martel, Joseph Irimia, Daniel Dasari, Ramachandra R. Choi, Wonshik Yaqoob, Zahid So, Peter TI Three-Dimensional Holographic Refractive-Index Measurement of Continuously Flowing Cells in a Microfluidic Channel SO PHYSICAL REVIEW APPLIED LA English DT Article ID OPTICAL DIFFRACTION TOMOGRAPHY; QUANTITATIVE PHASE MICROSCOPY; LOW-COHERENCE INTERFEROMETRY; SIZE HOMEOSTASIS; LIVING CELLS; GROWTH; FRACTIONATION; DYNAMICS; EQUATION AB The refractive index of biological specimens is a source of intrinsic contrast that can be explored without any concerns of photobleaching or harmful effects caused by extra contrast agents. In addition, the refractive index contains rich information related to the metabolism of cells at the cellular and subcellular levels. Here, we report a no-moving-parts approach that provides three-dimensional refractive-index maps of biological samples continuously flowing in a microfluidic channel. Specifically, we use line illumination and off-axis digital holography to record the angular spectra of light scattered from flowing samples at high speed. Applying the scalar diffraction theory, we obtain accurate refractive-index maps of the samples from the measured spectra. Using this method, we demonstrate label-free three-dimensional imaging of live RKO human colon cancer cells and RPMI8226 multiple myeloma cells, and obtain the volume, dry mass, and density of these cells from the measured three-dimensional refractive-index maps. Our results show that the reported method, alone or in combination with the existing flow cytometry techniques, shows promise as a quantitative tool for stain-free characterization of a large number of cells. C1 [Sung, Yongjin; Lue, Niyom; Dasari, Ramachandra R.; Yaqoob, Zahid; So, Peter] MIT, Laser Biomed Res Ctr, Cambridge, MA 02139 USA. [Hamza, Bashar; Martel, Joseph; Irimia, Daniel] Massachusetts Gen Hosp, BioMEMS Resource Ctr, Charlestown, MA 02129 USA. [Hamza, Bashar; Martel, Joseph; Irimia, Daniel] Harvard Univ, Sch Med, Charlestown, MA 02129 USA. [Choi, Wonshik] Korea Univ, Dept Phys, Seoul 136701, South Korea. [So, Peter] MIT, Dept Mech Engn, Cambridge, MA 02139 USA. [So, Peter] MIT, Dept Biol Engn, Cambridge, MA 02139 USA. RP Sung, YJ (reprint author), MIT, Laser Biomed Res Ctr, 77 Massachusetts Ave, Cambridge, MA 02139 USA. EM yongjin.sung@gmail.com FU National Institutes of Health [9P41EB015871-26A1, P41 EB002503]; Hamamatsu Photonics, Japan FX This work is funded by the National Institutes of Health (9P41EB015871-26A1 and P41 EB002503) and Hamamatsu Photonics, Japan. NR 48 TC 23 Z9 23 U1 5 U2 33 PU AMER PHYSICAL SOC PI COLLEGE PK PA ONE PHYSICS ELLIPSE, COLLEGE PK, MD 20740-3844 USA SN 2331-7019 J9 PHYS REV APPL JI Phys. Rev. Appl. PD FEB 27 PY 2014 VL 1 IS 1 AR 014002 DI 10.1103/PhysRevApplied.1.014002 PG 8 WC Physics, Applied SC Physics GA AS5QJ UT WOS:000344324600003 ER PT J AU Odejide, O Weigert, O Lane, AA Toscano, D Lunning, MA Kopp, N Kim, S van Bodegom, D Bolla, S Schatz, JH Teruya-Feldstein, J Hochberg, E Louissaint, A Dorfman, D Stevenson, K Rodig, SJ Piccaluga, PP Jacobsen, E Pileri, SA Harris, NL Ferrero, S Inghirami, G Horwitz, SM Weinstock, DM AF Odejide, Oreofe Weigert, Oliver Lane, Andrew A. Toscano, Dan Lunning, Matthew A. Kopp, Nadja Kim, Sunhee van Bodegom, Diederik Bolla, Sudha Schatz, Jonathan H. Teruya-Feldstein, Julie Hochberg, Ephraim Louissaint, Abner Dorfman, David Stevenson, Kristen Rodig, Scott J. Piccaluga, Pier Paolo Jacobsen, Eric Pileri, Stefano A. Harris, Nancy L. Ferrero, Simone Inghirami, Giorgio Horwitz, Steven M. Weinstock, David M. TI A targeted mutational landscape of angioimmunoblastic T-cell lymphoma SO BLOOD LA English DT Article ID LYMPHOCYTIC-LEUKEMIA; NOTCH1 MUTATIONS; STAT3 MUTATIONS; TET2; FREQUENT; GENES AB The genetics of angioimmunoblastic T-cell lymphoma (AITL) are very poorly understood. We defined the mutational landscape of AITL across 219 genes in 85 cases from the United States and Europe. We identified >= 2 mutations in 34 genes, nearly all of which were not previously implicated in AITL. These included loss-of-function mutations in TP53 (n = 4), ETV6 (n = 3), CCND3 (n = 2), and EP300 (n = 5), as well as gain-of-function mutations in JAK2 (n = 2) and STAT3 (n = 4). TET2 was mutated in 65 (76%) AITLs, including 43 that harbored 2 or 3 TET2 mutations. DNMT3A mutations occurred in 28 (33%) AITLs; 100% of these also harbored TET2 mutations (P < .0001). Seventeen AITLs harbored IDH2 R172 substitutions, including 15 with TET2 mutations. In summary, AITL is characterized by high frequencies of overlapping mutations in epigenetic modifiers and targetable mutations in a subset of cases. C1 [Odejide, Oreofe; Weigert, Oliver; Lane, Andrew A.; Kopp, Nadja; Kim, Sunhee; van Bodegom, Diederik; Bolla, Sudha; Jacobsen, Eric; Weinstock, David M.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Toscano, Dan; Lunning, Matthew A.; Horwitz, Steven M.] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10021 USA. [Schatz, Jonathan H.; Teruya-Feldstein, Julie] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10021 USA. [Hochberg, Ephraim; Louissaint, Abner; Harris, Nancy L.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Dorfman, David; Rodig, Scott J.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Stevenson, Kristen] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Piccaluga, Pier Paolo; Pileri, Stefano A.] Orsola Malpighi Hosp, Unit Hematopathol, Bologna, Italy. [Ferrero, Simone; Inghirami, Giorgio] Univ Turin, Div Ematol, Turin, Italy. RP Weinstock, DM (reprint author), Dana Farber Canc Inst, 450 Brookline Ave,Dana 510B, Boston, MA 02215 USA. EM dweinstock@partners.org OI Toscano, Daniel/0000-0002-1805-4416; FERRERO, Simone/0000-0002-9711-1502; Schatz, Jonathan/0000-0003-1842-228X FU Conquer Cancer Foundation; Lauri Strauss Leukemia Foundation; Leukemia and Lymphoma Society; AIRC [5x1000]; Cycle for Survival; Stellato Fund; American Cancer Society; Stand Up To Cancer Innovative Research Grant FX This work was supported by the Conquer Cancer Foundation (A.A.L.), Lauri Strauss Leukemia Foundation (A.A.L.), Leukemia and Lymphoma Society (A.A.L.), AIRC 5x1000 (G.O.), Cycle for Survival (S.M.H.), the Stellato Fund (D.MW.), American Cancer Society (D.M.W.), and a Stand Up To Cancer Innovative Research Grant (D.M.W.). NR 24 TC 64 Z9 65 U1 2 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 FEB 27 PY 2014 VL 123 IS 9 BP 1293 EP 1296 DI 10.1182/blood-2013-10-531509 PG 4 WC Hematology SC Hematology GA AH0VR UT WOS:000335839300010 PM 24345752 ER PT J AU Krause, DS Lazarides, K Lewis, JB von Andrian, UH Van Etten, RA AF Krause, Daniela S. Lazarides, Katherine Lewis, Juliana B. von Andrian, Ulrich H. Van Etten, Richard A. TI Selectins and their ligands are required for homing and engraftment of BCR-ABL1(+) leukemic stem cells in the bone marrow niche SO BLOOD LA English DT Article ID CHRONIC MYELOID-LEUKEMIA; CHRONIC MYELOGENOUS LEUKEMIA; P-SELECTIN; ADHESION MOLECULE-1; HEMATOPOIETIC-CELLS; MYELOPROLIFERATIVE DISEASE; ENDOTHELIAL SELECTINS; MEDIATED INHIBITION; LEUKOCYTE ADHESION; PROGENITOR CELLS AB We investigated adhesion pathways that contribute to engraftment of breakpoint cluster region-Abelson murine leukemia viral oncogene homolog 1 (BCR-ABL1)-induced chronic myelogenous leukemia (CML)-like myeloproliferative neoplasia in a mouse retroviral transduction/transplantation model. Compared with normal stem/progenitor cells, BCR-ABL1(+) progenitors had similar expression of very late antigen-4 (VLA4), VLA5, leukocyte functional antigen-1, and CXCR4 but lower expression of P-selectin glycoprotein ligand-1 (PSGL-1) and of L-selectin. Whereas vascular cell adhesion molecule-1 and P-selectin were not required, deficiency of E-selectin in the recipient bone marrow endothelium significantly reduced engraftment by BCR-ABL1-expressing stem cells following intravenous injection, with leukemogenesis restored by direct intrafemoral injection. BCR-ABL1-expressing cells deficient for PSGL-1 or the selectin ligand-synthesizing enzymes core-2 beta 1,6-N-acetylglucosaminyltransferase or fucosyltransferases IV/VII were impaired for engraftment, and destruction of selectin ligands on leukemic progenitors by neuraminidase reduced engraftment. BCR-ABL1-expressing L-selectin-deficient progenitors were also defective in homing and engraftment, with leukemogenesis rescued by coexpression of chimeric E/L-selectin. Antibody to L-selectin decreased the engraftment of BCR-ABL1-transduced stem cells. These results establish that BCR-ABL1(+) leukemic stem cells rely to a greater extent on selectins and their ligands for homing and engraftment than do normal stem cells. Selectin blockade is a novel strategy to exploit differences between normal and leukemic stem cells that may be beneficial in autologous transplantation for CML and perhaps other leukemias. C1 [Krause, Daniela S.; Lazarides, Katherine; Lewis, Juliana B.; Van Etten, Richard A.] Tufts Med Ctr, Div Hematol Oncol, Boston, MA USA. [Krause, Daniela S.; Lazarides, Katherine; Lewis, Juliana B.; Van Etten, Richard A.] Tufts Med Ctr, Mol Oncol Res Inst, Boston, MA USA. [Krause, Daniela S.] Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA. [Krause, Daniela S.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [von Andrian, Ulrich H.] Harvard Univ, Sch Med, Dept Microbiol & Immunobiol, Boston, MA USA. RP Van Etten, RA (reprint author), Univ Calif Irvine, Div Hematol Oncol, 839 Med Sci Court,Sprague Hall,Rm 124, Irvine, CA 92697 USA. EM vanetten@uci.edu FU National Institutes of Health, National Cancer Institute [R01 CA90576, F31 CA136153, K08 CA138916] FX This work was supported by National Institutes of Health, National Cancer Institute grants R01 CA90576 (R.A.V.E.), F31 CA136153 (J.B.L.), and K08 CA138916 (to D.S.K.). NR 56 TC 22 Z9 25 U1 1 U2 2 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 FEB 27 PY 2014 VL 123 IS 9 BP 1361 EP 1371 DI 10.1182/blood-2013-11-538694 PG 11 WC Hematology SC Hematology GA AH0VR UT WOS:000335839300019 PM 24394666 ER PT J AU Bachireddy, P Hainz, U Rooney, M Pozdnyakova, O Aldridge, J Zhang, WD Liao, XY Hodi, FS O'Connell, K Haining, WN Goldstein, NR Canning, CM Soiffer, RJ Ritz, J Hacohen, N Alyea, EP Kim, HT Wu, CJ AF Bachireddy, Pavan Hainz, Ursula Rooney, Michael Pozdnyakova, Olga Aldridge, Julie Zhang, Wandi Liao, Xiaoyun Hodi, F. Stephen O'Connell, Karyn Haining, W. Nicholas Goldstein, Natalie R. Canning, Christine M. Soiffer, Robert J. Ritz, Jerome Hacohen, Nir Alyea, Edwin P., III Kim, Haesook T. Wu, Catherine J. TI Reversal of in situ T-cell exhaustion during effective human antileukemia responses to donor lymphocyte infusion SO BLOOD LA English DT Article ID CHRONIC MYELOGENOUS LEUKEMIA; BONE-MARROW-TRANSPLANTATION; CHRONIC VIRAL-INFECTION; ACUTE MYELOID-LEUKEMIA; MELANOMA PATIENTS; B-CELL; CANCER; TUMOR; ANTIGEN; IMMUNOTHERAPY AB Increasing evidence across malignancies suggests that infiltrating T cells at the site of disease are crucial to tumor control. We hypothesized that marrow-infiltrating immune populations play a critical role in response to donor lymphocyte infusion (DLI), an established and potentially curative immune therapy whose precise mechanism remains unknown. We therefore analyzed marrow-infiltrating immune populations in 29 patients (22 responders, 7 nonresponders) with relapsed chronic myelogenous leukemia who received CD4(+) DLI in the pre-tyrosine kinase inhibitor era. Immunohistochemical analysis of pretreatment marrow revealed that the presence of >4% marrow-infiltrating CD8(+) (but not CD4(+)) T cells predicted DLI response, even in the setting of high leukemia burden. Furthermore, mRNAexpression profiling of marrow-infiltrating T cells of a subset of responders compared with nonresponders revealed enrichment of T-cell exhaustion-specific genes in pretreatment T cells of DLI responders and significant downregulation of gene components in the same pathway in responders in conjunction with clinical response. Our data demonstrate that response to DLI is associated with quantity of preexisting marrow CD8(+) T cells and local reversal of T-cell exhaustion. Our studies implicate T-cell exhaustion as a therapeutic target of DLI and support the potential use of novel anti-PD1/PDL1 agents in lieu of DLI. C1 [Bachireddy, Pavan; Liao, Xiaoyun; Hodi, F. Stephen; Goldstein, Natalie R.; Canning, Christine M.; Soiffer, Robert J.; Ritz, Jerome; Alyea, Edwin P., III; Wu, Catherine J.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Bachireddy, Pavan; Hainz, Ursula; Zhang, Wandi; O'Connell, Karyn; Canning, Christine M.; Ritz, Jerome; Wu, Catherine J.] Dana Farber Canc Inst, Canc Vaccine Ctr, Boston, MA 02115 USA. [Bachireddy, Pavan; Soiffer, Robert J.; Ritz, Jerome; Alyea, Edwin P., III; Wu, Catherine J.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Rooney, Michael; Hacohen, Nir] Broad Inst MIT & Harvard, Cambridge, MA USA. [Pozdnyakova, Olga] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Aldridge, Julie; Kim, Haesook T.] Dana Farber Canc Inst, Div Biostat & Computat Biol, Boston, MA 02115 USA. [Liao, Xiaoyun; Hodi, F. Stephen] Dana Farber Canc Inst, Ctr Immunooncol, Boston, MA 02115 USA. [Hodi, F. Stephen] Dana Farber Canc Inst, Melanoma Dis Ctr, Boston, MA 02115 USA. [Haining, W. Nicholas] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Hacohen, Nir] Massachusetts Gen Hosp, Dept Med, Div Rheumatol & Immunol, Boston, MA 02114 USA. RP Wu, CJ (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, 450 Brookline Ave,Dana 540B, Boston, MA 02215 USA. EM cwu@partners.org OI Ritz, Jerome/0000-0001-5526-4669 FU National Institutes of Health National Cancer Institute [5R21CA115043-2]; National Heart, Lung and Blood Institute [5R01HL103532-03]; Claudia Adams Barr Program in Cancer Research; Leukemia and Lymphoma Translational Research Program; Early Career Physician-Scientist Award of the Howard Hughes Medical Institute; Damon-Runyon Cancer Research Foundation [CI-38-07] FX This study was supported by the National Institutes of Health National Cancer Institute (5R21CA115043-2) and National Heart, Lung and Blood Institute (5R01HL103532-03), the Claudia Adams Barr Program in Cancer Research, the Leukemia and Lymphoma Translational Research Program, the Early Career Physician-Scientist Award of the Howard Hughes Medical Institute, and the Damon-Runyon Cancer Research Foundation (CI-38-07) (C.J.W.). Statistical analysis was supported by the National Cancer Institute PO1 (CA142106-06A1). NR 47 TC 19 Z9 19 U1 0 U2 3 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD FEB 27 PY 2014 VL 123 IS 9 BP 1412 EP 1421 DI 10.1182/blood-2013-08-523001 PG 10 WC Hematology SC Hematology GA AH0VR UT WOS:000335839300024 PM 24357730 ER PT J AU Fathi, AT Dec, GW Richter, JM Chen, YB Schwartzenberg, SS Holmvang, G Hasserjian, RP AF Fathi, Amir T. Dec, G. William, Jr. Richter, James M. Chen, Yi-Bin Schwartzenberg, Shmuel S. Holmvang, Godtfred Hasserjian, Robert P. TI Case 7-2014: A 27-Year-Old Man with Diarrhea, Fatigue, and Eosinophilia SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID IDIOPATHIC-HYPEREOSINOPHILIC-SYNDROME; BONE-MARROW-TRANSPLANTATION; IMATINIB MESYLATE; SYSTEMIC MASTOCYTOSIS; BLOOD EOSINOPHILIA; DRESS SYNDROME; DISORDERS; THERAPY; FUSION; GENE AB A 27-year-old man was admitted to the hospital because of diarrhea, fatigue, and eosinophilia. He had a history of ulcerative colitis, controlled with mesalamine. Examination revealed splenomegaly. Diagnostic procedures were performed. Presentation of CaseDr. Tilak Sundaresan (Medicine): A 27-year-old man was admitted to this hospital because of diarrhea, fatigue, and eosinophilia. The patient had been in good health until 2 weeks before admission, when fatigue developed. Eleven days before presentation, he had moved to the United States from Indonesia. After his arrival, he had bloating and nonbloody, loose bowel movements, without fever, chills, vomiting, cramping, or abdominal pain. One week later, the diarrhea persisted and his exercise tolerance sharply decreased. The day before admission, he was seen at his local health center. Testing included a complete blood count (Table 1) ... C1 [Fathi, Amir T.; Dec, G. William, Jr.; Richter, James M.; Chen, Yi-Bin; Schwartzenberg, Shmuel S.; Holmvang, Godtfred] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med, Boston, MA 02130 USA. [Hasserjian, Robert P.] Harvard Univ, Sch Med, Dept Pathol, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Fathi, Amir T.; Dec, G. William, Jr.; Richter, James M.; Chen, Yi-Bin; Schwartzenberg, Shmuel S.; Holmvang, Godtfred] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Hasserjian, Robert P.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Fathi, AT (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med, Boston, MA 02130 USA. FU Genzyme; Seattle Genetics; Concert Pharmaceuticals; Agios Pharmaceuticals; Teva Pharmaceuticals; Policy Analysis; Otsuka Pharmaceuticals; Bayer/Onyx; Sanofi; Incyte; Amgen FX Dr. Fathi reports receiving consulting fees for serving on the advisory boards of Genzyme, Seattle Genetics, Concert Pharmaceuticals, Agios Pharmaceuticals, and Teva Pharmaceuticals; Dr. Richter, consulting fees from Policy Analysis; Dr. Chen, consulting fees from Seattle Genetics and Otsuka Pharmaceuticals and grant funding from Seattle Genetics, Otsuka Pharmaceuticals, and Bayer/Onyx; and Dr. Hasserjian, consulting fees from Sanofi, Incyte, and Amgen. No other potential conflict of interest relevant to this article was reported. NR 60 TC 5 Z9 5 U1 3 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 FEB 27 PY 2014 VL 370 IS 9 BP 861 EP 872 DI 10.1056/NEJMcpc1302331 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA AB8AR UT WOS:000332013000012 PM 24571759 ER PT J AU Greene, MF Phimister, EG AF Greene, Michael F. Phimister, Elizabeth G. TI Screening for Trisomies in Circulating DNA SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID ALPHA-FETOPROTEIN; MATERNAL PLASMA; SERUM AB In the broadest sense, noninvasive prenatal testing began in the 1970s, when the first articulated-arm diagnostic ultrasound machines produced two-dimensional images of fetuses in utero. Initially, the crude new imaging technology was eagerly adopted for the simple measurement of embryos, fetuses, and fetal parts to develop normative data for gestational-age determination. But as technology and image quality rapidly improved, it quickly became obvious that fetal anatomy could be defined with increasing precision. At approximately the same time, Brock and Sutcliffe(1) recognized that alpha-fetoprotein, which is found in very high concentrations in fetal blood and cerebrospinal fluid, could be measured in ... C1 [Greene, Michael F.; Phimister, Elizabeth G.] Massachusetts Gen Hosp, Dept Obstet & Gynecol, Boston, MA 02114 USA. RP Greene, MF (reprint author), Massachusetts Gen Hosp, Dept Obstet & Gynecol, Boston, MA 02114 USA. NR 7 TC 4 Z9 4 U1 0 U2 1 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD FEB 27 PY 2014 VL 370 IS 9 BP 874 EP 875 DI 10.1056/NEJMe1401129 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA AB8AR UT WOS:000332013000013 PM 24571760 ER PT J AU Powe, CE Karumanchi, SA Thadhani, R AF Powe, Camille E. Karumanchi, S. Ananth Thadhani, Ravi TI Vitamin D-Binding Protein and Vitamin D in Blacks and Whites REPLY SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [Powe, Camille E.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Karumanchi, S. Ananth] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Thadhani, Ravi] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Powe, CE (reprint author), Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. NR 4 TC 21 Z9 21 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 FEB 27 PY 2014 VL 370 IS 9 BP 880 EP 881 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA AB8AR UT WOS:000332013000019 PM 24571762 ER PT J AU Bao, Y Rosner, BA Fuchs, CS AF Bao, Ying Rosner, Bernard A. Fuchs, Charles S. TI Nut Consumption and Mortality REPLY SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [Bao, Ying; Rosner, Bernard A.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Fuchs, Charles S.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Bao, Y (reprint author), Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. EM ying.bao@channing.harvard.edu NR 0 TC 1 Z9 1 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD FEB 27 PY 2014 VL 370 IS 9 BP 882 EP 882 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA AB8AR UT WOS:000332013000023 PM 24571767 ER PT J AU Arvanitis, M Anagnostou, T Kourkoumpetis, TK Ziakas, PD Desalermos, A Mylonakis, E AF Arvanitis, Marios Anagnostou, Theodora Kourkoumpetis, Themistoklis K. Ziakas, Panayiotis D. Desalermos, Athanasios Mylonakis, Eleftherios TI The Impact of Antimicrobial Resistance and Aging in VAP Outcomes: Experience from a Large Tertiary Care Center SO PLOS ONE LA English DT Article ID VENTILATOR-ASSOCIATED-PNEUMONIA; HOSPITAL-ACQUIRED PNEUMONIA; PSEUDOMONAS-AERUGINOSA; STAPHYLOCOCCUS-AUREUS; CANDIDA COLONIZATION; RESPIRATORY-TRACT; RISK-FACTORS; SURVEILLANCE; MORTALITY; INFECTION AB Background: Ventilator associated pneumonia (VAP) is a serious infection among patients in the intensive care unit (ICU). Methods: We reviewed the medical charts of all patients admitted to the adult intensive care units of the Massachusetts General Hospital that went on to develop VAP during a five year period. Results: 200 patients were included in the study of which 50 (25%) were infected with a multidrug resistant pathogen. Increased age, dialysis and late onset (>= 5 days from admission) VAP were associated with increased incidence of resistance. Multidrug resistant bacteria (MDRB) isolation was associated with a significant increase in median length of ICU stay (19 vs. 16 days, p = 0.02) and prolonged duration of mechanical ventilation (18 vs. 14 days, p = 0.03), but did not impact overall mortality (HR 1.12, 95% CI 0.51-2.46, p = 0.77). However, age (HR 1.04 95% CI 1.01-1.07, p = 0.003) was an independent risk factor for mortality and age >= 65 years was associated with increased incidence of methicillin-resistant Staphylococcus aureus (MRSA) infections (OR 2.83, 95% CI 1.27-6.32, p = 0.01). Conclusions: MDRB-related VAP is associated with prolonged ICU stay and mechanical ventilation. Interestingly, age >= 65 years is associated with MRSA VAP. C1 [Arvanitis, Marios; Anagnostou, Theodora; Ziakas, Panayiotis D.; Mylonakis, Eleftherios] Brown Univ, Rhode Isl Hosp, Warren Alpert Med Sch, Div Infect Dis,Dept Med, Providence, RI 02903 USA. [Arvanitis, Marios; Anagnostou, Theodora; Kourkoumpetis, Themistoklis K.; Desalermos, Athanasios; Mylonakis, Eleftherios] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Infect Dis,Dept Med, Boston, MA USA. RP Mylonakis, E (reprint author), Brown Univ, Rhode Isl Hosp, Warren Alpert Med Sch, Div Infect Dis,Dept Med, Providence, RI 02903 USA. EM emylonakis@lifespan.org FU Astellas, Inc. FX Part of this work was supported through a grant from Astellas, Inc. No additional funding received for this study. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 40 TC 5 Z9 6 U1 2 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 FEB 27 PY 2014 VL 9 IS 2 AR e89984 DI 10.1371/journal.pone.0089984 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AC3BU UT WOS:000332390800063 PM 24587166 ER PT J AU Lee, SA Sinclair, E Hatano, H Hsue, PY Epling, L Hecht, FM Bangsberg, DR Martin, JN McCune, JM Deeks, SG Hunt, PW AF Lee, Sulggi A. Sinclair, Elizabeth Hatano, Hiroyu Hsue, Priscilla Y. Epling, Lorrie Hecht, Frederick M. Bangsberg, David R. Martin, Jeffrey N. McCune, Joseph M. Deeks, Steven G. Hunt, Peter W. TI Impact of HIV on CD8+T Cell CD57 Expression Is Distinct from That of CMV and Aging SO PLOS ONE LA English DT Article ID CD8(+) T-CELLS; IMMUNE RISK PROFILE; SWEDISH NONA IMMUNE; CYTOMEGALOVIRUS-INFECTION; LYMPHOCYTE SUBPOPULATIONS; ANTIRETROVIRAL THERAPY; IMMUNOSENESCENCE; INDIVIDUALS; DISEASE; REPERTOIRE AB Background: Chronic antigenic stimulation by cytomegalovirus (CMV) is thought to increase "immunosenesence'' of aging, characterized by accumulation of terminally differentiated CD28-CD8+ T cells and increased CD57, a marker of proliferative history. Whether chronic HIV infection causes similar effects is currently unclear. Methods: We compared markers of CD8+ T cell differentiation (e. g., CD28, CD27, CCR7, CD45RA) and CD57 expression on CD28-CD8+ T cells in healthy HIV-uninfected adults with and without CMV infection and in both untreated and antiretroviral therapy (ART)-suppressed HIV-infected adults with asymptomatic CMV infection. Results: Compared to HIV-uninfected adults without CMV (n = 12), those with asymptomatic CMV infection (n = 31) had a higher proportion of CD28-CD8+ T cells expressing CD57 (P = 0.005). Older age was also associated with greater proportions of CD28-CD8+ T cells expressing CD57 (rho: 0.47, P = 0.007). In contrast, untreated HIV-infected CMV+ participants (n = 55) had much lower proportions of CD28-CD8+ cells expressing CD57 than HIV-uninfected CMV+ participants (P<0.0001) and were enriched for less well-differentiated CD28-transitional memory (T-TR) CD8+ T cells (P<0.0001). Chronically HIV-infected adults maintaining ART-mediated viral suppression (n = 96) had higher proportions of CD28-CD8+ T cells expressing CD57 than untreated patients (P<0.0001), but continued to have significantly lower levels than HIV-uninfected controls (P = 0.001). Among 45 HIV-infected individuals initiating their first ART regimen, the proportion of CD28-CD8+ T cells expressing CD57 declined (P<0.0001), which correlated with a decline in percent of transitional memory CD8+ T cells, and appeared to be largely explained by a decline in CD28-CD57-CD8+ T cell counts rather than an expansion of CD28-CD57+ CD8+ T cell counts. Conclusions: Unlike CMV and aging, which are associated with terminal differentiation and proliferation of effector memory CD8+ T cells, HIV inhibits this process, expanding less well-differentiated CD28-CD8+ T cells and decreasing the proportion of CD28-CD8+ T cells that express CD57. C1 [Lee, Sulggi A.; Sinclair, Elizabeth; Hatano, Hiroyu; Hsue, Priscilla Y.; Epling, Lorrie; Hecht, Frederick M.; Martin, Jeffrey N.; McCune, Joseph M.; Deeks, Steven G.; Hunt, Peter W.] Univ Calif San Francisco, Dept Epidemiol & Biostat, Dept Med, San Francisco, CA 94143 USA. [Bangsberg, David R.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Bangsberg, David R.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Bangsberg, David R.] Mbarara Univ Sci & Technol, Dept Med, Mbarara, Uganda. RP Hunt, PW (reprint author), Univ Calif San Francisco, Dept Epidemiol & Biostat, Dept Med, San Francisco, CA 94143 USA. EM phunt@php.ucsf.edu FU National Institute of Allergy and Infectious Diseases [R56AI100765, R21 AI087035, R21AI078774, RO1 AI087145, K24AI069994, P01AI076174]; National Institutes of Mental Health [R01 MH54907]; Doris Duke Charitable Foundation [2008047]; University of California San Francisco (UCSF)/Gladstone Institute of Virology & Immunology Centers for AIDS Research (CFAR) [P30 AI027763]; UCSF Clinical and Translational Research Institute Clinical Research Center [UL1 RR024131]; Center for AIDS Prevention Studies [P30 MH62246]; CFAR Network of Integrated Systems [R24 AI067039] FX This work was supported in part by the National Institute of Allergy and Infectious Diseases (R56AI100765, R21 AI087035, R21AI078774, RO1 AI087145, K24AI069994, P01AI076174), National Institutes of Mental Health (R01 MH54907), the Doris Duke Charitable Foundation (Clinical Scientist Development Award #2008047), the University of California San Francisco (UCSF)/Gladstone Institute of Virology & Immunology Centers for AIDS Research (CFAR) (grant number P30 AI027763), the UCSF Clinical and Translational Research Institute Clinical Research Center (UL1 RR024131), the Center for AIDS Prevention Studies (P30 MH62246), and the CFAR Network of Integrated Systems (R24 AI067039). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 37 TC 25 Z9 25 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD FEB 27 PY 2014 VL 9 IS 2 AR e89444 DI 10.1371/journal.pone.0089444 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AC3BU UT WOS:000332390800023 PM 24586783 ER PT J AU Taguchi, A Kawana, K Tomio, K Yamashita, A Isobe, Y Nagasaka, K Koga, K Inoue, T Nishida, H Kojima, S Adachi, K Matsumoto, Y Arimoto, T Wada-Hiraike, O Oda, K Kang, JX Arai, H Arita, M Osuga, Y Fujii, T AF Taguchi, Ayumi Kawana, Kei Tomio, Kensuke Yamashita, Aki Isobe, Yosuke Nagasaka, Kazunori Koga, Kaori Inoue, Tomoko Nishida, Haruka Kojima, Satoko Adachi, Katsuyuki Matsumoto, Yoko Arimoto, Takahide Wada-Hiraike, Osamu Oda, Katsutoshi Kang, Jing X. Arai, Hiroyuki Arita, Makoto Osuga, Yutaka Fujii, Tomoyuki TI Matrix Metalloproteinase (MMP)-9 in Cancer-Associated Fibroblasts (CAFs) Is Suppressed by Omega-3 Polyunsaturated Fatty Acids In Vitro and In Vivo SO PLOS ONE LA English DT Article ID KAPPA-B ACTIVATION; FAT-1 TRANSGENIC MICE; TNF-ALPHA; STROMAL FIBROBLASTS; TUMOR MICROENVIRONMENT; DOCOSAHEXAENOIC ACID; ENDOTHELIAL-CELLS; LINOLEIC-ACID; COLON-CANCER; EXPRESSION AB Cancer associated fibroblasts (CAFs) are responsible for tumor growth, angiogenesis, invasion, and metastasis. Matrix metalloproteinase (MMP)-9 secreted from cancer stroma populated by CAFs is a prerequisite for cancer angiogenesis and metastasis. Omega-3 polyunsaturated fatty acids (omega-3 PUFA) have been reported to have anti-tumor effects on diverse types of malignancies. Fat-1 mice, which can convert omega-6 to omega-3 PUFA independent of diet, are useful to investigate the functions of endogenous omega-3 PUFA. To examine the effect of omega-3 PUFA on tumorigenesis, TC-1 cells, a murine epithelial cell line immortalized by human papillomavirus (HPV) oncogenes, were injected subcutaneously into fat-1 or wild type mice. Tumor growth and angiogenesis of the TC-1 tumor were significantly suppressed in fat-1 compared to wild type mice. cDNA microarray of the tumors derived from fat-1 and wild type mice revealed that MMP-9 is downregulated in fat-1 mice. Immunohistochemical study demonstrated immunoreactivity for MMP-9 in the tumor stromal fibroblasts was diffusely positive in wild type whereas focal in fat-1 mice. MMP-9 was expressed in primary cultured fibroblasts isolated from fat-1 and wild type mice but was not expressed in TC-1 cells. Co-culture of fibroblasts with TC-1 cells enhanced the expression and the proteinase activity of MMP-9, although the protease activity of MMP-9 in fat-1-derived fibroblasts was lower than that in wild type fibroblasts. Our data suggests that omega-3 PUFAs suppress MMP-9 induction and tumor angiogenesis. These findings may provide insight into mechanisms by which omega-3 PUFAs exert anti-tumor effects by modulating tumor microenvironment. C1 [Taguchi, Ayumi; Kawana, Kei; Tomio, Kensuke; Yamashita, Aki; Nagasaka, Kazunori; Koga, Kaori; Inoue, Tomoko; Nishida, Haruka; Kojima, Satoko; Adachi, Katsuyuki; Matsumoto, Yoko; Arimoto, Takahide; Wada-Hiraike, Osamu; Oda, Katsutoshi; Osuga, Yutaka; Fujii, Tomoyuki] Univ Tokyo, Grad Sch Med, Dept Obstet & Gynecol, Bunkyo Ku, Tokyo, Japan. [Isobe, Yosuke; Arai, Hiroyuki; Arita, Makoto] Univ Tokyo, Grad Sch Pharmaceut Sci, Dept Hlth Chem, Tokyo, Japan. [Kang, Jing X.] Massachusetts Gen Hosp, Dept Med, Charlestown, MA USA. [Kang, Jing X.] Harvard Univ, Sch Med, Charlestown, MA USA. RP Kawana, K (reprint author), Univ Tokyo, Grad Sch Med, Dept Obstet & Gynecol, Bunkyo Ku, 7-3-1 Hongo, Tokyo, Japan. EM kkawana-tky@umin.org; marita@mol.f.u-tokyo.ac.jp OI Nagasaka, Kazunori/0000-0002-0696-5175 FU Tokyo IGAKUKAI; Japan Science and Technology Agency Precursory Research for Embryonic Science and Technology (PRESTO); Ministry of Education, Culture, Sports, Science, and Technology of Japan FX This study was funded by Tokyo IGAKUKAI (K.K.), the Japan Science and Technology Agency Precursory Research for Embryonic Science and Technology (PRESTO) (M.A.), the Ministry of Education, Culture, Sports, Science, and Technology of Japan (M.A.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 48 TC 13 Z9 15 U1 2 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 FEB 27 PY 2014 VL 9 IS 2 AR e89605 DI 10.1371/journal.pone.0089605 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AC3BU UT WOS:000332390800030 PM 24586907 ER PT J AU Neelamegam, R Hellenbrand, T Schroeder, FA Wang, CN Hooker, JM AF Neelamegam, Ramesh Hellenbrand, Tim Schroeder, Frederick A. Wang, Changning Hooker, Jacob M. TI Imaging Evaluation of 5HT(2C) Agonists, [C-11]WAY-163909 and [C-11]/abicaserin, Formed by Pictet-Spengler Cyclization SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID 5-HT2C RECEPTOR AGONIST; SEROTONIN RECEPTORS; SELECTIVE AGONIST; MESSENGER-RNA; BASAL GANGLIA; RAT-BRAIN; WAY-163909; MICE; LOCALIZATION; LORCASERIN AB The serotonin subtype 2C (5HT(2C)) receptor is an emerging and promising drug target to treat several disorders of the human central nervous system. In this current report, two potent and selective 5HT(2C) full agonists, WAY-163909 (2) and vabicaserin (3), were radiolabeled with carbon-11 via Pictet-Spengler cyclization with [C-11]formaldehyde and used in positron emission tomography (PET) imaging. Reaction conditions were optimized to exclude the major source of isotope dilution caused by the previously unknown breakdown of N,N-dimethylformamide (DMF) to formaldehyde at high temperature under mildly acid conditions. In vivo PET imaging was utilized to evaluate the pharmacokinetics and distribution of the carbon-11 labeled 5HT(2C) agonists. Both radiolabeled molecules exhibit high blood-brain barrier (BBB) penetration and nonspecific binding, which was unaltered by preadministration of the unlabeled agonist. Our work demonstrates that Pictet-Spengler cyclization can be used to label drugs with carbon-11 to study their pharmacokinetics and for evaluation as PET radiotracers. C1 [Neelamegam, Ramesh; Schroeder, Frederick A.; Wang, Changning; Hooker, Jacob M.] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Dept Radiol, Charlestown, MA 02129 USA. [Neelamegam, Ramesh; Schroeder, Frederick A.; Wang, Changning; Hooker, Jacob M.] Harvard Univ, Sch Med, Charlestown, MA 02129 USA. [Hellenbrand, Tim] Univ Munich, Dept Pharm, D-81377 Munich, Germany. [Schroeder, Frederick A.] Massachusetts Gen Hosp, Ctr Human Genet Res, Dept Psychiat, Boston, MA 02114 USA. [Schroeder, Frederick A.] Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Hooker, JM (reprint author), Athinoula A Martinos Ctr Biomed Imaging, Bldg 149,13th St,Suite 2301, Charlestown, MA 02129 USA. EM hooker@nmr.mgh.harvard.edu FU National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health [P41EB015896]; National Institutes of Health [1R21MH093874]; NIH [S10RR017208, S10RR026666, S10RR022976, S10RR019933, S10RR029495] FX This research was carried out at the Athinoula A. Martinos Center for Biomedical Imaging at the Massachusetts General Hospital, using resources provided by the Center for Functional Neuroimaging Technologies, P41EB015896, a P41 Regional Resource supported by the National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health. This project was funded by a grant from the National Institutes of Health (Grant 1R21MH093874). This work also involved the use of instrumentation supported by the NIH Shared Instrumentation Grant Program and/or High-End Instrumentation Grant Program, specifically, Grants S10RR017208, S10RR026666, S10RR022976, S10RR019933, and S10RR029495. We thank members of the Hooker research laboratory for helpful discussions. The authors are grateful to Grae Arabasz, Shirley Hsu, Joseph Mandeville, and Helen Deng for assistance during NHP imaging and to Christian Moseley and Stephen Carlin for technical assistance in the radiochemistry laboratory. The authors also thank Prof. Ritter's research group, Department of Chemistry, Harvard University, MA, for single crystal X-ray data collection. NR 33 TC 10 Z9 11 U1 0 U2 9 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 EI 1520-4804 J9 J MED CHEM JI J. Med. Chem. PD FEB 27 PY 2014 VL 57 IS 4 BP 1488 EP 1494 DI 10.1021/jm401802f PG 7 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA AC0LV UT WOS:000332187700026 PM 24491146 ER PT J AU Kim, TH Li, FG Ferreiro-Neira, I Ho, LL Luyten, A Nalapareddy, K Long, H Verzi, M Shivdasani, RA AF Kim, Tae-Hee Li, Fugen Ferreiro-Neira, Isabel Ho, Li-Lun Luyten, Annouck Nalapareddy, Kodandaramireddy Long, Henry Verzi, Michael Shivdasani, Ramesh A. TI Broadly permissive intestinal chromatin underlies lateral inhibition and cell plasticity SO NATURE LA English DT Article ID EMBRYONIC STEM-CELLS; ATONAL HOMOLOG 1; HUMAN GENOME; SECRETASE INHIBITORS; GENE-EXPRESSION; DIFFERENTIATION; ENHANCERS; REVEALS; LINEAGE; MATH1 AB Cells differentiate when transcription factors bind accessible cis-regulatory elements to establish specific gene expression programs. In differentiating embryonic stem cells, chromatin at lineage-restricted genes becomes sequentially accessible(1-4), probably by means of 'pioneer' transcription factor activity(5), but tissues may use other strategies in vivo. Lateral inhibition is a pervasive process in which one cell forces a different identity on its neighbours(6), and it is unclear how chromatin in equipotent progenitors undergoing lateral inhibition quickly enables distinct, transiently reversible cell fates. Here we report the chromatin and transcriptional underpinnings of differentiation in mouse small intestine crypts, where notch signalling mediates lateral inhibition to assign progenitor cells into absorptive or secretory lineages(7-9). Transcript profiles in isolated LGR5(+) intestinal stem cells(10) and secretory and absorptive progenitors indicated that each cell population was distinct and the progenitors specified. Nevertheless, secretory and absorptive progenitors showed comparable levels of H3K4me2 and H3K27ac histone marks and DNase I hypersensitivity-signifying accessible, permissive chromatin-at most of the same cis-elements. Enhancers acting uniquely in progenitors were well demarcated in LGR5(+) intestinal stem cells, revealing early priming of chromatin for divergent transcriptional programs, and retained active marks well after lineages were specified. On this chromatin background, ATOH1, a secretory-specific transcription factor, controls lateral inhibition through delta-like notch ligand genes and also drives the expression of numerous secretory lineage genes. Depletion of ATOH1 from specified secretory cells converted them into functional enterocytes, indicating prolonged responsiveness of marked enhancers to the presence or absence of a key transcription factor. Thus, lateral inhibition and intestinal crypt lineage plasticity involve interaction of a lineage-restricted transcription factor with broadly permissive chromatin established in multipotent stem cells. C1 [Kim, Tae-Hee; Li, Fugen; Ferreiro-Neira, Isabel; Ho, Li-Lun; Luyten, Annouck; Nalapareddy, Kodandaramireddy; Long, Henry; Verzi, Michael; Shivdasani, Ramesh A.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Kim, Tae-Hee; Li, Fugen; Ferreiro-Neira, Isabel; Ho, Li-Lun; Luyten, Annouck; Nalapareddy, Kodandaramireddy; Long, Henry; Verzi, Michael; Shivdasani, Ramesh A.] Dana Farber Canc Inst, Ctr Funct Canc Epigenet, Boston, MA 02215 USA. [Kim, Tae-Hee; Ferreiro-Neira, Isabel; Ho, Li-Lun; Luyten, Annouck; Nalapareddy, Kodandaramireddy; Verzi, Michael; Shivdasani, Ramesh A.] Brigham & Womens Hosp, Dept Med, Boston, MA 02215 USA. [Kim, Tae-Hee; Ferreiro-Neira, Isabel; Ho, Li-Lun; Luyten, Annouck; Nalapareddy, Kodandaramireddy; Verzi, Michael; Shivdasani, Ramesh A.] Harvard Univ, Sch Med, Boston, MA 02215 USA. RP Shivdasani, RA (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. EM ramesh_shivdasani@dfci.harvard.edu OI Nalapareddy, Kodandaramireddy/0000-0003-3290-5114 FU NIH [R01DK082889, R01DK081113, K99DK095983, K01DK088868, P50CA127003]; North American Neuroendocrine Tumor Society; Caring For Carcinoid Foundation FX This work was supported by NIH grants R01DK082889 and R01DK081113 (R. A. S.), K99DK095983 (T.-H. K.), K01DK088868 (M. V.), and P50CA127003; a North American Neuroendocrine Tumor Society fellowship (T.-H. K.); and the Caring For Carcinoid Foundation (R. A. S.). We thank S. Robine for villin-CreER-T2 mice; T. Honjo and S. Artavanis-Tsakonas for Rbpjfl mice; J. Johnson for ATOH1 antibody; D. Podolsky for TFF3 antibody; and M. Brown and P. Cejas for discussions. NR 41 TC 55 Z9 56 U1 2 U2 22 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 FEB 27 PY 2014 VL 506 IS 7489 BP 511 EP + DI 10.1038/nature12903 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AC0DN UT WOS:000332165100043 PM 24413398 ER PT J AU Drain, PK Losina, E Coleman, SM Giddy, J Ross, D Katz, JN Walensky, RP Freedberg, KA Bassett, IV AF Drain, Paul K. Losina, Elena Coleman, Sharon M. Giddy, Janet Ross, Douglas Katz, Jeffrey N. Walensky, Rochelle P. Freedberg, Kenneth A. Bassett, Ingrid V. TI Diagnostic accuracy of a point-of-care urine test for tuberculosis screening among newly-diagnosed hiv-infected adults: a prospective, clinic-based study SO BMC INFECTIOUS DISEASES LA English DT Article DE Tuberculosis; HIV/AIDS; Lipoarabinomannan (LAM); Urine; Diagnostic testing; Screening; South Africa ID ANTIRETROVIRAL THERAPY; PULMONARY TUBERCULOSIS; HOSPITALIZED-PATIENTS; SPUTUM SAMPLES; SOUTH-AFRICA; LAM-ELISA; LOW-COST; LIPOARABINOMANNAN; ASSAY; RESISTANCE AB Background: A rapid diagnostic test for active tuberculosis (TB) at the clinical point-of-care could expedite case detection and accelerate TB treatment initiation. We assessed the diagnostic accuracy of a rapid urine lipoarabinomannan (LAM) test for TB screening among HIV-infected adults in a TB-endemic setting. Methods: We prospectively enrolled newly-diagnosed HIV-infected adults (>= 18 years) at 4 outpatient clinics in Durban from Oct 2011 May 2012, excluding those on TB therapy. A physician evaluated all participants and offered CD4 cell count testing. Trained study nurses collected a sputum sample for acid-fast bacilli smear microscopy (AFB) and mycobacterial culture, and performed urine LAM testing using Determine(TM) TB LAM in the clinic. The presence of a band regardless of intensity on the urine LAM test was considered positive. We defined as the gold standard for active pulmonary TB a positive sputum culture for Mycobacterium tuberculosis. Diagnostic accuracy of urine LAM was assessed, alone and in combination with smear microscopy, and stratified by CD4 cell count. Results: Among 342 newly-diagnosed HIV-infected participants, 190 (56%) were male, mean age was 35.6 years, and median CD4 was 182/ mm(3). Sixty participants had culture-positive pulmonary TB, resulting in an estimated prevalence of 17.5% (95% CI 13.7-22.0%). Forty-five (13.2%) participants were urine LAM positive. Mean time from urine specimen collection to LAM test result was 40 minutes (95% CI 34-46 minutes). Urine LAM test sensitivity was 28.3% (95% CI 17.5-41.4) overall, and 37.5% (95% CI 21.1-56.3) for those with CD4 count < 100/mm(3), while specificity was 90.1% ( 95% CI 86.0-93.3) overall, and 86.9% (95% CI 75.8-94.2) for those with CD4 < 100/mm(3). When combined with sputum AFB (either test positive), sensitivity increased to 38.3% (95% CI 26.0-51.8), but specificity decreased to 85.8% (95% CI 81.1-89.7). Conclusions: In this prospective, clinic-based study with trained nurses, a rapid urine LAM test had low sensitivity for TB screening among newly-diagnosed HIV-infected adults, but improved sensitivity when combined with sputum smear microscopy. C1 [Drain, Paul K.; Losina, Elena; Walensky, Rochelle P.; Freedberg, Kenneth A.; Bassett, Ingrid V.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Drain, Paul K.; Losina, Elena; Walensky, Rochelle P.; Freedberg, Kenneth A.; Bassett, Ingrid V.] Massachusetts Gen Hosp, Med Practice Evaluat Ctr, Boston, MA 02114 USA. [Drain, Paul K.; Losina, Elena; Katz, Jeffrey N.; Walensky, Rochelle P.; Freedberg, Kenneth A.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Losina, Elena; Coleman, Sharon M.] Boston Univ, Sch Publ Hlth, Boston, MA USA. [Giddy, Janet] McCord Hosp, Durban, South Africa. [Ross, Douglas] St Marys Hosp, Durban, South Africa. [Drain, Paul K.] Massachusetts Gen Hosp, Dept Med, Med Practice Evaluat Ctr, Boston, MA 02114 USA. RP Drain, PK (reprint author), Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. EM pdrain@partners.org OI Walensky, Rochelle P./0000-0002-8795-379X; Drain, Paul/0000-0003-3300-3817 FU Harvard Global Health Institute; Fogarty International Clinical Research Scholars and Fellows Program at Vanderbilt University [R24 TW007988]; Program in AIDS Clinical Research Training Grant [T32 AI007433]; National Institute of Mental Health [R01 MH090326, R01 MH073445]; National Institute of Allergy and Infectious Disease [R01 AI058736]; Harvard University Center for AIDS Research [P30 AI060354]; National Institute of Arthritis and Musculoskeletal and Skin Diseases [K24 AR057827]; National Center for Research Resources [UL1 RR 025758] FX This research was supported by the Harvard Global Health Institute, the Fogarty International Clinical Research Scholars and Fellows Program at Vanderbilt University (R24 TW007988), The Program in AIDS Clinical Research Training Grant (T32 AI007433) (PKD); the National Institute of Mental Health R01 MH090326 (IVB) and R01 MH073445 (RPW); the National Institute of Allergy and Infectious Disease R01 AI058736 (KAF); the Harvard University Center for AIDS Research P30 AI060354; the National Institute of Arthritis and Musculoskeletal and Skin Diseases K24 AR057827 (EL); the National Center for Research Resources (the Harvard Catalyst UL1 RR 025758); and the Claflin Distinguished Scholar Award (IVB). NR 28 TC 15 Z9 15 U1 0 U2 10 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2334 J9 BMC INFECT DIS JI BMC Infect. Dis. PD FEB 26 PY 2014 VL 14 AR 110 DI 10.1186/1471-2334-14-110 PG 9 WC Infectious Diseases SC Infectious Diseases GA AC6JS UT WOS:000332629200002 PM 24571362 ER PT J AU Farrar, CT William, CM Hudry, E Hashimoto, T Hyman, BT AF Farrar, Christian T. William, Christopher M. Hudry, Eloise Hashimoto, Tadafumi Hyman, Bradley T. TI RNA Aptamer Probes as Optical Imaging Agents for the Detection of Amyloid Plaques SO PLOS ONE LA English DT Article ID A-BETA OLIGOMERS; ALZHEIMERS-DISEASE; TRANSGENIC MICE; SENILE PLAQUES; ANTIBODIES RECOGNIZE; EMERGING CLASS; SYNAPSE LOSS; IN-VIVO; PROTEIN; BRAIN AB Optical imaging using multiphoton microscopy and whole body near infrared imaging has become a routine part of biomedical research. However, optical imaging methods rely on the availability of either small molecule reporters or genetically encoded fluorescent proteins, which are challenging and time consuming to develop. While directly labeled antibodies can also be used as imaging agents, antibodies are species specific, can typically not be tagged with multiple fluorescent reporters without interfering with target binding, and are bioactive, almost always eliciting a biological response and thereby influencing the process that is being studied. We examined the possibility of developing highly specific and sensitive optical imaging agents using aptamer technology. We developed a fluorescently tagged anti-A beta RNA aptamer, beta 55, which binds amyloid plaques in both ex vivo human Alzheimer's disease brain tissue and in vivo APP/PS1 transgenic mice. Diffuse beta 55 positive halos, attributed to oligomeric A beta, were observed surrounding the methoxy-XO4 positive plaque cores. Dot blots of synthetic A beta aggregates provide further evidence that beta 55 binds both fibrillar and non-fibrillar A beta. The high binding affinity, the ease of probe development, and the ability to incorporate multiple and multimodal imaging reporters suggest that RNA aptamers may have complementary and perhaps advantageous properties compared to conventional optical imaging probes and reporters. C1 [Farrar, Christian T.] Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Farrar, Christian T.; William, Christopher M.; Hudry, Eloise; Hashimoto, Tadafumi; Hyman, Bradley T.] Harvard Univ, Sch Med, Charlestown, MA USA. [William, Christopher M.] Massachusetts Gen Hosp, Dept Pathol, Charlestown, MA USA. [Hudry, Eloise; Hashimoto, Tadafumi; Hyman, Bradley T.] Massachusetts Gen Hosp, Dept Neurol, Charlestown, MA USA. RP Farrar, CT (reprint author), Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. EM cfarrar@nmr.mgh.harvard.edu OI William, Christopher/0000-0001-8933-1639 FU Massachusetts Alzheimer's Disease Research Center National Institutes of Health (NIH) [P50-AG05134]; NIH [K25-AG029415, K08-NS069811, R01-AG08487] FX This work was supported by the Massachusetts Alzheimer's Disease Research Center National Institutes of Health (NIH) grant P50-AG05134 and by NIH grants K25-AG029415, K08-NS069811, and R01-AG08487. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 52 TC 8 Z9 9 U1 6 U2 53 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 FEB 26 PY 2014 VL 9 IS 2 AR e89901 DI 10.1371/journal.pone.0089901 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AC3BC UT WOS:000332389000108 PM 24587111 ER PT J AU Robertson, AL Holmes, GR Bojarczuk, AN Burgon, J Loynes, CA Chimen, M Sawtell, AK Hamza, B Willson, J Walmsley, SR Anderson, SR Coles, MC Farrow, SN Solari, R Jones, S Prince, LR Irimia, D Rainger, GE Kadirkamanathan, V Whyte, MKB Renshaw, SA AF Robertson, Anne L. Holmes, Geoffrey R. Bojarczuk, Aleksandra N. Burgon, Joseph Loynes, Catherine A. Chimen, Myriam Sawtell, Amy K. Hamza, Bashar Willson, Joseph Walmsley, Sarah R. Anderson, Sean R. Coles, Mark C. Farrow, Stuart N. Solari, Roberto Jones, Simon Prince, Lynne R. Irimia, Daniel Rainger, G. Ed Kadirkamanathan, Visakan Whyte, Moira K. B. Renshaw, Stephen A. TI A Zebrafish Compound Screen Reveals Modulation of Neutrophil Reverse Migration as an Anti-Inflammatory Mechanism SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID NF-KAPPA-B; INFLAMMATORY CELL APOPTOSIS; TRANSGENIC ZEBRAFISH; ENDOTHELIAL-CELLS; KINASE INHIBITOR; GENE-EXPRESSION; RAW-264.7 CELLS; IN-VIVO; RESOLUTION; ADHESION AB Diseases of failed inflammation resolution are common and largely incurable. Therapeutic induction of inflammation resolution is an attractive strategy to bring about healing without increasing susceptibility to infection. However, therapeutic targeting of inflammation resolution has been hampered by a lack of understanding of the underlying molecular controls. To address this drug development challenge, we developed an in vivo screen for proresolution therapeutics in a transgenic zebrafish model. Inflammation induced by sterile tissue injury was assessed for accelerated resolution in the presence of a library of known compounds. Of the molecules with proresolution activity, tanshinone IIA, derived from a Chinese medicinal herb, potently induced inflammation resolution in vivo both by induction of neutrophil apoptosis and by promoting reverse migration of neutrophils. Tanshinone IIA blocked proinflammatory signals in vivo, and its effects are conserved in human neutrophils, supporting a potential role in treating human inflammation and providing compelling evidence of the translational potential of this screening strategy. C1 [Robertson, Anne L.; Bojarczuk, Aleksandra N.; Burgon, Joseph; Loynes, Catherine A.; Whyte, Moira K. B.; Renshaw, Stephen A.] Univ Sheffield, Med Res Council Ctr Dev & Biomed Genet, Sheffield S10 2TN, S Yorkshire, England. [Robertson, Anne L.; Loynes, Catherine A.; Willson, Joseph; Walmsley, Sarah R.; Prince, Lynne R.; Whyte, Moira K. B.; Renshaw, Stephen A.] Univ Sheffield, Dept Infect & Immun, Sheffield S10 2RX, S Yorkshire, England. [Holmes, Geoffrey R.; Anderson, Sean R.; Kadirkamanathan, Visakan] Univ Sheffield, Dept Automat Control & Syst Engn, Sheffield S1 3JD, S Yorkshire, England. [Chimen, Myriam; Rainger, G. Ed] Univ Birmingham, Sch Clin & Expt Med, Ctr Cardiovasc Sci, Birmingham B15 2TT, W Midlands, England. [Sawtell, Amy K.; Coles, Mark C.] Univ York, Dept Biol, Ctr Immunol & Infect, York YO10 5DD, N Yorkshire, England. [Hamza, Bashar; Irimia, Daniel] Harvard Univ, Sch Med, Dept Surg, Massachusetts Gen Hosp, Boston, MA 02114 USA. [Farrow, Stuart N.] GlaxoSmithKline, Resp Therapy Area, Stevenage SG1 2NY, Herts, England. [Solari, Roberto] Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, London W2 1PG, England. [Jones, Simon] Univ Sheffield, Dept Chem, Sheffield S3 7HF, S Yorkshire, England. RP Renshaw, SA (reprint author), Univ Sheffield, Med Res Council Ctr Dev & Biomed Genet, Sheffield S10 2TN, S Yorkshire, England. EM s.a.renshaw@sheffield.ac.uk RI Jones, Simon/F-6940-2010; Chimen, Myriam/D-6344-2015; Renshaw, Stephen/E-6192-2010; OI Jones, Simon/0000-0001-8043-7998; Chimen, Myriam/0000-0002-3567-1731; Renshaw, Stephen/0000-0003-1790-1641; Irimia, Daniel/0000-0001-7347-2082; Anderson, Sean/0000-0002-7452-5681 FU MRC [G0701932]; Wellcome Trust [098516, GR077544AIA]; MRC Center grant [G0700091]; MRC Pump-Priming Translational Research Initiative grant [G0802527] FX Funding: This work was supported by an MRC Senior Clinical Fellowship (G0701932, to S. A. R.), a Wellcome Trust Senior Research Fellowship in Clinical Science (098516, to S. R. W.), an MRC Center grant (G0700091), and an MRC Pump-Priming Translational Research Initiative grant (G0802527). Microscopy studies were supported by a Wellcome Trust grant to the Molecular Biology and Biotechnology/Biomedical Science Light Microscopy Facility (GR077544AIA). NR 52 TC 26 Z9 27 U1 3 U2 38 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 FEB 26 PY 2014 VL 6 IS 225 AR 225ra29 DI 10.1126/scitranslmed.3007672 PG 10 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA AC4EN UT WOS:000332473800006 PM 24574340 ER PT J AU Friedberg, MW Schneider, EC Rosenthal, MB Volpp, KG Werner, RM AF Friedberg, Mark W. Schneider, Eric C. Rosenthal, Meredith B. Volpp, Kevin G. Werner, Rachel M. TI Association Between Participation in a Multipayer Medical Home Intervention and Changes in Quality, Utilization, and Costs of Care SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID LONGITUDINAL DATA-ANALYSIS; STRUCTURAL CAPABILITIES; TRANSFORMATION; EFFICIENCY; MODELS; TRIAL; WILL AB IMPORTANCE Interventions to transform primary care practices into medical homes are increasingly common, but their effectiveness in improving quality and containing costs is unclear. OBJECTIVE To measure associations between participation in the Southeastern Pennsylvania Chronic Care Initiative, one of the earliest and largest multipayer medical home pilots conducted in the United States, and changes in the quality, utilization, and costs of care. DESIGN, SETTING, AND PARTICIPANTS Thirty-two volunteering primary care practices participated in the pilot (conducted from June 1, 2008, to May 31, 2011). We surveyed pilot practices to compare their structural capabilities at the pilot's beginning and end. Using claims data from 4 participating health plans, we compared changes (in each year, relative to before the intervention) in the quality, utilization, and costs of care delivered to 64 243 patients who were attributed to pilot practices and 55 959 patients attributed to 29 comparison practices (selected for size, specialty, and location similar to pilot practices) using a difference-in-differences design. EXPOSURES Pilot practices received disease registries and technical assistance and could earn bonus payments for achieving patient-centered medical home recognition by the National Committee for Quality Assurance (NCQA). MAIN OUTCOMES AND MEASURES Practice structural capabilities; performance on 11 quality measures for diabetes, asthma, and preventive care; utilization of hospital, emergency department, and ambulatory care; standardized costs of care. RESULTS Pilot practices successfully achieved NCQA recognition and adopted new structural capabilities such as registries to identify patients overdue for chronic disease services. Pilot participation was associated with statistically significantly greater performance improvement, relative to comparison practices, on 1 of 11 investigated quality measures: nephropathy screening in diabetes (adjusted performance of 82.7% vs 71.7% by year 3, P<.001). Pilot participation was not associated with statistically significant changes in utilization or costs of care. Pilot practices accumulated average bonuses of $92 000 per primary care physician during the 3-year intervention. CONCLUSIONS AND RELEVANCE A multipayer medical home pilot, in which participating practices adopted new structural capabilities and received NCQA certification, was associated with limited improvements in quality and was not associated with reductions in utilization of hospital, emergency department, or ambulatory care services or total costs over 3 years. These findings suggest that medical home interventions may need further refinement. C1 [Friedberg, Mark W.; Schneider, Eric C.] RAND Corp, Boston, MA USA. [Friedberg, Mark W.; Schneider, Eric C.] Brigham & Womens Hosp, Div Gen Internal Med, Boston, MA 02115 USA. [Friedberg, Mark W.; Schneider, Eric C.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Schneider, Eric C.; Rosenthal, Meredith B.] Harvard Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA 02115 USA. [Volpp, Kevin G.; Werner, Rachel M.] Philadelphia VA Med Ctr, Ctr Hlth Equ Res & Promot, Philadelphia, PA USA. [Volpp, Kevin G.] Univ Penn, Perelman Sch Med, Ctr Hlth Incent & Behav Econ, Philadelphia, PA 19104 USA. [Volpp, Kevin G.; Werner, Rachel M.] Univ Penn, Div Gen Internal Med, Perelman Sch Med, Philadelphia, PA 19104 USA. [Volpp, Kevin G.] Wharton Business Sch, Dept Hlth Care Management, Philadelphia, PA USA. [Volpp, Kevin G.] Penn Med Ctr Hlth Care Innovat, Philadelphia, PA USA. RP Friedberg, MW (reprint author), 20 Pk Plaza,Ste 920, Boston, MA 02116 USA. EM mfriedbe@rand.org OI Rosenthal, Meredith/0000-0003-3410-0184; Schneider, Eric/0000-0002-1132-5084 FU Commonwealth Fund; Aetna FX This study was sponsored by the Commonwealth Fund and Aetna. NR 42 TC 139 Z9 139 U1 5 U2 33 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 FEB 26 PY 2014 VL 311 IS 8 BP 815 EP 825 DI 10.1001/jama.2014.353 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA AB4XQ UT WOS:000331793700021 PM 24570245 ER PT J AU Glass, K Girvan, M AF Glass, Kimberly Girvan, Michelle TI Annotation Enrichment Analysis: An Alternative Method for Evaluating the Functional Properties of Gene Sets SO SCIENTIFIC REPORTS LA English DT Article ID T-CELL-LYMPHOMA; BREAST-CANCER; EXPRESSION PROFILES; DIFFERENTIAL EXPRESSION; MOLECULAR SIGNATURE; CURATED DATABASE; IMMUNE-RESPONSE; P53 STATUS; PROGNOSIS; PROLIFERATION AB Gene annotation databases (compendiums maintained by the scientific community that describe the biological functions performed by individual genes) are commonly used to evaluate the functional properties of experimentally derived gene sets. Overlap statistics, such as Fishers Exact test (FET), are often employed to assess these associations, but don't account for non-uniformity in the number of genes annotated to individual functions or the number of functions associated with individual genes. We find FET is strongly biased toward over-estimating overlap significance if a gene set has an unusually high number of annotations. To correct for these biases, we develop Annotation Enrichment Analysis (AEA), which properly accounts for the non-uniformity of annotations. We show that AEA is able to identify biologically meaningful functional enrichments that are obscured by numerous false-positive enrichment scores in FET, and we therefore suggest it be used to more accurately assess the biological properties of gene sets. C1 [Glass, Kimberly] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Glass, Kimberly] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Glass, Kimberly; Girvan, Michelle] Univ Maryland, Dept Phys, College Pk, MD 20742 USA. [Girvan, Michelle] Univ Maryland, Inst Phys Sci & Technol, College Pk, MD 20742 USA. [Girvan, Michelle] Santa Fe Inst, Santa Fe, NM 87501 USA. RP Glass, K (reprint author), Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. EM kglass@jimmy.harvard.edu NR 73 TC 11 Z9 11 U1 1 U2 12 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD FEB 26 PY 2014 VL 4 AR 4191 DI 10.1038/srep04191 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AB6HQ UT WOS:000331888600002 PM 24569707 ER PT J AU Anderson, RI Becker, HC Adams, BL Jesudason, CD Rorick-Kehn, LM AF Anderson, Rachel I. Becker, Howard C. Adams, Benjamin L. Jesudason, Cynthia D. Rorick-Kehn, Linda M. TI Orexin-1 and orexin-2 receptor antagonists reduce ethanol self-administration in high-drinking rodent models SO FRONTIERS IN NEUROSCIENCE LA English DT Article DE hypocretins/orexins; ethanol consumption; operant progressive ratio; P rat; C57BL/6J mouse ID PREFERRING P RATS; ALCOHOL-SEEKING; OREXIN/HYPOCRETIN; ADDICTION; INVOLVEMENT; ACTIVATION; AROUSAL; NEURONS; SYSTEM; REWARD AB To examine the role of orexin-1 and orexin-2 receptor activity on ethanol self-administration, compounds that differentially target orexin (OX) receptor subtypes were assessed in various self-administration paradigms using high-drinking rodent models. Effects of the OX1 antagonist SB334867, the OX2 antagonist LSN2424100, and the mixed OX1/2 antagonist almorexant (ACT-078573) on home cage ethanol consumption were tested in ethanol-preferring (P) rats using a 2-bottle choice procedure. In separate experiments, effects of SB334867, LSN2424100, and almorexant on operant ethanol self-administration were assessed in P rats maintained on a progressive ratio operant schedule of reinforcement. In a third series of experiments, SB334867 LSN2424100, and almorexant were administered to ethanol-preferring C57BL/6J mice to examine effects of OX receptor blockade on ethanol intake in a binge-like drinking (drinking-in-the-dark) model. In P rats with chronic home cage free-choice ethanol access, SB334867 and almorexant significantly reduced ethanol intake, but almorexant also reduced water intake, suggesting non-specific effects on consummatory behavior. In the progressive ratio operant experiments, LSN2424100 and almorexant reduced breakpoints and ethanol consumption in P rats, whereas the almorexant inactive enantiomer and SB334867 did not significantly affect the motivation to consume ethanol. As expected, vehicle-injected mice exhibited binge-like drinking patterns in the drinking-in-the-dark model. All three OX antagonists reduced both ethanol intake and resulting blood ethanol concentrations relative to vehicle-injected controls, but SB334867 and LSN2424100 also reduced sucrose consumption in a different cohort of mice, suggesting non-specific effects. Collectively, these results contribute to a growing body of evidence indicating that OX1 and OX2 receptor activity influences ethanol self-administration, although the effects may not be selective for ethanol consumption. C1 [Anderson, Rachel I.; Becker, Howard C.] Med Univ S Carolina, Charleston, SC 29425 USA. [Anderson, Rachel I.; Becker, Howard C.] Charleston Alcohol Res Ctr, Charleston, SC USA. [Becker, Howard C.] Ralph H Johnson VA Med Ctr, Charleston, SC 29401 USA. [Adams, Benjamin L.; Jesudason, Cynthia D.; Rorick-Kehn, Linda M.] Eli Lilly & Co, Lilly Res Labs, Indianapolis, IN 46285 USA. RP Rorick-Kehn, LM (reprint author), Lilly Corp Ctr, Lilly Res Labs, Neurosci Discovery Res, DC0510, Indianapolis, IN 46285 USA. EM rorickkehnlm@lilly.com OI Anderson, Rachel/0000-0002-6671-4810 FU Eli Lilly and Company; NIH/NIAAA [P50 AA010761, U01 AA014095, U01 AA020929, T32 AA007474]; Department of Veterans Affairs FX Financial support for P-rat studies was provided by Eli Lilly and Company. Mouse studies were supported by NIH/NIAAA grants to Howard C. Becker (P50 AA010761, U01 AA014095, and U01 AA020929) and the Department of Veterans Affairs. Rachel I. Anderson is supported by NIH/NIAAA grant T32 AA007474. NR 31 TC 16 Z9 16 U1 0 U2 4 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1662-453X J9 FRONT NEUROSCI-SWITZ JI Front. Neurosci. PD FEB 25 PY 2014 VL 8 AR 33 DI 10.3389/fnins.2014.00033 PG 9 WC Neurosciences SC Neurosciences & Neurology GA AW7ED UT WOS:000346426500002 PM 24616657 ER PT J AU Zhong, J Sharma, J Raju, R Palapetta, SM Prasad, TSK Huang, TC Yoda, A Tyner, JW van Bodegom, D Weinstock, DM Ziegler, SF Pandey, A AF Zhong, Jun Sharma, Jyoti Raju, Rajesh Palapetta, Shyam Mohan Prasad, T. S. Keshava Huang, Tai-Chung Yoda, Akinori Tyner, Jeffrey W. van Bodegom, Diederik Weinstock, David M. Ziegler, Steven F. Pandey, Akhilesh TI TSLP signaling pathway map: a platform for analysis of TSLP-mediated signaling SO DATABASE-THE JOURNAL OF BIOLOGICAL DATABASES AND CURATION LA English DT Article ID THYMIC STROMAL LYMPHOPOIETIN; ACUTE LYMPHOBLASTIC-LEUKEMIA; IGM(+) B-CELLS; CD4(+) T-CELLS; BIOLOGICAL PATHWAYS; HUMAN TROPHOBLASTS; IN-VITRO; EXPRESSION; RECEPTOR; PROLIFERATION AB Thymic stromal lymphopoietin (TSLP) is a four-helix bundle cytokine that plays a critical role in the regulation of immune responses and in the differentiation of hematopoietic cells. TSLP signals through a heterodimeric receptor complex consisting of an interleukin-7 receptor alpha chain and a unique TSLP receptor (TSLPR) [ also known as cytokine receptor-like factor 2 (CRLF2)]. Cellular targets of TSLP include dendritic cells, B cells, mast cells, regulatory T (Treg) cells and CD4+ and CD8+ T cells. The TSLP/TSLPR axis can activate multiple signaling transduction pathways including the JAK/STAT pathway and the PI-3 kinase pathway. Aberrant TSLP/TSLPR signaling has been associated with a variety of human diseases including asthma, atopic dermatitis, nasal polyposis, inflammatory bowel disease, eosinophilic eosophagitis and, most recently, acute lymphoblastic leukemia. A centralized resource of the TSLP signaling pathway cataloging signaling events is not yet available. In this study, we present a literature-annotated resource of reactions in the TSLP signaling pathway. This pathway map is publicly available through NetPath (http://www.netpath.org/), an open access signal transduction pathway resource developed previously by our group. This map includes 236 molecules and 252 reactions that are involved in TSLP/TSLPR signaling pathway. We expect that the TSLP signaling pathway map will provide a rich resource to study the biology of this important cytokine as well as to identify novel therapeutic targets for diseases associated with dysregulated TSLP/TSLPR signaling. C1 [Zhong, Jun; Huang, Tai-Chung; Pandey, Akhilesh] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD 21205 USA. [Zhong, Jun; Huang, Tai-Chung; Pandey, Akhilesh] Johns Hopkins Univ, Sch Med, Dept Biol Chem, Baltimore, MD 21205 USA. [Zhong, Jun; Huang, Tai-Chung; Pandey, Akhilesh] Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21205 USA. [Zhong, Jun; Huang, Tai-Chung; Pandey, Akhilesh] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. [Sharma, Jyoti; Raju, Rajesh; Palapetta, Shyam Mohan; Prasad, T. S. Keshava] Inst Bioinformat, Bangalore 560066, Karnataka, India. [Sharma, Jyoti; Prasad, T. S. Keshava] Manipal Univ, Manipal 576104, India. [Palapetta, Shyam Mohan; Prasad, T. S. Keshava] Pondicherry Univ, Sch Life Sci, Ctr Excellence Bioinformat, Pondicherry 605014, India. [Yoda, Akinori; van Bodegom, Diederik; Weinstock, David M.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Tyner, Jeffrey W.] Oregon Hlth & Sci Univ, Knight Canc Inst, Div Hematol & Med Oncol, Portland, OR 97239 USA. [Ziegler, Steven F.] Benaroya Res Inst Virginia Mason, Program Immunol, Seattle, WA 98101 USA. RP Pandey, A (reprint author), Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, 733 N Broadway, Baltimore, MD 21205 USA. EM pandey@jhmi.edu RI Prasad, T. S. Keshava/F-7631-2010; Zhong, Jun/D-1662-2010; OI Prasad, T. S. Keshava/0000-0002-6206-2384; Huang, Tai-Chung/0000-0002-1625-7295; Zhong, Jun/0000-0003-3148-4143; Palapetta, Shyam Mohan/0000-0002-7674-1310 FU National Heart Lung and Blood Institute [HHSN268201000032C]; NIH Roadmap grant 'Technology Center for Networks and Pathways' [U54 GM103520]; Council of Scientific and Industrial Research (CSIR) FX National Heart Lung and Blood Institute (HHSN268201000032C to A. P.) and an NIH Roadmap grant 'Technology Center for Networks and Pathways' (U54 GM103520 to A. P.). Senior Research fellowship award from Council of Scientific and Industrial Research (CSIR) (to J. S. and S.M.P.). NR 57 TC 15 Z9 15 U1 0 U2 8 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1758-0463 J9 DATABASE-OXFORD JI Database PD FEB 25 PY 2014 AR bau007 DI 10.1093/database/bau007 PG 8 WC Mathematical & Computational Biology SC Mathematical & Computational Biology GA AF1ZA UT WOS:000334511200001 ER PT J AU Nunes, MCP Tan, TC Elmariah, S do Lago, R Margey, R Cruz-Gonzalez, I Zheng, H Handschumacher, MD Inglessis, I Palacios, IF Weyman, AE Hung, J AF Nunes, Maria Carmo P. Tan, Timothy C. Elmariah, Sammy do Lago, Rodrigo Margey, Ronan Cruz-Gonzalez, Ignacio Zheng, Hui Handschumacher, Mark D. Inglessis, Ignacio Palacios, Igor F. Weyman, Arthur E. Hung, Judy TI The Echo Score Revisited Impact of Incorporating Commissural Morphology and Leaflet Displacement to the Prediction of Outcome for Patients Undergoing Percutaneous Mitral Valvuloplasty SO CIRCULATION LA English DT Article DE balloon valvuloplasty; echocardiography; mitral valve stenosis ID BALLOON VALVULOPLASTY; INOUE BALLOON; ECHOCARDIOGRAPHIC-ASSESSMENT; VALVE MORPHOLOGY; ROC CURVE; FOLLOW-UP; REGURGITATION; VALVOTOMY; IMMEDIATE; AREA AB Background Current echocardiographic scoring systems for percutaneous mitral valvuloplasty (PMV) have limitations. This study examined new, more quantitative methods for assessing valvular involvement and the combination of parameters that best predicts immediate and long-term outcome after PMV. Methods and Results Two cohorts (derivation n=204 and validation n=121) of patients with symptomatic mitral stenosis undergoing PMV were studied. Mitral valve morphology was assessed by using both the conventional Wilkins qualitative parameters and novel quantitative parameters, including the ratio between the commissural areas and the maximal excursion of the leaflets from the annulus in diastole. Independent predictors of outcome were assigned a points value proportional to their regression coefficients: mitral valve area 1 cm(2) (2), maximum leaflets displacement 12 mm (3), commissural area ratio 1.25 (3), and subvalvular involvement (3). Three risk groups were defined: low (score of 0-3), intermediate (score of 5), and high (score of 6-11) with observed suboptimal PMV results of 16.9%, 56.3%, and 73.8%, respectively. The use of the same scoring system in the validation cohort yielded suboptimal PMV results of 11.8%, 72.7%, and 87.5% in the low-, intermediate-, and high-risk groups, respectively. The model improved risk classification in comparison with the Wilkins score (net reclassification improvement 45.2%; P<0.0001). Long-term outcome was predicted by age and postprocedural variables, including mitral regurgitation, mean gradient, and pulmonary pressure. Conclusions A scoring system incorporating new quantitative echocardiographic parameters more accurately predicts outcome following PMV than existing models. Long-term post-PMV event-free survival was predicted by age, degree of mitral regurgitation, and postprocedural hemodynamic data. C1 [Nunes, Maria Carmo P.; Tan, Timothy C.; Handschumacher, Mark D.; Weyman, Arthur E.; Hung, Judy] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ultrasound Lab, Boston, MA USA. [Nunes, Maria Carmo P.] Univ Fed Minas Gerais, Sch Med, Belo Horizonte, MG, Brazil. [Elmariah, Sammy; do Lago, Rodrigo; Margey, Ronan; Cruz-Gonzalez, Ignacio; Inglessis, Ignacio; Palacios, Igor F.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med,Div Cardiol, Boston, MA USA. [Zheng, Hui] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Biostat, Boston, MA USA. RP Hung, J (reprint author), Massachusetts Gen Hosp, Blake 256,55 Fruit St, Boston, MA 02114 USA. EM jhung@partners.org FU CAPES (Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior, Brasilia, Brazil); National Institutes of Health (NIH)/National Heart, Lung, and Blood Institute (NHLBI) [R01 HL092101] FX This study was supported in part by grants from CAPES (Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior, Brasilia, Brazil) and National Institutes of Health (NIH)/National Heart, Lung, and Blood Institute (NHLBI) R01 HL092101 (to Dr Hung). NR 51 TC 6 Z9 7 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 FEB 25 PY 2014 VL 129 IS 8 BP 886 EP 895 DI 10.1161/CIRCULATIONAHA.113.001252 PG 10 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA AB4RF UT WOS:000331776900013 PM 24281331 ER PT J AU Nallamothu, BK Tommaso, CL Anderson, HV Anderson, JL Cleveland, JC Dudley, RA Duffy, PL Faxon, DP Gurm, HS Hamilton, LA Jensen, NC Josephson, RA Malenka, DJ Maniu, CV McCabe, KW Mortimer, JD Patel, MR Persell, SD Rumsfeld, JS Shunk, KA Smith, SC Stanko, SJ Watts, B AF Nallamothu, Brahmajee K. Tommaso, Carl L. Anderson, H. Vernon Anderson, Jeffrey L. Cleveland, Joseph C., Jr. Dudley, R. Adams Duffy, Peter Louis Faxon, David P. Gurm, Hitinder S. Hamilton, Lawrence A. Jensen, Neil C. Josephson, Richard A. Malenka, David J. Maniu, Calin V. McCabe, Kevin W. Mortimer, James D. Patel, Manesh R. Persell, Stephen D. Rumsfeld, John S. Shunk, Kendrick A. Smith, Sidney C., Jr. Stanko, Stephen J. Watts, Brook CA Amer Assoc Cardiovasc Pulm TI ACC/AHA/SCAI/AMA-Convened PCPI/NCQA 2013 Performance Measures for Adults Undergoing Percutaneous Coronary Intervention A Report of the American College of Cardiology/American Heart Association Task Force on Performance Measures, the Society for Cardiovascular Angiography and Interventions, the American Medical Association-Convened Physician Consortium for Performance Improvement, and the National Committee for Quality Assurance SO CIRCULATION LA English DT Article DE AHA Scientific Statements; health policy and outcome research; quality indicators; ambulatory-level quality; hospital quality; percutaneous coronary intervention ID ELEVATION MYOCARDIAL-INFARCTION; CONTRAST-INDUCED NEPHROPATHY; APPROPRIATE USE CRITERIA; ACCF/AHA FOCUSED UPDATE; CARDIAC REHABILITATION; PRACTICE GUIDELINES; ARTERY-DISEASE; SECONDARY PREVENTION; THORACIC-SURGEONS; COMPUTED-TOMOGRAPHY C1 [Nallamothu, Brahmajee K.] Univ Michigan, Ann Arbor VAMC Ctr Clin Management Res, Ann Arbor, MI 48109 USA. [Nallamothu, Brahmajee K.] NorthShore Univ HealthSyst, Evanston, IL USA. [Tommaso, Carl L.] Univ Texas Hlth Sci Ctr Houston, Dept Med, Houston, TX 77030 USA. [Anderson, H. Vernon] Intermt Med Ctr, Murray, UT USA. [Cleveland, Joseph C., Jr.] Univ Colorado, Denver, CO 80202 USA. [Faxon, David P.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Gurm, Hitinder S.] Univ Michigan, Cardiovasc Ctr, Ann Arbor, MI 48109 USA. [Hamilton, Lawrence A.] Kaiser Permanente No Calif, Cardiac & Renal Serv, Oakland, CA USA. [Josephson, Richard A.] Univ Hosp Cleveland Med Grp, Cleveland, OH USA. [Josephson, Richard A.] Case Western Reserve Univ, Sch Med, Cleveland, OH 44106 USA. [Malenka, David J.] Dartmouth Hitchcock Med Ctr, Div Cardiol, Dartmouth, NS, Canada. [Maniu, Calin V.] Bon Secours Hlth Syst, Suffolk, VA USA. [Patel, Manesh R.] Duke Univ, Med Ctr, Durham, NC 27706 USA. [Persell, Stephen D.] Northwestern Univ, Feinberg Sch Med, Evanston, IL 60208 USA. [Rumsfeld, John S.] US Vet Hlth Adm, Oakland, CA USA. [Shunk, Kendrick A.] San Francisco VA Med Ctr, San Francisco, CA USA. [Smith, Sidney C., Jr.] Univ N Carolina, Chapel Hill, NC USA. [Stanko, Stephen J.] Mended Hearts Inc, Dallas, TX USA. [Watts, Brook] Louis Stokes Cleveland VA Med Ctr, Cleveland, OH USA. [Watts, Brook] Case Western Reserve Univ, Cleveland, OH 44106 USA. RP Nallamothu, BK (reprint author), Univ Michigan, Ann Arbor VAMC Ctr Clin Management Res, Ann Arbor, MI 48109 USA. FU Aastrom Biosciences; Abbott; Abiomed; Acom Cardiovascular; Adolor Corp.; Advanced Cardiovascular Systems; Advanced Stent Technologies; Adynnx; Aijnomoto; Allergan; Amgen; Alnylam Pharma; Alpharma; Amylin Pharmaceuticals; Anadys; Anesiva; Angel Medical Systems; ANGES MG; Angiomedtrix; APT Nidus Center; ASCA Biopharma; Astellas Pharma; Asklepios; AstraZeneca; Atritech; Attention Therapeutics; Aventis; Baxter; Bayer; Berlex; BG Medicine; Biogen; Biolex Therapeutics; Biomarker Factory; Biosite; Boehringer Ingelheim Biogen; Boston Scientific; Bristol-Myers Squibb; BMS Pfizer; Carbomed; CardioDx; CardioKinetix; Cardiovascular Systems; Cardiovax; Celsion Corp.; Centocor; Cerexa; Chase Medical; Conatus Pharmaceuticals; Conor Medsystems; Cortex; Corgentech; CSL Behring; CV Therapeutics; Daiichi Pharmaceuticals; Daiichi Sankyo; Daiichi Sankyo Lilly; Ev3; F2G; General Electric Medical Systems; Genzyme Corp.; Genome Canada; KAI Pharmaceuticals; Nabriva; Novartis AG Group; Roche Molecular Systems; Roche Group; Roche Diagnostic; Salix Pharmaceuticals; Sanofi-Pasteur, Inc; Sanofi-aventis; Santaris Pharmaceuticals; TherOx; Tethys Bioscience; Theregen; Three Rivers Pharmaceuticals; EMMES Corporation; UCB; Valentis; Valleylab; Vertex; Viacor; Wyeth FX DCRI has numerous grants and contracts sponsored by industry. These include the following: Aastrom Biosciences; Abbott; Abiomed; Acom Cardiovascular; Adolor Corp.; Advanced Cardiovascular Systems; Advanced Stent Technologies; Adynnx; Aijnomoto; Allergan; Amgen; Alnylam Pharma; Alpharma; Amylin Pharmaceuticals; Anadys; Anesiva; Angel Medical Systems; ANGES MG; Angiomedtrix; APT Nidus Center; ASCA Biopharma; Astellas Pharma; Asklepios; AstraZeneca; Atritech; Attention Therapeutics; Aventis; Baxter; Bayer; Berlex BG Medicine; Biogen; Biolex Therapeutics; Biomarker Factory; Biosite; Boehringer Ingelheim Biogen; Boston Scientific; Bristol-Myers Squibb; BMS Pfizer; Carbomed; CardioDx; CardioKinetix; Cardiovascular Systems; Cardiovax; Celsion Corp; Centocor; Cerexa; Chase Medical; Conatus Pharmaceuticals; Conor Medsystems; Cortex; Corgentech; CSL Behring; CV Therapeutics; Daiichi Pharmaceuticals; Daiichi Sankyo; Daiichi Sankyo Lilly; Datascope; Dendreon; Dainippon; Dr. Reddy's Laboratories; Eclipse Surgical Technologies; Edwards Lifesciences; Eisai; Endicor; EnteroMedics; Enzon Pharmaceuticals; Eli Lilly; Ethicon; Ev3; Evalve; F2G; Flow Cardia; Fox Hollow Pharmaceuticals; Fujisawa; Genetech; General Electric; General Electric Co.; General Electric Healthcare; General Electric Medical Systems; Genzyme Corp.; Genome Canada; Gilead Sciences; GlaxoSmithKline; Guidant Corp.; Heartscape Technologies; Hoffman-LaRoche; Hospira; Idera Pharmaceuticals; Ikaria; Imcor Pharmaceuticals; Immunex; INFORMD; Inimex; Inspire Pharmaceuticals; Ischemix; Janssen; Johnson and Johnson; Jomed; Juventus Therapeutics; KAI Pharmaceuticals; King Pharmaceuticals; Kyowa Pharma; Luitpold; Mardil; MedImmune; Medscape; Medtronic Diabetes; Medtronic; Medtronic Vascular; Merck Group; MicroMed Technology; Millennium Pharmaceuticals; Mitsubishi Tanabe Momenta; Nabriva; Neuron Pharmaceuticals; NitroMed; NovaCardia Inc; Novartis AG Group; Novartis Pharmaceuticals; Oncura; Orexigen; Ortho-McNeil-Janssen; OSI Eyetech; OSI Pharmaceuticals; Pfizer; Pharmacyclics; Pharmasset; Pharmos; Phyxius Pharmaceuticals; Pharsight; Pluristen Therapeutics; Portola Pharmaceuticals; Proventys; Radiant; Regado Biosciences; Rengeneron Pharmaceuticals; Roche Molecular Systems; Roche Group; Roche Diagnostic; Salix Pharmaceuticals; Sanofi-Pasteur, Inc; Sanofi-aventis; Santaris Pharmaceuticals; Schering-Plough; Scios; Siemens; Southwest Oncology Group; Spectranetics; Summit; Sunovion Pharmaceuticals; TAP Pharmaceutical Products; Tengion; The Medicines Company; Theravance; TherOx; Tethys Bioscience; Theregen; Three Rivers Pharmaceuticals; The EMMES Corporation; UCB; Valentis; Valleylab Vertex; Viacor; and Wyeth . NR 50 TC 8 Z9 8 U1 0 U2 6 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 FEB 25 PY 2014 VL 129 IS 8 BP 926 EP 949 DI 10.1161/01.cir.0000441966.31451.3f PG 24 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA AB4RF UT WOS:000331776900019 PM 24357402 ER PT J AU Sheng, J Li, L Engelhart, AE Gan, JH Wang, JW Szostak, JW AF Sheng, Jia Li, Li Engelhart, Aaron E. Gan, Jianhua Wang, Jiawei Szostak, Jack W. TI Structural insights into the effects of 2 '-5 ' linkages on the RNA duplex SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE origin of life; backbone heterogeneity; X-ray crystallography ID NUCLEIC ACID INTERACTIONS; PHOSPHODIESTER BONDS; BACKBONE HETEROGENEITY; MOLECULAR-DYNAMICS; INTERCALATION SITE; 2',5'-LINKED RNA; DNA; OLIGORIBONUCLEOTIDES; OLIGOMERIZATION; REFINEMENT AB The mixture of 2'-5' and 3'-5' linkages generated during the nonenzymatic replication of RNA has long been regarded as a central problem for the origin of the RNA world. However, we recently observed that both a ribozyme and an RNA aptamer retain considerable functionality in the presence of prebiotically plausible levels of linkage heterogeneity. To better understand the RNA structure and function in the presence of backbone linkage heterogeneity, we obtained high-resolution X-ray crystal structures of a native 10-mer RNA duplex (1.32 angstrom) and two variants: one containing one 2'-5' linkage per strand (1.55 angstrom) and one containing three such linkages per strand (1.20 angstrom). We found that RNA duplexes adjust their local structures to accommodate the perturbation caused by 2'-5' linkages, with the flanking nucleotides buffering the disruptive effects of the isomeric linkage and resulting in a minimally altered global structure. Although most 2'-linked sugars were in the expected 2'-endo conformation, some were partially or fully in the 3'-endo conformation, suggesting that the energy difference between these conformations was relatively small. Our structural and molecular dynamic studies also provide insight into the diminished thermal and chemical stability of the duplex state associated with the presence of 2'-5' linkages. Our results contribute to the view that a low level of 2'-5' substitution would not have been fatal in an early RNA world and may in contrast have been helpful for both the emergence of nonenzymatic RNA replication and the early evolution of functional RNAs. C1 [Sheng, Jia; Li, Li; Engelhart, Aaron E.; Szostak, Jack W.] Massachusetts Gen Hosp, Howard Hughes Med Inst, Boston, MA 02114 USA. [Sheng, Jia; Li, Li; Engelhart, Aaron E.; Szostak, Jack W.] Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Boston, MA 02114 USA. [Sheng, Jia; Li, Li; Engelhart, Aaron E.; Szostak, Jack W.] Massachusetts Gen Hosp, Simches Res Ctr, Dept Mol Biol, Boston, MA 02114 USA. [Gan, Jianhua] Fudan Univ, Sch Life Sci, Shanghai 200433, Peoples R China. [Wang, Jiawei] Tsinghua Univ, Sch Life Sci, Beijing 100084, Peoples R China. RP Szostak, JW (reprint author), Massachusetts Gen Hosp, Howard Hughes Med Inst, Boston, MA 02114 USA. EM szostak@molbio.mgh.harvard.edu FU National Institutes of Health, National Institute of General Medical Sciences; Howard Hughes Medical Institute; Office of Science, Office of Basic Energy Sciences, of the US Department of Energy [DE-AC02-05CH11231]; National Science Foundation [CHE-0809413]; NASA FX We thank Dr. J. Craig Blain for the LC-MS support and Dr. Garib N. Murshudov for the JLigand instruction. All X-ray diffraction data were collected at the Advanced Light Source (ALS) beamlines 8.2.1 and 8.2.2. The Berkeley Center for Structural Biology is supported in part by the National Institutes of Health, National Institute of General Medical Sciences, and the Howard Hughes Medical Institute. The ALS is supported by the Director, Office of Science, Office of Basic Energy Sciences, of the US Department of Energy under Contract DE-AC02-05CH11231. The computation time was provided by the Orchestra cluster of Harvard Medical School. This work was supported in part by National Science Foundation Grant CHE-0809413. J.W.S. is an Investigator of the Howard Hughes Medical Institute. A.E.E. was supported by an appointment to the National Aeronautics and Space Administration (NASA) Postdoctoral Program, administered by Oak Ridge Associated Universities through a contract with NASA. NR 59 TC 13 Z9 14 U1 6 U2 36 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 FEB 25 PY 2014 VL 111 IS 8 BP 3050 EP 3055 DI 10.1073/pnas.1317799111 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AC0JP UT WOS:000332180900042 PM 24516151 ER PT J AU Kobiyama, K Aoshi, T Narita, H Kuroda, E Hayashi, M Tetsutani, K Koyama, S Mochizuki, S Sakurai, K Katakai, Y Yasutomi, Y Saijo, S Iwakura, Y Akira, S Coban, C Ishii, KJ AF Kobiyama, Kouji Aoshi, Taiki Narita, Hirotaka Kuroda, Etsushi Hayashi, Masayuki Tetsutani, Kohhei Koyama, Shohei Mochizuki, Shinichi Sakurai, Kazuo Katakai, Yuko Yasutomi, Yasuhiro Saijo, Shinobu Iwakura, Yoichiro Akira, Shizuo Coban, Cevayir Ishii, Ken J. TI Nonagonistic Dectin-1 ligand transforms CpG into a multitask nanoparticulate TLR9 agonist SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE innate immunity; two-photon microscopy; MARCO; Siglec-1; beta-glucan ID PLASMACYTOID DENDRITIC CELLS; POLYSACCHARIDE-POLYNUCLEOTIDE COMPLEXES; B-CELL; TOLL-LIKE-RECEPTOR-9 ACTIVATION; ANTIGEN PRESENTATION; ALPHA INDUCTION; DNA; SCHIZOPHYLLAN; MACROPHAGES; OLIGONUCLEOTIDES AB CpG DNA, a ligand for Toll-like receptor 9 (TLR9), has been one of the most promising immunotherapeutic agents. Although there are several types of potent humanized CpG oligodeoxynucleotide (ODN), developing "all-in-one" CpG ODNs activating both B cells and plasmacytoid dendritic cells forming a stable nanoparticle without aggregation has not been successful. In this study, we generated a novel nanoparticulate K CpG ODN (K3) wrapped by the nonagonistic Dectin-1 ligand schizophyllan (SPG), K3-SPG. In sharp contrast to K3 alone, K3-SPG stimulates human peripheral blood mononuclear cells to produce a large amount of both type I and type II IFN, targeting the same endosome where IFN-inducing D CpG ODN resides without losing its K-type activity. K3-SPG thus became a potent adjuvant for induction of both humoral and cellular immune responses, particularly CTL induction, to coadministered protein antigens without conjugation. Such potent adjuvant activity of K3-SPG is attributed to its nature of being a nanoparticle rather than targeting Dectin-1 by SPG, accumulating and activating antigen-bearing macrophages and dendritic cells in the draining lymph node. K3-SPG acting as an influenza vaccine adjuvant was demonstrated in vivo in both murine and nonhuman primate models. Taken together, K3-SPG may be useful for immunotherapeutic applications that require type I and type II IFN as well as CTL induction. C1 [Kobiyama, Kouji; Aoshi, Taiki; Kuroda, Etsushi; Hayashi, Masayuki; Tetsutani, Kohhei; Ishii, Ken J.] Natl Inst Biomed Innovat, Lab Adjuvant Innovat, Osaka 5670085, Japan. [Kobiyama, Kouji; Aoshi, Taiki; Kuroda, Etsushi; Hayashi, Masayuki; Tetsutani, Kohhei; Ishii, Ken J.] Osaka Univ, Inst Prot Res, Lab Vaccine Sci, Osaka 5650871, Japan. [Akira, Shizuo] Osaka Univ, Inst Prot Res, Host Def Lab, Osaka 5650871, Japan. [Coban, Cevayir] Osaka Univ, Inst Prot Res, World Premier Int Immunol Frontier Res Ctr, Lab Malaria Immunol, Osaka 5650871, Japan. [Narita, Hirotaka] Osaka Univ, Inst Prot Res, Res Ctr Struct & Funct Prote, Osaka 5650871, Japan. [Koyama, Shohei] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Koyama, Shohei] Dana Farber Canc Inst, Canc Vaccine Ctr, Boston, MA 02115 USA. [Mochizuki, Shinichi; Sakurai, Kazuo] Univ Kitakyushu, Dept Chem & Biochem, Fukuoka 8080135, Japan. [Katakai, Yuko] Corp Prod & Res Lab Primates, Ibaraki 3050843, Japan. [Yasutomi, Yasuhiro] Natl Inst Biomed Innovat, Tsukuba Primate Res Ctr, Ibaraki 3050843, Japan. [Saijo, Shinobu] Chiba Univ, Med Mycol Res Ctr, Dept Mol Immunol, Chiba 2608673, Japan. [Saijo, Shinobu] Japan Sci & Technol Agcy, Precursory Res Embryon Sci & Technol, Saitama 3320012, Japan. [Iwakura, Yoichiro] Tokyo Univ Sci, Res Inst Biomed Sci, Div Expt Anim Immunol, Chiba 2788510, Japan. RP Ishii, KJ (reprint author), Natl Inst Biomed Innovat, Lab Adjuvant Innovat, Osaka 5670085, Japan. EM kenishii@biken.osaka-u.ac.jp RI Akira, Shizuo/C-3134-2009; Ishii, Ken/B-1685-2012; Iwakura, Yoichiro/E-5457-2011; OI Ishii, Ken/0000-0002-6728-3872; Iwakura, Yoichiro/0000-0002-9934-5775; Koyama, Shohei/0000-0002-6897-9417 FU Health and Labour Sciences Research Grant; Japan Science and Technology Agency Core Research for Evolutionary Science and Technology Program FX This study was supported by a Health and Labour Sciences Research Grant and the Japan Science and Technology Agency Core Research for Evolutionary Science and Technology Program. NR 37 TC 30 Z9 34 U1 2 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 FEB 25 PY 2014 VL 111 IS 8 BP 3086 EP 3091 DI 10.1073/pnas.1319268111 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AC0JP UT WOS:000332180900048 PM 24516163 ER PT J AU Hoffman, GR Rahal, R Buxton, F Xiang, K McAllister, G Frias, E Bagdasarian, L Huber, J Lindeman, A Chen, DS Romero, R Ramadan, N Phadke, T Haas, K Jaskelioff, M Wilson, BG Meyer, MJ Saenz-Vash, V Zhai, HL Myer, VE Porter, JA Keen, N McLaughlin, ME Mickanin, C Roberts, CWM Stegmeier, F Jagani, Z AF Hoffman, Gregory R. Rahal, Rami Buxton, Frank Xiang, Kay McAllister, Gregory Frias, Elizabeth Bagdasarian, Linda Huber, Janina Lindeman, Alicia Chen, Dongshu Romero, Rodrigo Ramadan, Nadire Phadke, Tanushree Haas, Kristy Jaskelioff, Mariela Wilson, Boris G. Meyer, Matthew J. Saenz-Vash, Veronica Zhai, Huili Myer, Vic E. Porter, Jeffery A. Keen, Nicholas McLaughlin, Margaret E. Mickanin, Craig Roberts, Charles W. M. Stegmeier, Frank Jagani, Zainab TI Functional epigenetics approach identifies BRM/SMARCA2 as a critical synthetic lethal target in BRG1-deficient cancers SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID MAMMALIAN SWI/SNF COMPLEXES; REMODELING FACTOR BRG1; SWI-SNF COMPLEX; LUNG-CANCER; CELL-LINES; RNAI SCREENS; CHROMATIN; MUTATIONS; TUMORIGENESIS; SUPPRESSION AB Defects in epigenetic regulation play a fundamental role in the development of cancer, and epigenetic regulators have recently emerged as promising therapeutic candidates. We therefore set out to systematically interrogate epigenetic cancer dependencies by screening an epigenome-focused deep-coverage design shRNA (DECODER) library across 58 cancer cell lines. This screen identified BRM/SMARCA2, a DNA-dependent ATPase of the mammalian SWI/SNF (mSWI/SNF) chromatin remodeling complex, as being essential for the growth of tumor cells that harbor loss of function mutations in BRG1/SMARCA4. Depletion of BRM in BRG1-deficient cancer cells leads to a cell cycle arrest, induction of senescence, and increased levels of global H3K9me3. We further demonstrate the selective dependency of BRG1-mutant tumors on BRM in vivo. Genetic alterations of the mSWI/SNF chromatin remodeling complexes are the most frequent among chromatin regulators in cancers, with BRG1/SMARCA4 mutations occurring in similar to 10-15% of lung adenocarcinomas. Our findings position BRM as an attractive therapeutic target for BRG1 mutated cancers. Because BRG1 and BRM function as mutually exclusive catalytic subunits of the mSWI/SNF complex, we propose that such synthetic lethality may be explained by paralog insufficiency, in which loss of one family member unveils critical dependence on paralogous subunits. This concept of "cancer-selective paralog dependency" may provide a more general strategy for targeting other tumor suppressor lesions/complexes with paralogous subunits. C1 [Hoffman, Gregory R.; Buxton, Frank; McAllister, Gregory; Frias, Elizabeth; Lindeman, Alicia; Ramadan, Nadire; Phadke, Tanushree; Myer, Vic E.; Porter, Jeffery A.; Mickanin, Craig] Novartis Inst BioMed Res, Dept Dev & Mol Pathways, Cambridge, MA 02139 USA. [Rahal, Rami; Xiang, Kay; Huber, Janina; Chen, Dongshu; Romero, Rodrigo; Haas, Kristy; Jaskelioff, Mariela; Meyer, Matthew J.; Saenz-Vash, Veronica; Zhai, Huili; Keen, Nicholas; Stegmeier, Frank; Jagani, Zainab] Novartis Inst BioMed Res, Dept Oncol, Cambridge, MA 02139 USA. [Bagdasarian, Linda; McLaughlin, Margaret E.] Novartis Pharmaceut, Oncol Translat Med, Cambridge, MA 02139 USA. [Wilson, Boris G.; Roberts, Charles W. M.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02215 USA. RP Stegmeier, F (reprint author), Novartis Inst BioMed Res, Dept Oncol, Cambridge, MA 02139 USA. EM frank.stegmeier@novartis.com; zainab.jagani@novartis.com NR 36 TC 69 Z9 71 U1 1 U2 17 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 25 PY 2014 VL 111 IS 8 BP 3128 EP 3133 DI 10.1073/pnas.1316793111 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AC0JP UT WOS:000332180900055 PM 24520176 ER PT J AU King, AL Polhemus, DJ Bhushan, S Otsuka, H Kondo, K Nicholson, CK Bradley, JM Islam, KN Calvert, JW Tao, YX Dugas, TR Kelley, EE Elrod, JW Huang, PL Wang, R Lefer, DJ AF King, Adrienne L. Polhemus, David J. Bhushan, Shashi Otsuka, Hiroyuki Kondo, Kazuhisa Nicholson, Chad K. Bradley, Jessica M. Islam, Kazi N. Calvert, John W. Tao, Ya-Xiong Dugas, Tammy R. Kelley, Eric E. Elrod, John W. Huang, Paul L. Wang, Rui Lefer, David J. TI Hydrogen sulfide cytoprotective signaling is endothelial nitric oxide synthase-nitric oxide dependent SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE eNOS uncoupling; myocardial infarction; cystathionase; Cth; nitrite ID ISCHEMIA-REPERFUSION INJURY; INDUCED HEART-FAILURE; CYTOCHROME-C-OXIDASE; MYOCARDIAL ISCHEMIA; MOUSE HEART; IN-VIVO; PHOSPHORYLATION; PROTECTS; AKT; H2S AB Previous studies have demonstrated that hydrogen sulfide (H2S) protects against multiple cardiovascular disease states in a similar manner as nitric oxide (NO). H2S therapy also has been shown to augment NO bioavailability and signaling. The purpose of this study was to investigate the impact of H2S deficiency on endothelial NO synthase (eNOS) function, NO production, and ischemia/reperfusion (I/R) injury. We found that mice lacking the H2S-producing enzyme cystathionine gamma-lyase (CSE) exhibit elevated oxidative stress, dysfunctional eNOS, diminished NO levels, and exacerbated myocardial and hepatic I/R injury. In CSE KO mice, acute H2S therapy restored eNOS function and NO bioavailability and attenuated I/R injury. In addition, we found that H2S therapy fails to protect against I/R in eNOS phosphomutant mice (S1179A). Our results suggest that H2S-mediated cytoprotective signaling in the setting of I/R injury is dependent in large part on eNOS activation and NO generation. C1 [King, Adrienne L.; Kondo, Kazuhisa; Nicholson, Chad K.; Calvert, John W.] Emory Univ, Sch Med, Dept Surg, Atlanta, GA 30308 USA. [King, Adrienne L.; Kondo, Kazuhisa; Nicholson, Chad K.; Calvert, John W.] Emory Univ, Sch Med, Carlyle Fraser Heart Ctr, Atlanta, GA 30308 USA. [Polhemus, David J.; Bhushan, Shashi; Otsuka, Hiroyuki; Bradley, Jessica M.; Islam, Kazi N.; Lefer, David J.] Louisiana State Univ, Hlth Sci Ctr, Dept Pharmacol & Expt Therapeut, New Orleans, LA 70112 USA. [Polhemus, David J.; Bhushan, Shashi; Otsuka, Hiroyuki; Bradley, Jessica M.; Islam, Kazi N.; Lefer, David J.] Louisiana State Univ, Hlth Sci Ctr, Cardiovasc Ctr Excellence, New Orleans, LA 70112 USA. [Tao, Ya-Xiong] Auburn Univ, Coll Vet Med, Dept Anat Physiol & Pharmacol, Auburn, AL 36832 USA. [Dugas, Tammy R.] Louisiana State Univ, Hlth Sci Ctr Shreveport, Dept Pharmacol Toxicol & Neurosci, Shreveport, LA 71130 USA. [Kelley, Eric E.] Univ Pittsburgh, Dept Anesthesiol, Pittsburgh, PA 15213 USA. [Kelley, Eric E.] Univ Pittsburgh, Vasc Med Inst, Pittsburgh, PA 15213 USA. [Elrod, John W.] Temple Univ, Dept Pharmacol, Ctr Translat Med, Philadelphia, PA 19140 USA. [Huang, Paul L.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Huang, Paul L.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Wang, Rui] Lakehead Univ, Dept Biol, Thunder Bay, ON P7B 5E1, Canada. RP Lefer, DJ (reprint author), Louisiana State Univ, Hlth Sci Ctr, Dept Pharmacol & Expt Therapeut, New Orleans, LA 70112 USA. EM dlefe1@lsuhsc.edu RI Calvert, John/F-4497-2014; OI Calvert, John/0000-0001-6858-6042; Elrod, John/0000-0003-3925-2224; Tao, Ya-Xiong/0000-0003-4737-749X FU National Heart, Lung, and Blood Institute [1R01 HL092141, 1R01 HL093579, 1U24 HL 094373, 1P20 HL113452, 5R01 HL 098481]; Canadian Institutes of Health Research; Carlyle Fraser Heart Center of Emory University; Louisiana State University Health Foundation in New Orleans FX We thank Valeria Hebert, Marah Condit, and Benjamin Predmore, as well as the University of Pittsburgh Center for Biological Imaging, for expert technical assistance. This work was supported by Grants from the National Heart, Lung, and Blood Institute (1R01 HL092141, 1R01 HL093579, 1U24 HL 094373, and 1P20 HL113452 to D.J.L., and 5R01 HL 098481 to J.W.C.). These studies were also supported by the Canadian Institutes of Health Research (R. W.). We are also grateful for the generous financial support from the Carlyle Fraser Heart Center of Emory University and the Louisiana State University Health Foundation in New Orleans. NR 49 TC 86 Z9 90 U1 7 U2 35 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 FEB 25 PY 2014 VL 111 IS 8 BP 3182 EP 3187 DI 10.1073/pnas.1321871111 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AC0JP UT WOS:000332180900064 PM 24516168 ER PT J AU Jaff, MR AF Jaff, Michael R. TI PAD Is No Longer Related to Rodney SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Editorial Material ID PERIPHERAL ARTERIAL-DISEASE; TERM PROGNOSIS; STATIN USE C1 [Jaff, Michael R.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. RP Jaff, MR (reprint author), Massachusetts Gen Hosp, 55 Fruit St,W 905, Boston, MA 02114 USA. EM mjaff@partners.org NR 11 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 FEB 25 PY 2014 VL 63 IS 7 BP 691 EP 692 DI 10.1016/j.jacc.2013.10.066 PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AB3WB UT WOS:000331719800012 PM 24315908 ER PT J AU Nallamothu, BK Tommaso, CL Anderson, HV Anderson, JL Cleveland, JC Dudley, RA Duffy, PL Faxon, DP Gurm, HS Hamilton, LA Jensen, NC Josephson, RA Malenka, DJ Maniu, CV McCabe, KW Mortimer, JD Patel, MR Persell, SD Rumsfeld, JS Shunk, KA Smith, SC Stanko, SJ Watts, B AF Nallamothu, Brahmajee K. Tommaso, Carl L. Anderson, H. Vernon Anderson, Jeffrey L. Cleveland, Joseph C., Jr. Dudley, R. Adams Duffy, Peter Louis Faxon, David P. Gurm, Hitinder S. Hamilton, Lawrence A. Jensen, Neil C. Josephson, Richard A. Malenka, David J. Maniu, Calin V. McCabe, Kevin W. Mortimer, James D. Patel, Manesh R. Persell, Stephen D. Rumsfeld, John S. Shunk, Kendrick A. Smith, Sidney C., Jr. Stanko, Stephen J. Watts, Brook TI ACC/AHA/SCAI/AMA-Convened PCPI/NCQA 2013 Performance Measures for Adults Undergoing Percutaneous Coronary Intervention A Report of the American College of Cardiology/American Heart Association Task Force on Performance Measures, the Society for Cardiovascular Angiography and Interventions, the American Medical Association-Convened Physician Consortium for Performance Improvement, and the National Committee for Quality Assurance SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE ACC/AHA/SCAI/AMA-PCPI/NCQA Performance Measures; health policy and outcome research; quality indicators; ambulatory-level quality; hospital quality; percutaneous coronary intervention ID ELEVATION MYOCARDIAL-INFARCTION; CONTRAST-INDUCED NEPHROPATHY; APPROPRIATE USE CRITERIA; ACCF/AHA FOCUSED UPDATE; OF-CARDIOLOGY; CARDIAC REHABILITATION; PRACTICE GUIDELINES; ARTERY-DISEASE; SECONDARY PREVENTION; 30-DAY READMISSION C1 [Nallamothu, Brahmajee K.] Univ Michigan, Ann Arbor VAMC Ctr Clin Management Res, Ann Arbor, MI 48109 USA. [Tommaso, Carl L.] NorthShore Univ HealthSyst, Rush Med Coll Phys, Evanston, IL USA. [Anderson, H. Vernon] Univ Texas Hlth Sci Ctr Houston, Dept Med, Houston, TX 77030 USA. [Anderson, Jeffrey L.] Intermt Med Ctr, Murray, UT USA. [Cleveland, Joseph C., Jr.] Univ Colorado, Denver, CO 80202 USA. [Cleveland, Joseph C., Jr.] Cardiac Transplant & MCS, Chicago, IL USA. [Dudley, R. Adams] Inst Hlth Policy Studies, San Francisco, CA USA. [Duffy, Peter Louis] FirstHlth Carolinas, Pinehurst, NC USA. [Duffy, Peter Louis] Reid Heart Ctr Intervent Cardiol, Cardiovasc Serv Line, Ottawa, ON, Canada. [Faxon, David P.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Gurm, Hitinder S.] Univ Michigan, Cardiovasc Ctr, Ann Arbor, MI 48109 USA. [Hamilton, Lawrence A.] Kaiser Permanente, Columbia, SC USA. [Jensen, Neil C.] United Healthcare, Minnetonka, MN USA. [Josephson, Richard A.] Case Western Reserve Univ, Sch Med, Univ Hosp Cleveland Med Grp, Cleveland, OH 44106 USA. [Malenka, David J.] Dartmouth Hitchcock Med Ctr, Div Cardiol, Lebanon, NH USA. [Maniu, Calin V.] Bon Secours Hlth Syst, Suffolk, VA USA. [McCabe, Kevin W.] SC Johnson & Son Inc, Racine, WI USA. [Mortimer, James D.] Jim Mortimer Consulting, Chicago, IL USA. [Patel, Manesh R.] Duke Univ, Med Ctr, Durham, NC 27706 USA. [Persell, Stephen D.] Northwestern Univ, Feinberg Sch Med, Evanston, IL 60208 USA. [Rumsfeld, John S.] US Vet Hlth Adm, Oakland, CA USA. [Rumsfeld, John S.] Natl Cardiovasc Data Registry, Washington, DC USA. [Shunk, Kendrick A.] San Francisco VA Med Ctr, San Francisco, CA USA. [Smith, Sidney C., Jr.] Univ N Carolina, Chapel Hill, NC USA. [Stanko, Stephen J.] Mended Hearts Inc, Dallas, TX USA. [Watts, Brook] Case Western Reserve Univ, Louis Stokes Cleveland VA Med Ctr, Cleveland, OH 44106 USA. RP Nallamothu, BK (reprint author), Univ Michigan, Ann Arbor VAMC Ctr Clin Management Res, Ann Arbor, MI 48109 USA. NR 50 TC 16 Z9 16 U1 1 U2 6 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 FEB 25 PY 2014 VL 63 IS 7 BP 722 EP 745 DI 10.1016/j.jacc.2013.12.003 PG 24 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AB3WB UT WOS:000331719800018 PM 24361978 ER PT J AU Yuan, JP Kashiwagi, S Reeves, P Nezivar, J Yang, Y Arrifin, NH Nguyen, M Jean-Mary, G Tong, XY Uppal, P Korochkina, S Forbes, B Chen, T Righi, E Bronson, R Chen, H Orsulic, S Brauns, T Leblanc, P Scholler, N Dranoff, G Gelfand, J Poznansky, MC AF Yuan, Jianping Kashiwagi, Satoshi Reeves, Patrick Nezivar, Jean Yang, Yuan Arrifin, Nadiah Hashim Nguyen, Mai Jean-Mary, Gilberte Tong, Xiaoyun Uppal, Paramjit Korochkina, Svetlana Forbes, Ben Chen, Tao Righi, Elda Bronson, Roderick Chen, Huabiao Orsulic, Sandra Brauns, Timothy Leblanc, Pierre Scholler, Nathalie Dranoff, Glenn Gelfand, Jeffrey Poznansky, Mark C. TI A novel mycobacterial Hsp70-containing fusion protein targeting mesothelin augments antitumor immunity and prolongs survival in murine models of ovarian cancer and mesothelioma SO JOURNAL OF HEMATOLOGY & ONCOLOGY LA English DT Article DE Mycobacterial Hsp70; Mesothelin; Single chain variable fragment; Cancer immunotherapy; Murine tumor model ID DENDRITIC CELLS; IN-VIVO; MOUSE MODEL; BREAST-CANCER; PHASE-I; HEAT-SHOCK-PROTEIN-70; HSP70; IMMUNOTHERAPY; TUBERCULOSIS; RECEPTOR AB Background: Although dendritic cell (DC) vaccines are considered to be promising treatments for advanced cancer, their production and administration is costly and labor-intensive. We developed a novel immunotherapeutic agent that links a single-chain antibody variable fragment (scFv) targeting mesothelin (MSLN), which is overexpressed on ovarian cancer and mesothelioma cells, to Mycobacterium tuberculosis (MTB) heat shock protein 70 (Hsp70), which is a potent immune activator that stimulates monocytes and DCs, enhances DC aggregation and maturation and improves cross-priming of T cells mediated by DCs. Methods: Binding of this fusion protein with MSLN on the surface of tumor cells was measured by flow cytometry and fluorescence microscopy. The therapeutic efficacy of this fusion protein was evaluated in syngeneic and orthotopic mouse models of papillary ovarian cancer and malignant mesothelioma. Mice received 4 intraperitoneal (i.p.) treatments with experimental or control proteins post i.p. injection of tumor cells. Ascites-free and overall survival time was measured. For the investigation of anti-tumor T-cell responses, a time-matched study was performed. Splenocytes were stimulated with peptides, and IFN gamma- or Granzyme B-generating CD3(+)CD8(+) T cells were detected by flow cytometry. To examine the role of CD8(+) T cells in the antitumor effect, we performed in vivo CD8(+) cell depletion. We further determined if the fusion protein increases DC maturation and improves antigen presentation as well as cross-presentation by DCs. Results: We demonstrated in vitro that the scFvMTBHsp70 fusion protein bound to the tumor cells used in this study through the interaction of scFv with MSLN on the surface of these cells, and induced maturation of bone marrow-derived DCs. Use of this bifunctional fusion protein in both mouse models significantly enhanced survival and slowed tumor growth while augmenting tumor-specific CD8(+) T-cell dependent immune responses. We also demonstrated in vitro and in vivo that the fusion protein enhanced antigen presentation and cross-presentation by targeting tumor antigens towards DCs. Conclusions: This new cancer immunotherapy has the potential to be cost-effective and broadly applicable to tumors that overexpress mesothelin. C1 [Yuan, Jianping; Kashiwagi, Satoshi; Reeves, Patrick; Nezivar, Jean; Yang, Yuan; Arrifin, Nadiah Hashim; Nguyen, Mai; Jean-Mary, Gilberte; Tong, Xiaoyun; Uppal, Paramjit; Korochkina, Svetlana; Forbes, Ben; Chen, Tao; Righi, Elda; Brauns, Timothy; Leblanc, Pierre; Gelfand, Jeffrey; Poznansky, Mark C.] Massachusetts Gen Hosp, Vaccine & Immunotherapy Ctr, Dept Med, Div Infect Dis, Boston, MA 02129 USA. [Bronson, Roderick] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Chen, Huabiao] MIT, Ragon Inst MGH, Boston, MA USA. [Chen, Huabiao] Harvard Univ, Boston, MA 02115 USA. [Orsulic, Sandra] Womens Canc Res Inst, Cedars Sinai Med Ctr, Los Angeles, CA USA. [Scholler, Nathalie] Univ Penn, Penn Ovarian Canc Res Ctr, Dept Obstet & Gynecol, Philadelphia, PA USA. [Dranoff, Glenn] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Dranoff, Glenn] Dana Farber Canc Inst, Canc Vaccine Ctr, Boston, MA 02115 USA. [Dranoff, Glenn] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Med, Boston, MA USA. RP Poznansky, MC (reprint author), Massachusetts Gen Hosp, Vaccine & Immunotherapy Ctr, Dept Med, Div Infect Dis, 149 13th St, Boston, MA 02129 USA. EM mpoznansky@partners.org RI Scholler, Nathalie/O-9003-2014 FU Prof. Dulcie V. Coleman Studentship at Imperial College, London FX This manuscript is dedicated to the memory of Janet Gelfand, a victim of ovarian cancer. The authors gratefully acknowledge the continuing support for this work from the Edmund C. Lynch Jr. Cancer Fund, Arthur Luxenberg Esq., Perry Weitz Esq., and the VIC Mesothelioma Research and Resource Program at MGH and the Friends of VIC Fund. PU and NHA were supported by the Prof. Dulcie V. Coleman Studentship at Imperial College, London. We thank Oliver Mitchell, John Cao, Lujia Zhou, Rumbidzai Mushavi, and Sayinthen Vivekanantham for their technical assistances, Dr. Yuhui Huang for his useful comments, Michael Waring, Dr. Michael Santuosuosso and Dr. Ravi Mylvaganam for their technical advice, Dr. Musie Ghebremichael for his advice in statistical analysis, and Mahnoor Valibhoy for her assistance with the schematic figure. NR 48 TC 11 Z9 11 U1 3 U2 11 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1756-8722 J9 J HEMATOL ONCOL JI J. Hematol. Oncol. PD FEB 24 PY 2014 VL 7 AR 15 DI 10.1186/1756-8722-7-15 PG 14 WC Oncology; Hematology SC Oncology; Hematology GA AF3SL UT WOS:000334632400001 PM 24565018 ER PT J AU Nissim, S Sherwood, RI Wucherpfennig, J Saunders, D Harris, JM Esain, V Carro, KJ Frechette, GM Kim, AJ Hwang, KL Cutting, CC Elledge, S North, TE Goessling, W AF Nissim, Sahar Sherwood, Richard I. Wucherpfennig, Julia Saunders, Diane Harris, James M. Esain, Virginie Carro, Kelli J. Frechette, Gregory M. Kim, Andrew J. Hwang, Katie L. Cutting, Claire C. Elledge, Susanna North, Trista E. Goessling, Wolfram TI Prostaglandin E-2 Regulates Liver versus Pancreas Cell-Fate Decisions and Endodermal Outgrowth SO DEVELOPMENTAL CELL LA English DT Article ID PROGENITOR CELLS; SPECIFICATION; ZEBRAFISH; REGENERATION; REQUIREMENT; GENERATION; BIOLOGY; HNF-6 AB The liver and pancreas arise from common endodermal progenitors. How these distinct cell fates are specified is poorly understood. Here we describe prostaglandin E-2 (PGE(2)) as a regulator of endodermal fate specification during development. Modulating PGE(2) activity has opposing effects on liver versus pancreas specification in zebrafish embryos as well as mouse endodermal progenitors. The PGE(2) synthetic enzyme cox2a and receptor ep2a are patterned such that cells closest to PGE(2) synthesis acquire a liver fate, whereas more distant cells acquire a pancreas fate. PGE(2) interacts with the bmp2b pathway to regulate fate specification. At later stages of development, PGE(2) acting via the ep4a receptor promotes outgrowth of both the liver and pancreas. PGE(2) remains important for adult organ growth, as it modulates liver regeneration. This work provides in vivo evidence that PGE(2) may act as a morphogen to regulate cell-fate decisions and outgrowth of the embryonic endodermal anlagen. C1 [Nissim, Sahar; Goessling, Wolfram] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Gastroenterol, Boston, MA 02215 USA. [Nissim, Sahar; Sherwood, Richard I.; Wucherpfennig, Julia; Saunders, Diane; Kim, Andrew J.; Hwang, Katie L.; Cutting, Claire C.; Elledge, Susanna; Goessling, Wolfram] Brigham & Womens Hosp, Div Genet, Boston, MA 02115 USA. [Harris, James M.; Esain, Virginie; Carro, Kelli J.; Frechette, Gregory M.; North, Trista E.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Dept Pathol, Boston, MA 02215 USA. [North, Trista E.; Goessling, Wolfram] Harvard Univ, Stem Cell Inst, Cambridge, MA 02138 USA. [Goessling, Wolfram] Dana Farber Canc Inst, Boston, MA 02115 USA. [Goessling, Wolfram] MIT, Broad Inst, Cambridge, MA 02142 USA. [Goessling, Wolfram] Harvard Univ, Cambridge, MA 02142 USA. RP North, TE (reprint author), Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Dept Pathol, Boston, MA 02215 USA. EM tnorth@bidmc.harvard.edu; wgoessling@partners.org OI Goessling, Wolfram/0000-0001-9972-1569 FU National Pancreas Foundation; National Institutes of Health (NIH) National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [132]; NIH NIDDK [R03DK085445, R01DK090311, K01DK080226]; Harvard Stem Cell Institute; Pew Charitable Trusts FX This work was supported by the National Pancreas Foundation and National Institutes of Health (NIH) National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) grant 132 (S.N.) and by NIH NIDDK grants R03DK085445 and R01DK090311 (W.G.) and K01DK080226 (T.E.N.), the Harvard Stem Cell Institute (W.G. and T.E.N.), and the Pew Charitable Trusts (W.G.). NR 29 TC 15 Z9 15 U1 0 U2 4 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 FEB 24 PY 2014 VL 28 IS 4 BP 423 EP 437 DI 10.1016/j.devcel.2014.01.006 PG 15 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA AC0OS UT WOS:000332195200007 PM 24530296 ER PT J AU Duncan, LE Holmans, PA Lee, PH O'Dushlaine, CT Kirby, AW Smoller, JW Ongur, D Cohen, BM AF Duncan, Laramie E. Holmans, Peter A. Lee, Phil H. O'Dushlaine, Colm T. Kirby, Andrew W. Smoller, Jordan W. Oenguer, Dost Cohen, Bruce M. TI Pathway Analyses Implicate Glial Cells in Schizophrenia SO PLOS ONE LA English DT Article ID MITOCHONDRIAL DYSFUNCTION; PSYCHIATRIC-DISORDERS; BIPOLAR DISORDER; PREFRONTAL CORTEX; ASSOCIATION; GENOMEWIDE; DENSITY AB Background: The quest to understand the neurobiology of schizophrenia and bipolar disorder is ongoing with multiple lines of evidence indicating abnormalities of glia, mitochondria, and glutamate in both disorders. Despite high heritability estimates of 81% for schizophrenia and 75% for bipolar disorder, compelling links between findings from neurobiological studies, and findings from large-scale genetic analyses, are only beginning to emerge. Method: Ten publically available gene sets (pathways) related to glia, mitochondria, and glutamate were tested for association to schizophrenia and bipolar disorder using MAGENTA as the primary analysis method. To determine the robustness of associations, secondary analyses were performed with: ALIGATOR, INRICH, and Set Screen. Data from the Psychiatric Genomics Consortium (PGC) were used for all analyses. There were 1,068,286 SNP-level p-values for schizophrenia (9,394 cases/12,462 controls), and 2,088,878 SNP-level p-values for bipolar disorder (7,481 cases/9,250 controls). Results: The Glia-Oligodendrocyte pathway was associated with schizophrenia, after correction for multiple tests, according to primary analysis (MAGENTA p = 0.0005, 75% requirement for individual gene significance) and also achieved nominal levels of significance with INRICH (p = 0.0057) and ALIGATOR (p = 0.022). For bipolar disorder, Set Screen yielded nominally and method-wide significant associations to all three glial pathways, with strongest association to the Glia-Astrocyte pathway (p = 0.002). Conclusions: Consistent with findings of white matter abnormalities in schizophrenia by other methods of study, the Glia-Oligodendrocyte pathway was associated with schizophrenia in our genomic study. These findings suggest that the abnormalities of myelination observed in schizophrenia are at least in part due to inherited factors, contrasted with the alternative of purely environmental causes (e.g. medication effects or lifestyle). While not the primary purpose of our study, our results also highlight the consequential nature of alternative choices regarding pathway analysis, in that results varied somewhat across methods, despite application to identical datasets and pathways. C1 [Duncan, Laramie E.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Duncan, Laramie E.; Lee, Phil H.; Smoller, Jordan W.] Massachusetts Gen Hosp, PNGU, Boston, MA 02114 USA. [Duncan, Laramie E.; Lee, Phil H.; Smoller, Jordan W.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Duncan, Laramie E.; Lee, Phil H.; O'Dushlaine, Colm T.] Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Cambridge, MA USA. [Duncan, Laramie E.; Lee, Phil H.; Oenguer, Dost; Cohen, Bruce M.] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Holmans, Peter A.] Cardiff Univ, MRC Ctr Neuropsychiat Genet & Genom, Cardiff CF10 3AX, S Glam, Wales. [Lee, Phil H.; Kirby, Andrew W.] Massachusetts Gen Hosp, ATGU, Boston, MA 02114 USA. [Oenguer, Dost] McLean Hosp, Schizophrenia & Bipolar Disorder Program, Belmont, MA 02178 USA. [Cohen, Bruce M.] McLean Hosp, Shervert Frazier Res Inst, Belmont, MA 02178 USA. RP Duncan, LE (reprint author), Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. EM laramied@gmail.com RI Holmans, Peter/F-4518-2015 OI Holmans, Peter/0000-0003-0870-9412 FU LED - Jonathan Edwards Brooking Memorial Fund for Mental Health Research at McLean Hospital; National Institute of Mental Health (NIMH) [T32MH017119]; JWS - National Institute of Mental Health (NIMH) [K24MH094614]; DO - NIMH [R21MH096107-01A1]; BMC - Maltz Distinguished Investigator Award; National Alliance for Research on Schizophrenia and Depression (NARSAD) FX Funding supporting for this work is as follows: LED - Jonathan Edwards Brooking Memorial Fund for Mental Health Research at McLean Hospital & National Institute of Mental Health (NIMH) grant T32MH017119; JWS - National Institute of Mental Health (NIMH) grant K24MH094614; DO - NIMH grant R21MH096107-01A1; BMC - Maltz Distinguished Investigator Award, National Alliance for Research on Schizophrenia and Depression (NARSAD). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 39 TC 17 Z9 17 U1 0 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 FEB 24 PY 2014 VL 9 IS 2 AR e89441 DI 10.1371/journal.pone.0089441 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AB6EP UT WOS:000331880700045 PM 24586781 ER PT J AU Yan, HQ Shin, SS Ma, XC Li, YM Dixon, CE AF Yan, Hong Q. Shin, Samuel S. Ma, Xiecheng Li, Youming Dixon, C. Edward TI Differential effect of traumatic brain injury on the nuclear factor of activated T Cells C3 and C4 isoforms in the rat hippocampus SO BRAIN RESEARCH LA English DT Article DE Nuclear factor of activated T cells (NFAT); Immunohistochemistry; Rat; Traumatic brain injury (TBI); Calcineurin ID FLUID PERCUSSION INJURY; DELAYED NEURONAL DEATH; GENE-EXPRESSION; TRANSCRIPTION FACTORS; TYROSINE-HYDROXYLASE; CALCINEURIN SUBUNIT; REACTIVE ASTROCYTES; FRONTAL-CORTEX; NFAT; APOPTOSIS AB The interaction between the phosphatase calcineurin and transcription factor nuclear factor of activated T cells (NFAT) plays an important role numerous signaling and the regulatory events. Although NFAT is mostly known for its transcription function in the immune system, NFAT also has essential functions even in the central nervous system (CNS). The effects of traumatic brain injury (TBI) on NFAT are currently unknown. To determine if there is an alteration in NFAT after TBI, we examined NFATc3 and c4 levels at 6 h, 1 day, 1 week, 2 weeks and 4 weeks post injury. Rats were anesthetized and surgically prepared for controlled cortical impact (CCI) injury or sham surgery. Semi-quantitative measurements of NFATc3 and c4 in the hippocampal homogenates from injured and sham rats sacrificed at the appropriate time after injury were assessed using Western blot analysis. After TBI insult, in the hippocampus ipsilateral to the injury, NFATc3 expression levels were decreased both in the cytoplasmic and nuclear fractions. However, NFATc4 expression levels were increased in the cytoplasmic fraction but decreased in the nuclear fraction. Double labeling (with NeuN and GFAP) immunohistochemistry revealed that NFATc3 was expressed in subset of astrocytes and NFATc4 was expressed primarily in neurons. These differential responses in NFATc3 and c4 expression after TBI insult may indicate long-term changes in hippocampal excitability and may contribute to behavioral deficits. Further study is warranted to illustrate the role of NFATc3 and c4 in the setting of TBI. Published by Elsevier B.V. C1 [Yan, Hong Q.; Shin, Samuel S.; Ma, Xiecheng; Li, Youming; Dixon, C. Edward] Univ Pittsburgh, Dept Neurol Surg, Pittsburgh, PA 15260 USA. [Dixon, C. Edward] Vet Affairs Pittsburgh Healthcare Syst, Pittsburgh, PA 15240 USA. RP Dixon, CE (reprint author), Univ Pittsburgh, Dept Neurol Surg, Safar Ctr, 201 Hill Bldg,3434 Fifth Ave, Pittsburgh, PA 15260 USA. EM dixonec@upmc.edu FU NIH/NINDS [NS33150, NS060672, NS079061]; Veterans Affairs grant [B6761R] FX This work was supported by NIH/NINDS grants NS33150, NS060672 and NS079061; and the Veterans Affairs grant B6761R. NR 50 TC 6 Z9 7 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 EI 1872-6240 J9 BRAIN RES JI Brain Res. PD FEB 22 PY 2014 VL 1548 BP 63 EP 72 DI 10.1016/j.brainres.2013.12.028 PG 10 WC Neurosciences SC Neurosciences & Neurology GA AB6UM UT WOS:000331925000006 PM 24389074 ER PT J AU Vazquez, J Reboli, AC Pappas, PG Patterson, TF Reinhardt, J Chin-Hong, P Tobin, E Kett, DH Biswas, P Swanson, R AF Vazquez, Jose Reboli, Annette C. Pappas, Peter G. Patterson, Thomas F. Reinhardt, John Chin-Hong, Peter Tobin, Ellis Kett, Daniel H. Biswas, Pinaki Swanson, Robert TI Evaluation of an early step-down strategy from intravenous anidulafungin to oral azole therapy for the treatment of candidemia and other forms of invasive candidiasis: results from an open-label trial SO BMC INFECTIOUS DISEASES LA English DT Article DE Anidulafungin; Azole; Candidemia; Step-down strategy ID GUIDELINES; ANTIBIOTICS; FLUCONAZOLE; MANAGEMENT; CASPOFUNGIN; INFECTIONS; MORTALITY; EFFICACY; OUTCOMES; PHASE-2 AB Background: Hospitalized patients are at increased risk for candidemia and invasive candidiasis (C/ IC). Improved therapeutic regimens with enhanced clinical and pharmacoeconomic outcomes utilizing existing antifungal agents are still needed. Methods: An open-label, non-comparative study evaluated an intravenous (IV) to oral step-down strategy. Patients with C/ IC were treated with IV anidulafungin and after 5 days of IV therapy had the option to step-down to oral azole therapy (fluconazole or voriconazole) if they met prespecified criteria. The primary endpoint was the global response rate (clinical + microbiological) at end of treatment (EOT) in the modified intent-to-treat (MITT) population (at least one dose of anidulafungin plus positive Candida within 96 hours of study entry). Secondary endpoints included efficacy at other time points and in predefined patient subpopulations. Patients who stepped down early (<= 7 days' anidulafungin) were identified as the " early switch" subpopulation. Results: In total, 282 patients were enrolled, of whom 250 were included in the MITT population. The MITT global response rate at EOT was 83.7% (95% confidence interval, 78.7-88.8). Global response rates at all time points were generally similar in the early switch subpopulation compared with the MITT population. Global response rates were also similar across multiple Candida species, including C. albicans, C. glabrata, and C. parapsilosis. The most common treatment-related adverse events were nausea and vomiting (four patients each). Conclusions: A short course of IV anidulafungin, followed by early step-down to oral azole therapy, is an effective and well-tolerated approach for the treatment of C/IC. C1 [Vazquez, Jose] Georgia Regents Univ, Augusta, GA USA. [Reboli, Annette C.] Rowan Univ, Cooper Med Sch, Camden, NJ USA. [Pappas, Peter G.] Univ Alabama Birmingham, Birmingham, AL USA. [Patterson, Thomas F.] Univ Texas San Antonio, San Antonio, TX USA. [Patterson, Thomas F.] South Texas Vet Hlth Care Syst, San Antonio, TX USA. [Reinhardt, John] Christiana Care Hlth Syst, Newark, DE USA. [Chin-Hong, Peter] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Tobin, Ellis] Albany Med Ctr, Albany, NY USA. [Kett, Daniel H.] Univ Miami, Miller Sch Med, Miami, FL 33136 USA. [Kett, Daniel H.] Jackson Mem Hosp, Miami, FL 33136 USA. [Biswas, Pinaki; Swanson, Robert] Pfizer Inc, New York, NY USA. RP Swanson, R (reprint author), Pfizer Inc, New York, NY USA. EM swansr1@pfizer.com FU Pfizer Inc. FX The authors would like to thank the A8851011 investigators and study team. Editorial support was provided by Anne Marie Reid, PhD, and Philip Matthews, PhD, at Complete Medical Communications and was funded by Pfizer Inc. This study was sponsored by Pfizer Inc. NR 21 TC 18 Z9 18 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2334 J9 BMC INFECT DIS JI BMC Infect. Dis. PD FEB 21 PY 2014 VL 14 AR 14:97 DI 10.1186/1471-2334-14-97 PG 10 WC Infectious Diseases SC Infectious Diseases GA AC6IW UT WOS:000332626500002 PM 24559321 ER PT J AU Elman, JS Murray, RM Wang, FJ Shen, KY Gao, S Conway, KE Yarmush, ML Tannous, BA Weissleder, R Parekkadan, B AF Elman, Jessica S. Murray, Ryan M. Wang, Fangjing Shen, Keyue Gao, Shan Conway, Kevin E. Yarmush, Martin L. Tannous, Bakhos A. Weissleder, Ralph Parekkadan, Biju TI Pharmacokinetics of Natural and Engineered Secreted Factors Delivered by Mesenchymal Stromal Cells SO PLOS ONE LA English DT Article ID STEM-CELLS; IN-VIVO; THERAPY INDUSTRY; REGENERATION; RESPONSES; RAT; TRANSPLANTATION; INFUSION; IMMUNE; INJURY AB Transient cell therapy is an emerging drug class that requires new approaches for pharmacological monitoring during use. Human mesenchymal stem cells (MSCs) are a clinically-tested transient cell therapeutic that naturally secrete antiinflammatory factors to attenuate immune-mediated diseases. MSCs were used as a proof-of-concept with the hypothesis that measuring the release of secreted factors after cell transplantation, rather than the biodistribution of the cells alone, would be an alternative monitoring tool to understand the exposure of a subject to MSCs. By comparing cellular engraftment and the associated serum concentration of secreted factors released from the graft, we observed clear differences between the pharmacokinetics of MSCs and their secreted factors. Exploration of the effects of natural or engineered secreted proteins, active cellular secretion pathways, and clearance mechanisms revealed novel aspects that affect the systemic exposure of the host to secreted factors from a cellular therapeutic. We assert that a combined consideration of cell delivery strategies and molecular pharmacokinetics can provide a more predictive model for outcomes of MSC transplantation and potentially other transient cell therapeutics. C1 [Elman, Jessica S.; Murray, Ryan M.; Wang, Fangjing; Shen, Keyue; Gao, Shan; Yarmush, Martin L.; Parekkadan, Biju] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Surg,Ctr Engn Med, Boston, MA 02114 USA. [Elman, Jessica S.; Murray, Ryan M.; Wang, Fangjing; Shen, Keyue; Gao, Shan; Yarmush, Martin L.; Parekkadan, Biju] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Surg Serv, Boston, MA USA. [Elman, Jessica S.; Murray, Ryan M.; Wang, Fangjing; Shen, Keyue; Gao, Shan; Yarmush, Martin L.; Parekkadan, Biju] Shriners Hosp Children, Boston, MA USA. [Yarmush, Martin L.] Rutgers State Univ, Dept Biomed Engn, Piscataway, NJ USA. [Weissleder, Ralph] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Syst Biol, Boston, MA USA. [Conway, Kevin E.; Tannous, Bakhos A.] Massachusetts Gen Hosp, Dept Neurol, Expt Therapeut & Mol Imaging Lab, Charlestown, MA USA. [Parekkadan, Biju] Harvard Stem Cell Inst, Boston, MA USA. RP Parekkadan, B (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Surg,Ctr Engn Med, Boston, MA 02114 USA. EM biju_parekkadan@hms.harvard.edu FU National Institutes of Health [R01EB012521, K01DK087770]; Broad Medical Research Program of The Broad Foundation [BMRP498382]; Shriners Hospitals for Children FX This work was supported of the National Institutes of Health (R01EB012521 and K01DK087770) and the Broad Medical Research Program of The Broad Foundation (BMRP498382) and Shriners Hospitals for Children. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 40 TC 4 Z9 4 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 FEB 21 PY 2014 VL 9 IS 2 AR e89882 DI 10.1371/journal.pone.0089882 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AB3VI UT WOS:000331717900151 PM 24587097 ER PT J AU Guha, A Vasconcelos, M Zhao, R Gower, AC Rajagopal, J Cardoso, WV AF Guha, Arjun Vasconcelos, Michelle Zhao, Rui Gower, Adam C. Rajagopal, Jayaraj Cardoso, Wellington V. TI Analysis of Notch Signaling-Dependent Gene Expression in Developing Airways Reveals Diversity of Clara Cells SO PLOS ONE LA English DT Article ID PROGENITOR CELLS; LUNG; INJURY; REPAIR; MICE; REGENERATION; MAINTENANCE; ALVEOLAR AB Clara cells (CCs) are a morphologically and operationally heterogeneous population of Secretoglobin Scgb1a1-expressing secretory cells that are crucial for airway homeostasis and post-injury repair. Analysis of the extent and origin of CC diversity are limited by knowledge of genes expressed in these cells and their precursors. To identify novel putative markers of CCs and explore the origins of CC diversity, we characterized global changes in gene expression in embryonic lungs in which CCs do not form due to conditional disruption of Notch signaling (Rbpjk(CNULL)). Microarray profiling, Real Time PCR (qRTPCR), and RNA in situ hybridization (ISH) identified eleven genes downregulated in the E18.5 airways of Rbpjk(cnull) compared to controls, nearly half not previously known to mark CCs. ISH revealed that several genes had overlapping but distinct domains of expression of in the normal developing lung (E18.5). Notably, Reg3g, Chad, Gabrp and Lrrc26 were enriched in proximal airways, Hp in the distal airways and Upk3a in clusters of cells surrounding Neuroepithelial Bodies (NEBs). Seven of the eleven genes, including Reg3g, Hp, and Upk3a, were expressed in the adult lung in CCs in a pattern similar to that observed in the developing airways. qRT-PCR-based analysis of gene expression of CCs isolated from different airway regions of B1-EGFP reporter mice corroborated the spatial enrichment in gene expression observed by ISH. Our study identifies candidate markers for CC-precursors and CCs and supports the idea that the diversification of the CC phenotype occurs already during embryonic development. C1 [Guha, Arjun; Vasconcelos, Michelle; Cardoso, Wellington V.] Boston Univ, Sch Med, Ctr Pulm, Boston, MA 02118 USA. [Zhao, Rui; Rajagopal, Jayaraj] Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA. [Zhao, Rui; Rajagopal, Jayaraj] Massachusetts Gen Hosp, Dept Internal Med, Pulm & Crit Care Unit, Boston, MA 02114 USA. [Zhao, Rui; Rajagopal, Jayaraj] Massachusetts Gen Hosp, Dept Pediat, Pulm & Crit Care Unit, Boston, MA 02114 USA. [Gower, Adam C.] Boston Univ, Clin & Translat Sci Inst, Boston, MA 02215 USA. RP Guha, A (reprint author), Boston Univ, Sch Med, Ctr Pulm, Boston, MA 02118 USA. EM aguha@bu.edu; wvc2104@columbia.edu RI Zhao, Rui/J-7110-2014 FU NIH-NHLBI [PO1 HL47049, R01 HL105971-01]; BUMC start-up grant; CTSA grant [UL1-TR000157] FX This work was funded by NIH-NHLBI (PO1 HL47049, R01 HL105971-01 to WVC) and a BUMC start-up grant (to A. Guha, A.) and CTSA grant #UL1-TR000157 (A. Gower). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 20 TC 7 Z9 7 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 FEB 21 PY 2014 VL 9 IS 2 AR e88848 DI 10.1371/journal.pone.0088848 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AB3VI UT WOS:000331717900030 PM 24586412 ER PT J AU Koybasi, O Mishra, P James, SS Lewis, JH Seco, J AF Koybasi, Ozhan Mishra, Pankaj James, Sara St. Lewis, John H. Seco, Joao TI Simulation of dosimetric consequences of 4D-CT-based motion margin estimation for proton radiotherapy using patient tumor motion data SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article DE four-dimensional computed tomography; internal target volume; lung tumor motion; XCAT phantom; proton radiotherapy ID 4D XCAT PHANTOM; LUNG-CANCER; RESPIRATORY MOTION; TARGET VOLUME; THERAPY; TRACKING; PROJECTIONS; ALGORITHM; SIZE AB For the radiation treatment of lung cancer patients, four-dimensional computed tomography (4D-CT) is a common practice used clinically to image tumor motion and subsequently determine the internal target volume (ITV) from the maximum intensity projection (MIP) images. ITV, which is derived from short pre-treatment 4D-CT scan (<6 s per couch position), may not adequately cover the extent of tumor motion during the treatment, particularly for patients that exhibit a large respiratory variability. Inaccurate tumor localization may result in under-dosage of the tumor or over-dosage of the surrounding tissues. The purpose of this study is therefore to assess the degree of tumor under-dosage in case of regular and irregular breathing for proton radiotherapy using ITV-based treatment planning. We place a spherical lesion into a modified XCAT phantom that is also capable of producing 4D images based on irregular breathing, and move the tumor according to real tumor motion data, which is acquired over multiple days by tracking gold fiducial markers implanted into the lung tumors of patients. We derive ITVs by taking the union of all tumor positions during 6 s of tumor motion in the phantom using the first day patient tumor tracking data. This is equivalent to ITVs generated clinically from cine-mode 4D-CT MIP images. The treatment plans created for different ITVs are then implemented on dynamic phantoms with tumor motion governed by real tumor tracking data from consecutive days. By comparing gross tumor volume dose distribution on days of 'treatment' with the ITV dose distribution, we evaluate the deviation of the actually delivered dose from the predicted dose. Our results have shown that the proton treatment planning on ITV derived from pre-treatment cine-mode 4D-CT can result in under-dosage (dose covering 95% of volume) of the tumor by up to 25.7% over 3 min of treatment for the patient with irregular respiratory motion. Tumor under-dosage is less significant for the patient with relatively regular breathing. We have demonstrated that proton therapy using the pre-treatment 4D-CT based ITV method can lead to significant under-dosage of the tumor, highlighting the need for daily customization to generate a target volume that represents tumor positions during the treatment more accurately. C1 [Koybasi, Ozhan; Seco, Joao] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Koybasi, Ozhan; Mishra, Pankaj; James, Sara St.; Lewis, John H.; Seco, Joao] Harvard Univ, Sch Med, Boston, MA USA. [Mishra, Pankaj; James, Sara St.; Lewis, John H.] Brigham & Womens Hosp, Dept Radiat Oncol, Boston, MA 02115 USA. [Mishra, Pankaj; James, Sara St.; Lewis, John H.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Koybasi, O (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. EM ozhankoybasi@gmail.com NR 22 TC 8 Z9 8 U1 0 U2 8 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 FEB 21 PY 2014 VL 59 IS 4 BP 853 EP 867 DI 10.1088/0031-9155/59/4/853 PG 15 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA AB6YZ UT WOS:000331937500005 PM 24487573 ER PT J AU Abbasi, SA Ertel, A Shah, RV Dandekar, V Chung, J Bhat, G Desai, AA Kwong, RY Farzaneh-Far, A AF Abbasi, Siddique A. Ertel, Andrew Shah, Ravi V. Dandekar, Vineet Chung, Jaehoon Bhat, Geetha Desai, Ankit A. Kwong, Raymond Y. Farzaneh-Far, Afshin TI Impact of cardiovascular magnetic resonance on management and clinical decision-making in heart failure patients (vol 15, pg 89, 2013) SO JOURNAL OF CARDIOVASCULAR MAGNETIC RESONANCE LA English DT Correction C1 [Abbasi, Siddique A.; Shah, Ravi V.; Kwong, Raymond Y.] Brigham & Womens Hosp, Dept Med, Div Cardiovasc Med, Boston, MA 02115 USA. [Abbasi, Siddique A.; Shah, Ravi V.; Kwong, Raymond Y.] Harvard Univ, Sch Med, Boston, MA USA. [Abbasi, Siddique A.; Ertel, Andrew; Dandekar, Vineet; Chung, Jaehoon; Bhat, Geetha; Desai, Ankit A.; Farzaneh-Far, Afshin] Univ Illinois, Dept Med, Cardiol Sect, Chicago, IL 60612 USA. [Shah, Ravi V.] Massachusetts Gen Hosp, Dept Med, Div Cardiol, Boston, MA 02114 USA. [Bhat, Geetha] Advocate Christ Med Ctr, Ctr Heart Transplant & Assist Devices, Oak Lawn, IL USA. [Farzaneh-Far, Afshin] Univ Illinois, Dept Radiol, Chicago, IL USA. RP Farzaneh-Far, A (reprint author), Univ Illinois, Dept Med, Cardiol Sect, 840 South Wood St M-C 715,Suite 920 S, Chicago, IL 60612 USA. EM afshin@uic.edu OI Abbasi, Siddique/0000-0002-9601-7565 NR 1 TC 2 Z9 2 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1097-6647 EI 1532-429X J9 J CARDIOVASC MAGN R JI J. Cardiov. Magn. Reson. PD FEB 21 PY 2014 VL 16 AR 20 DI 10.1186/1532-429X-16-20 PG 1 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA AB7XX UT WOS:000332005500001 ER PT J AU Brooks, GA Abrams, TA Meyerhardt, JA Enzinger, PC Sommer, K Dalby, CK Uno, H Jacobson, JO Fuchs, CS Schrag, D AF Brooks, Gabriel A. Abrams, Thomas A. Meyerhardt, Jeffrey A. Enzinger, Peter C. Sommer, Karen Dalby, Carole K. Uno, Hajime Jacobson, Joseph O. Fuchs, Charles S. Schrag, Deborah TI Identification of Potentially Avoidable Hospitalizations in Patients With GI Cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID OF-LIFE CARE; PALLIATIVE CARE; UNITED-STATES; HOSPICE CARE; HEALTH-CARE; COST; END; REHOSPITALIZATIONS; OPPORTUNITIES; READMISSIONS AB Purpose To identify and characterize potentially avoidable hospitalizations in patients with GI malignancies. Patients and Methods We compiled a retrospective series of sequential hospital admissions in patients with GI cancer. Patients were admitted to an inpatient medical oncology or palliative care service between December 2011 and July 2012. Practicing oncology clinicians used a consensus-driven medical record review process to categorize each hospitalization as potentially avoidable or not avoidable. Patient demographic and clinical data were abstracted, and quantitative and qualitative analyses were performed to identify patient characteristics and outcomes associated with potentially avoidable hospitalizations. Results We evaluated 201 hospitalizations in 154 unique patients. The median age was 62 years, and colorectal cancer was the most common diagnosis (32%). The majority of hospitalized patients had metastatic cancer (81%). In all, 53% of hospitalizations were attributable to cancer symptoms, and 28% were attributable to complications of cancer treatment. Medical oncologists identified 39 hospitalizations (19%) as potentially avoidable. Hospitalizations were more likely to be categorized as potentially avoidable for patients with the following characteristics: age 70 years (odds ratio [OR], 2.63; 95% CI, 1.15 to 6.02), receipt of an oncologist's advice to consider hospice (OR, 6.09; 95% CI, 2.54 to 14.58), or receipt of three or more lines of chemotherapy (OR, 2.68; 95% CI, 1.01 to 7.08). Ninety-day mortality was higher after avoidable hospitalizations compared with hospitalizations that were not avoidable (OR, 6.4; 95% CI, 1.8 to 22.3). Conclusion Potentially avoidable hospitalizations are common in patients with advanced GI cancer. The majority of potentially avoidable hospitalizations occurred in patients with advanced treatment-refractory cancers near the end of life. (C) 2014 by American Society of Clinical Oncology C1 [Brooks, Gabriel A.; Abrams, Thomas A.; Meyerhardt, Jeffrey A.; Enzinger, Peter C.; Sommer, Karen; Dalby, Carole K.; Uno, Hajime; Jacobson, Joseph O.; Fuchs, Charles S.; Schrag, Deborah] Dana Farber Canc Inst, Boston, MA 02215 USA. RP Brooks, GA (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. EM gabriel_brooks@dfci.harvard.edu OI Brooks, Gabriel/0000-0003-3984-9995 FU Conquer Cancer Foundation of the American Society of Clinical Oncology [5R01CA131847]; National Cancer Institute, National Institutes of Health [T32CA009172] FX Supported by the Conquer Cancer Foundation of the American Society of Clinical Oncology (Young Investigator Award [G.A.B.]) and by Grant No. 5R01CA131847 (D.S.) and Institutional Training Grant No. T32CA009172 (G.A.B.) from the National Cancer Institute, National Institutes of Health. NR 33 TC 22 Z9 24 U1 3 U2 8 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 20 PY 2014 VL 32 IS 6 BP 496 EP + DI 10.1200/JCO.2013.52.4330 PG 9 WC Oncology SC Oncology GA AC8ND UT WOS:000332788900007 PM 24419123 ER PT J AU Marcucci, G Yan, P Maharry, K Frankhouser, D Nicolet, D Metzeler, KH Kohlschmidt, J Mrozek, K Wu, YZ Bucci, D Curfman, JP Whitman, SP Eisfeld, AK Mendler, JH Schwind, S Becker, H Bar, C Carroll, AJ Baer, MR Wetzler, M Carter, TH Powell, BL Kolitz, JE Byrd, JC Plass, C Garzon, R Caligiuri, MA Stone, RM Volinia, S Bundschuh, R Bloomfield, CD AF Marcucci, Guido Yan, Pearlly Maharry, Kati Frankhouser, David Nicolet, Deedra Metzeler, Klaus H. Kohlschmidt, Jessica Mrozek, Krzysztof Wu, Yue-Zhong Bucci, Donna Curfman, John P. Whitman, Susan P. Eisfeld, Ann-Kathrin Mendler, Jason H. Schwind, Sebastian Becker, Heiko Baer, Constance Carroll, Andrew J. Baer, Maria R. Wetzler, Meir Carter, Thomas H. Powell, Bayard L. Kolitz, Jonathan E. Byrd, John C. Plass, Christoph Garzon, Ramiro Caligiuri, Michael A. Stone, Richard M. Volinia, Stefano Bundschuh, Ralf Bloomfield, Clara D. TI Epigenetics Meets Genetics in Acute Myeloid Leukemia: Clinical Impact of a Novel Seven-Gene Score SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID MICRORNA-EXPRESSION SIGNATURES; DNA METHYLATION; OLDER PATIENTS; PROGNOSTIC IMPACT; DNMT3A MUTATIONS; CANCER; AML; ISLANDS; RISK; HYPERMETHYLATION AB Purpose Molecular risk stratification of acute myeloid leukemia (AML) is largely based on genetic markers. However, epigenetic changes, including DNA methylation, deregulate gene expression and may also have prognostic impact. We evaluated the clinical relevance of integrating DNA methylation and genetic information in AML. Methods Next-generation sequencing analysis of methylated DNA identified differentially methylated regions (DMRs) associated with prognostic mutations in older ( 60 years) cytogenetically normal (CN) patients with AML (n = 134). Genes with promoter DMRs and expression levels significantly associated with outcome were used to compute a prognostic gene expression weighted summary score that was tested and validated in four independent patient sets (n = 355). Results In the training set, we identified seven genes (CD34, RHOC, SCRN1, F2RL1, FAM92A1, MIR155HG, and VWA8) with promoter DMRs and expression associated with overall survival (OS; P .001). Each gene had high DMR methylation and lower expression, which were associated with better outcome. A weighted summary expression score of the seven gene expression levels was computed. A low score was associated with a higher complete remission (CR) rate and longer disease-free survival and OS (P < .001 for all end points). This was validated in multivariable models and in two younger (< 60 years) and two older independent sets of patients with CN-AML. Considering the seven genes individually, the fewer the genes with high expression, the better the outcome. Younger and older patients with no genes or one gene with high expression had the best outcomes (CR rate, 94% and 87%, respectively; 3-year OS, 80% and 42%, respectively). Conclusion A seven-gene score encompassing epigenetic and genetic prognostic information identifies novel AML subsets that are meaningful for treatment guidance. (C) 2013 by American Society of Clinical Oncology C1 [Marcucci, Guido; Yan, Pearlly; Maharry, Kati; Frankhouser, David; Nicolet, Deedra; Metzeler, Klaus H.; Kohlschmidt, Jessica; Mrozek, Krzysztof; Wu, Yue-Zhong; Bucci, Donna; Curfman, John P.; Whitman, Susan P.; Eisfeld, Ann-Kathrin; Mendler, Jason H.; Schwind, Sebastian; Becker, Heiko; Byrd, John C.; Garzon, Ramiro; Caligiuri, Michael A.; Volinia, Stefano; Bloomfield, Clara D.] Ohio State Univ, Ctr Comprehens Canc, Columbus, OH 43210 USA. [Bundschuh, Ralf] Ohio State Univ, Columbus, OH 43210 USA. [Maharry, Kati; Nicolet, Deedra; Kohlschmidt, Jessica] Mayo Clin, Alliance Clin Trials Oncol Stat, Rochester, MN USA. [Maharry, Kati; Nicolet, Deedra; Kohlschmidt, Jessica] Mayo Clin, Ctr Data, Rochester, MN USA. [Carroll, Andrew J.] Univ Alabama Birmingham, Birmingham, AL USA. [Baer, Maria R.] Univ Maryland, Greenebaum Canc Ctr, Baltimore, MD 21201 USA. [Wetzler, Meir] Roswell Pk Canc Inst, Buffalo, NY 14263 USA. [Kolitz, Jonathan E.] Monter Canc Ctr, Lake Success, NY USA. [Carter, Thomas H.] Univ Iowa, Iowa City, IA USA. [Powell, Bayard L.] Wake Forest Univ, Ctr Comprehens Canc, Winston Salem, NC 27109 USA. [Stone, Richard M.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Baer, Maria R.; Plass, Christoph] German Canc Res Ctr, Heidelberg, Germany. RP Marcucci, G (reprint author), Ohio State Univ, Ctr Comprehens Canc, 410 Biomed Res Tower,460 W 12th Ave, Columbus, OH 43210 USA. EM guido.marcucci@osumc.edu RI Metzeler, Klaus/C-2118-2009; Plass, Christoph/H-7192-2014; Bundschuh, Ralf/B-9623-2008; Garzon, Ramiro/E-3104-2011; Mrozek, Krzysztof/A-3142-2008; Yan, Pearlly/E-4339-2011; OI Volinia, Stefano/0000-0003-0910-3893; Metzeler, Klaus/0000-0003-3920-7490; Bundschuh, Ralf/0000-0002-6699-8614; Yan, Pearlly/0000-0003-1965-4920; Carter, Thomas/0000-0001-7796-2986; Mendler, Jason/0000-0001-5605-5324 FU National Cancer Institute [CA101140, CA114725, CA31946, CA33601, CA16058, CA77658, CA129657, CA140158]; Deutsche Krebshilfe-Dr Mildred Scheel Cancer Foundation; Pelotonia Fellowship Program; Conquer Cancer Foundation; Coleman Leukemia Research Foundation FX Supported in part by Grants No. CA101140, CA114725, CA31946, CA33601, CA16058, CA77658, CA129657, and CA140158 from the National Cancer Institute; the Coleman Leukemia Research Foundation; the Deutsche Krebshilfe-Dr Mildred Scheel Cancer Foundation (H.B.); the Pelotonia Fellowship Program (A.-K.E.); and the Conquer Cancer Foundation (J.H.M.). NR 38 TC 53 Z9 53 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 FEB 20 PY 2014 VL 32 IS 6 BP 548 EP 556 DI 10.1200/JCO.2013.50.6337 PG 9 WC Oncology SC Oncology GA AC8ND UT WOS:000332788900014 PM 24378410 ER PT J AU Palumbo, A Rajkumar, SV San Miguel, JF Larocca, A Niesvizky, R Morgan, G Landgren, O Hajek, R Einsele, H Anderson, KC Dimopoulos, MA Richardson, PG Cavo, M Spencer, A Stewart, AK Shimizu, K Lonial, S Sonneveld, P Durie, BGM Moreau, P Orlowski, RZ AF Palumbo, Antonio Rajkumar, S. Vincent San Miguel, Jesus F. Larocca, Alessandra Niesvizky, Ruben Morgan, Gareth Landgren, Ola Hajek, Roman Einsele, Hermann Anderson, Kenneth C. Dimopoulos, Meletios A. Richardson, Paul G. Cavo, Michele Spencer, Andrew Stewart, A. Keith Shimizu, Kazuyuki Lonial, Sagar Sonneveld, Pieter Durie, Brian G. M. Moreau, Philippe Orlowski, Robert Z. TI International Myeloma Working Group Consensus Statement for the Management, Treatment, and Supportive Care of Patients With Myeloma Not Eligible for Standard Autologous Stem-Cell Transplantation SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID DIAGNOSED MULTIPLE-MYELOMA; RANDOMIZED CONTROLLED-TRIAL; LENALIDOMIDE PLUS DEXAMETHASONE; IMPAIRED RENAL-FUNCTION; BORTEZOMIB-MELPHALAN-PREDNISONE; NEUROPATHIC CANCER PAIN; ELDERLY-PATIENTS; PERIPHERAL NEUROPATHY; ZOLEDRONIC ACID; BONE-DISEASE AB Purpose To provide an update on recent advances in the management of patients with multiple myeloma who are not eligible for autologous stem-cell transplantation. Methods A comprehensive review of the literature on diagnostic criteria is provided, and treatment options and management of adverse events are summarized. Results Patients with symptomatic disease and organ damage (ie, hypercalcemia, renal failure, anemia, or bone lesions) require immediate treatment. The International Staging System and chromosomal abnormalities identify high- and standard-risk patients. Proteasome inhibitors, immunomodulatory drugs, corticosteroids, and alkylating agents are the most active agents. The presence of concomitant diseases, frailty, or disability should be assessed and, if present, treated with reduced-dose approaches. Bone disease, renal damage, hematologic toxicities, infections, thromboembolism, and peripheral neuropathy are the most frequent disabling events requiring prompt and active supportive care. Conclusion These recommendations will help clinicians ensure the most appropriate care for patients with myeloma in everyday clinical practice. (C) 2014 by American Society of Clinical Oncology C1 [Palumbo, Antonio; Larocca, Alessandra] Univ Turin, I-10126 Turin, Italy. [Cavo, Michele] Univ Bologna, Sch Med, Seragnoli Inst Hematol, Bologna, Italy. [Rajkumar, S. Vincent] Mayo Clin, Rochester, MN USA. [San Miguel, Jesus F.] Univ Hosp Salamanca, Salamanca, Spain. [Niesvizky, Ruben] Weill Cornell Med Coll, New York, NY USA. [Morgan, Gareth] Royal Marsden Hosp, London SW3 6JJ, England. [Landgren, Ola] NCI, Bethesda, MD 20892 USA. [Hajek, Roman] Univ Ostrava, Sch Med, CZ-70103 Ostrava, Czech Republic. [Hajek, Roman] Univ Hosp Ostrava, Ostrava, Czech Republic. [Einsele, Hermann] Univ Wurzburg, D-97070 Wurzburg, Germany. [Anderson, Kenneth C.; Richardson, Paul G.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Dimopoulos, Meletios A.] Univ Athens, Sch Med, GR-11527 Athens, Greece. [Spencer, Andrew] Alfred Hosp, Melbourne, Vic, Australia. [Stewart, A. Keith] Mayo Clin, Scottsdale, AZ USA. [Shimizu, Kazuyuki] Aichi Gakuin Hosp, Nagoya, Aichi, Japan. [Lonial, Sagar] Emory Univ, Atlanta, GA 30322 USA. [Sonneveld, Pieter] Erasmus MC, Rotterdam, Netherlands. [Durie, Brian G. M.] Cedars Sinai Comprehens Canc Ctr, Los Angeles, CA USA. [Moreau, Philippe] Univ Hosp, Nantes, France. [Orlowski, Robert Z.] Univ Texas Houston, MD Anderson Canc Ctr, Houston, TX 77030 USA. RP Palumbo, A (reprint author), Univ Turin, Dept Hematol, Via Genova 3, I-10126 Turin, Italy. EM appalumbo@yahoo.com RI richard, chrystelle/K-8595-2015; OI SAN MIGUEL, JESUS/0000-0002-9183-4857; CAVO, MICHELE/0000-0003-4514-3227 FU Onyx Pharmaceuticals; Millennium Pharmaceuticals; Celgene; Janssen-Cilag; Daiichi Sankyo; Bristol-Myers Squibb FX Research Funding: Ruben Niesvizky, Onyx Pharmaceuticals, Millennium Pharmaceuticals, Celgene; Hermann Einsele, Celgene, Janssen-Cilag; Meletios A. Dimopoulos, Celgene; Kazuyuki Shimizu, Daiichi Sankyo; Pieter Sonneveld, Celgene, Janssen-Cilag, Onyx Pharmaceuticals; Robert Z. Orlowski, Celgene, Millennium Pharmaceuticals, Onyx Pharmaceuticals, Bristol-Myers Squibb NR 122 TC 84 Z9 88 U1 1 U2 11 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 20 PY 2014 VL 32 IS 6 BP 587 EP + DI 10.1200/JCO.2013.48.7934 PG 17 WC Oncology SC Oncology GA AC8ND UT WOS:000332788900019 PM 24419113 ER PT J AU Davids, MS AF Davids, Matthew S. TI Boldly Targeting Kinases without mutations SO BLOOD LA English DT Editorial Material ID CHRONIC LYMPHOCYTIC-LEUKEMIA; CELL; IBRUTINIB; LYMPHOMA; PATHWAY; CANCER; BTK C1 Dana Farber Canc Inst, Boston, MA 02215 USA. RP Davids, MS (reprint author), Dana Farber Canc Inst, Boston, MA 02215 USA. NR 13 TC 4 Z9 4 U1 1 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 FEB 20 PY 2014 VL 123 IS 8 BP 1119 EP 1121 DI 10.1182/blood-2013-12-543322 PG 5 WC Hematology SC Hematology GA AH0VG UT WOS:000335838100005 PM 24558189 ER PT J AU Ackerly, DC Grabowski, DC AF Ackerly, D. Clay Grabowski, David C. TI Post-Acute Care Reform - Beyond the ACA SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material C1 [Ackerly, D. Clay] Partners HealthCare, Boston, MA 02199 USA. [Ackerly, D. Clay] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Ackerly, D. Clay] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Ackerly, D. Clay; Grabowski, David C.] Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. RP Ackerly, DC (reprint author), Partners HealthCare, Boston, MA 02199 USA. NR 6 TC 18 Z9 18 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 FEB 20 PY 2014 VL 370 IS 8 BP 689 EP 691 DI 10.1056/NEJMp1315350 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA AB1DO UT WOS:000331531900002 PM 24552314 ER PT J AU Tewari, KS Sill, MW Long, HJ Penson, RT Huang, H Ramondetta, LM Landrum, LM Oaknin, A Reid, TJ Leitao, MM Michael, HE Monk, BJ AF Tewari, Krishnansu S. Sill, Michael W. Long, Harry J., III Penson, Richard T. Huang, Helen Ramondetta, Lois M. Landrum, Lisa M. Oaknin, Ana Reid, Thomas J. Leitao, Mario M. Michael, Helen E. Monk, Bradley J. TI Improved Survival with Bevacizumab in Advanced Cervical Cancer SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID GYNECOLOGIC-ONCOLOGY-GROUP; SQUAMOUS-CELL CARCINOMA; ENDOTHELIAL GROWTH-FACTOR; RANDOMIZED-TRIAL; UTERINE CERVIX; PHASE-II; CISPLATIN; RECURRENT; PERSISTENT; TOPOTECAN AB BackgroundVascular endothelial growth factor (VEGF) promotes angiogenesis, a mediator of disease progression in cervical cancer. Bevacizumab, a humanized anti-VEGF monoclonal antibody, has single-agent activity in previously treated, recurrent disease. Most patients in whom recurrent cervical cancer develops have previously received cisplatin with radiation therapy, which reduces the effectiveness of cisplatin at the time of recurrence. We evaluated the effectiveness of bevacizumab and nonplatinum combination chemotherapy in patients with recurrent, persistent, or metastatic cervical cancer. MethodsUsing a 2-by-2 factorial design, we randomly assigned 452 patients to chemotherapy with or without bevacizumab at a dose of 15 mg per kilogram of body weight. Chemotherapy consisted of cisplatin at a dose of 50 mg per square meter of body-surface area, plus paclitaxel at a dose of 135 or 175 mg per square meter or topotecan at a dose of 0.75 mg per square meter on days 1 to 3, plus paclitaxel at a dose of 175 mg per square meter on day 1. Cycles were repeated every 21 days until disease progression, the development of unacceptable toxic effects, or a complete response was documented. The primary end point was overall survival; a reduction of 30% in the hazard ratio for death was considered clinically important. ResultsGroups were well balanced with respect to age, histologic findings, performance status, previous use or nonuse of a radiosensitizing platinum agent, and disease status. Topotecan-paclitaxel was not superior to cisplatin-paclitaxel (hazard ratio for death, 1.20). With the data for the two chemotherapy regimens combined, the addition of bevacizumab to chemotherapy was associated with increased overall survival (17.0 months vs. 13.3 months; hazard ratio for death, 0.71; 98% confidence interval, 0.54 to 0.95; P=0.004 in a one-sided test) and higher response rates (48% vs. 36%, P=0.008). Bevacizumab, as compared with chemotherapy alone, was associated with an increased incidence of hypertension of grade 2 or higher (25% vs. 2%), thromboembolic events of grade 3 or higher (8% vs. 1%), and gastrointestinal fistulas of grade 3 or higher (3% vs. 0%). ConclusionsThe addition of bevacizumab to combination chemotherapy in patients with recurrent, persistent, or metastatic cervical cancer was associated with an improvement of 3.7 months in median overall survival. (Funded by the National Cancer Institute; GOG 240 ClinicalTrials.gov number, NCT00803062.) C1 [Tewari, Krishnansu S.] Univ Calif Irvine, Med Ctr, Orange, CA 92868 USA. [Sill, Michael W.; Huang, Helen] SUNY Buffalo, Roswell Pk Canc Inst, Buffalo, NY 14260 USA. [Long, Harry J., III] Mayo Clin, Rochester, MN USA. [Penson, Richard T.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Ramondetta, Lois M.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Landrum, Lisa M.] Univ Oklahoma, Oklahoma City, OK USA. [Oaknin, Ana] Vall dHebron Univ Hosp, Barcelona, Spain. [Reid, Thomas J.] Univ Cincinnati, Coll Med, Womens Canc Ctr Kettering, Kettering, OH USA. [Leitao, Mario M.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Michael, Helen E.] Indiana Univ Sch Med, Indianapolis, IN 46202 USA. [Monk, Bradley J.] Univ Arizona, Ctr Canc, Phoenix, AZ USA. [Monk, Bradley J.] Creighton Univ, St Josephs Hosp & Med Ctr, Phoenix, AZ USA. RP Tewari, KS (reprint author), Univ Calif Irvine, Med Ctr, Div Gynecol Oncol, 101 City Dr S,Bldg 56, Orange, CA 92868 USA. EM ktewari@uci.edu FU NCI NIH HHS [P30 CA016672, U10 CA037517] NR 38 TC 244 Z9 257 U1 7 U2 38 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 FEB 20 PY 2014 VL 370 IS 8 BP 734 EP 743 DI 10.1056/NEJMoa1309748 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA AB1DO UT WOS:000331531900008 PM 24552320 ER PT J AU Yager, PH Luginbuhl, LM Dekker, JP AF Yager, Phoebe H. Luginbuhl, Lynn M. Dekker, John P. TI Case 6-2014: A 35-Day-Old Boy with Fever, Vomiting, Mottled Skin, and Severe Anemia SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID NEW-YORK-STATE; EXCHANGE-TRANSFUSION; HUMAN BABESIOSIS; CONGENITAL BABESIOSIS; NEW-JERSEY; INFECTIONS; MALARIA; SEPSIS; INFANT; TICKS C1 [Yager, Phoebe H.; Luginbuhl, Lynn M.] Massachusetts Gen Hosp, Dept Pediat, Boston, MA 02114 USA. [Dekker, John P.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Yager, Phoebe H.; Luginbuhl, Lynn M.] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Dekker, John P.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Yager, PH (reprint author), Massachusetts Gen Hosp, Dept Pediat, Boston, MA 02114 USA. NR 23 TC 5 Z9 5 U1 0 U2 9 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 FEB 20 PY 2014 VL 370 IS 8 BP 753 EP 762 DI 10.1056/NEJMcpc1208155 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA AB1DO UT WOS:000331531900011 PM 24552323 ER PT J AU Fried, LF Emanuele, N Zhang, JH AF Fried, Linda F. Emanuele, Nicholas Zhang, Jane H. TI Combined Angiotensin Inhibition in Diabetic Nephropathy REPLY SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [Fried, Linda F.] Vet Affairs Pittsburgh Healthcare Syst, Pittsburgh, PA 15261 USA. [Emanuele, Nicholas] US Dept Vet Affairs, Vet Affairs Edward Hines Jr Hosp, Hines, IL 60141 USA. [Zhang, Jane H.] Vet Affairs Connecticut Healthcare Syst, West Haven, CT USA. RP Fried, LF (reprint author), Vet Affairs Pittsburgh Healthcare Syst, Pittsburgh, PA 15261 USA. EM linda.fried@va.gov NR 4 TC 2 Z9 2 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD FEB 20 PY 2014 VL 370 IS 8 BP 779 EP 779 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA AB1DO UT WOS:000331531900020 PM 24552328 ER PT J AU Goldfinger, S AF Goldfinger, Stephen TI A Randomized Trial of Colchicine for Acute Pericarditis SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter AB To the Editor: With regard to the use of colchicine to prevent recurrent pericarditis, Imazio et al. (Oct. 17 issue)(1) might have achieved an even more favorable outcome in their study if they had used a dose of colchicine higher than 0.5 mg per deciliter for patients weighing less than 70 kg. I routinely treat patients with familial Mediterranean fever with 1.2 mg per deciliter regardless of their weight. Of approximately 40 such patients followed for many years while taking colchicine daily, none have reported side effects other than mild and easily managed diarrhea, which occurred in a few. In ... C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Goldfinger, S (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. EM sgoldfinger@partners.org NR 0 TC 3 Z9 3 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD FEB 20 PY 2014 VL 370 IS 8 BP 780 EP 780 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA AB1DO UT WOS:000331531900021 PM 24552334 ER PT J AU Barnes, JA Abramson, JS AF Barnes, Jeffrey A. Abramson, Jeremy S. TI Case 35-2013: A Man with Confusion and Malaise REPLY SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter AB To the Editor: Dense-deposit disease is a complement-mediated disorder characterized by a proliferative glomerulonephritis, bright capillary-wall C3 staining on immunofluorescence microscopy, and large intramembranous osmiophilic dense deposits that markedly thicken the glomerular capillary walls.(1),(2) The underlying pathophysiology fluid-phase dysregulation of the alternative pathway leads to accumulation of C3 breakdown products in the glomerular basement membrane. C4 is conspicuously absent.(3) Proteinuria was detected in a 12-year-old Hispanic girl at a well-child visit. The blood urea nitrogen and serum creatinine levels were normal, urinalysis showed trace blood with a urinary protein-to-creatinine ratio of 1.5, and renal ultrasonography showed normal-size ... C1 [Barnes, Jeffrey A.; Abramson, Jeremy S.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Barnes, JA (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD FEB 20 PY 2014 VL 370 IS 8 BP 784 EP 784 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA AB1DO UT WOS:000331531900032 PM 24552343 ER PT J AU Zhu, W Begum, G Pointer, K Clark, PA Yang, SS Lin, SH Kahle, KT Kuo, JS Sun, DD AF Zhu, Wen Begum, Gulnaz Pointer, Kelli Clark, Paul A. Yang, Sung-Sen Lin, Shih-Hua Kahle, Kristopher T. Kuo, John S. Sun, Dandan TI WNK1-OSR1 kinase-mediated phospho-activation of Na+-K+-2Cl(-) cotransporter facilitates glioma migration SO MOLECULAR CANCER LA English DT Article DE Bumetanide; Cell volume; Ezrin; Ion cotransporter; Temozolomide ID LOWERS BLOOD-PRESSURE; CELL-MIGRATION; CONFERS PROTECTION; MALIGNANT GLIOMA; CL-COTRANSPORTER; ERM PROTEINS; WNK1; TEMOZOLOMIDE; INHIBITION; GROWTH AB Background: The bumetanide (BMT)-sensitive Na+-K+-2Cl(-) cotransporter isoform 1 (NKCC1) maintains cell volume homeostasis by increasing intracellular K+ and Cl- content via regulatory volume increase (RVI). Expression levels of NKCC1 positively correlate with the histological grade and severity of gliomas, the most common primary adult brain tumors, and up-regulated NKCC1 activity facilitates glioma cell migration and apoptotic resistance to the chemotherapeutic drug temozolomide (TMZ). However, the cellular mechanisms underlying NKCC1 functional up-regulation in glioma and in response to TMZ administration remain unknown. Methods: Expression of NKCC1 and its upstream kinases With-No-K (Lysine) kinase 1 (WNK1) and oxidative stress-responsive kinase-1 (OSR1) in different human glioma cell lines and glioma specimens were detected by western blotting and immunostaining. Live cell imaging and microchemotaxis assay were applied to record glioma cell movements under different treatment conditions. Fluorescence indicators were utilized to measure cell volume, intracellular K+ and Cl- content to reflect the activity of NKCC1 on ion transportation. Small interfering RNA (siRNA)-mediated knockdown of WNK1 or OSR1 was used to explore their roles in regulation of NKCC1 activity in glioma cells. Results of different treatment groups were compared by one-way ANOVA using the Bonferroni post-hoc test in the case of multiple comparisons. Results: We show that compared to human neural stem cells and astrocytes, human glioma cells exhibit robust increases in the activation and phosphorylation of NKCC1 and its two upstream regulatory kinases, WNK1 and OSR1. siRNA-mediated knockdown of WNK1 or OSR1 reduces intracellular K+ and Cl- content and RVI in glioma cells by abolishing NKCC1 regulatory phospho-activation. Unexpectedly, TMZ activates the WNK1/OSR1/NKCC1 signaling pathway and enhances glioma migration. Pharmacological inhibition of NKCC1 with its potent inhibitor BMT or siRNA knockdown of WNK1 or OSR1 significantly decreases glioma cell migration after TMZ treatment. Conclusion: Together, our data show a novel role for the WNK1/OSR1/NKCC1 pathway in basal and TMZ-induced glioma migration, and suggest that glioma treatment with TMZ might be improved by drugs that inhibit elements of the WNK1/OSR1/NKCC1 signaling pathway. C1 [Zhu, Wen; Begum, Gulnaz; Sun, Dandan] Univ Pittsburgh, Dept Neurol, Pittsburgh, PA 15213 USA. [Pointer, Kelli; Kuo, John S.] Univ Wisconsin, Sch Med & Publ Hlth, Cellular & Mol Biol Program, Madison, WI USA. [Pointer, Kelli; Clark, Paul A.; Kuo, John S.] Univ Wisconsin, Sch Med & Publ Hlth, Dept Neurol Surg, Madison, WI USA. [Kuo, John S.] Univ Wisconsin, Carbone Canc Ctr, Madison, WI USA. [Yang, Sung-Sen; Lin, Shih-Hua] Natl Def Med Ctr, Tri Serv Gen Hosp, Div Nephrol, Dept Med, Taipei, Taiwan. [Kahle, Kristopher T.] Massachusetts Gen Hosp, Dept Neurol Surg, Boston, MA 02114 USA. [Kahle, Kristopher T.] Harvard Univ, Sch Med, Boston, MA USA. [Sun, Dandan] Vet Affairs Pittsburgh Hlth Care Syst, Geriatr Res Educ & Clin Ctr, Pittsburgh, PA USA. RP Sun, DD (reprint author), Univ Pittsburgh, Dept Neurol, S-598 South Biomed Sci Tower BST,3500 Terrace St, Pittsburgh, PA 15213 USA. EM sund@upmc.edu OI Kuo, John/0000-0001-6809-4806 FU NIH [R01NS75995, R01NS38118]; HEADRUSH Brain Tumor Research Professorship; Roger Loff Memorial GBM Research Fund; Department of Neurological Surgery FX This work was supported in part by NIH grant R01NS75995 and R01NS38118 (DS, JSK, KP), and the HEADRUSH Brain Tumor Research Professorship, Roger Loff Memorial GBM Research Fund, and Department of Neurological Surgery (JSK). NR 42 TC 16 Z9 18 U1 0 U2 16 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 FEB 20 PY 2014 VL 13 AR 31 DI 10.1186/1476-4598-13-31 PG 15 WC Biochemistry & Molecular Biology; Oncology SC Biochemistry & Molecular Biology; Oncology GA AF2ID UT WOS:000334534900002 PM 24555568 ER PT J AU Parikh, RV Scherzer, R Nitta, EM Leone, A Hur, S Mistry, V Macgregor, JS Martin, JN Deeks, SG Ganz, P Hsue, PY AF Parikh, Rushi V. Scherzer, Rebecca Nitta, Elaine M. Leone, Anna Hur, Sophia Mistry, Vanita Macgregor, John S. Martin, Jeffrey N. Deeks, Steven G. Ganz, Peter Hsue, Priscilla Y. TI Increased levels of asymmetric dimethylarginine are associated with pulmonary arterial hypertension in HIV infection SO AIDS LA English DT Article DE HIV; endothelial dysfunction; nitric oxide; asymmetric dimethylarginine; pulmonary arterial hypertension ID HUMAN-IMMUNODEFICIENCY-VIRUS; ANTIRETROVIRAL THERAPY; ENDOTHELIAL DYSFUNCTION; PROGNOSTIC-FACTORS; SURVIVAL; ERA; INFLAMMATION; PRESSURE; REGISTRY; ADMA AB Objective: To examine the relationship between asymmetric dimethylarginine (ADMA) and HIV-associated pulmonary arterial hypertension (PAH). Design: HIV infection is an independent risk factor for PAH, but the underlying pathogenesis remains unclear. Chronic inflammation resulting in nitric oxide-mediated endothelial dysfunction is a key mechanism underlying other types of PAH. ADMA is an endogenous inhibitor of endothelial nitric oxide synthase. Among uninfected individuals, ADMA is associated with PAH and predicts disease-related mortality. Methods: We measured ADMA, high sensitivity C-reactive protein, interleukin-6 (IL-6), D-dimer, and pulmonary artery systolic pressure (PASP) using echocardiography in HIV-infected individuals. Right heart catheterization (RHC) was performed in individuals with a PASP at least 30 mmHg. We performed multivariable analysis to identify factors associated with high PASP by echocardiogram and PAH by RHC. Results: Among 214 HIV-infected individuals, the median age was 50 years, 82% were men, 71% were on antiretroviral therapy, and 4.2% carried a prior diagnosis of PAH. ADMA and IL-6 were associated with increased values of PASP following multivariable adjustment (7.2% per 0.1 mu mol/l, P = 0.0049 and 3.9% per doubling, P = 0.027, respectively). In adjusted analysis among the 85 participants who underwent RHC, ADMA and IL-6 were associated with higher values of mean PAP (14.2% per 0.1 mu mol/l, P = 0.0014 and 5.8% per doubling, P = 0.038, respectively). However, only ADMA was associated with PAH (prevalence ratio = 1.74, P = 0.029). Conclusion: Elevated levels of ADMA are independently associated with PAH among HIV-infected individuals. Our findings suggest that chronic HIV-associated inflammation leading to an accumulation of ADMA and subsequent nitric oxide-mediated endothelial dysfunction may represent a novel mechanism for HIV-associated PAH. C1 [Parikh, Rushi V.; Scherzer, Rebecca] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Scherzer, Rebecca] San Francisco VA Med Ctr, Div Endocrinol & Metab, San Francisco, CA USA. [Nitta, Elaine M.; Hur, Sophia; Mistry, Vanita; Macgregor, John S.; Ganz, Peter; Hsue, Priscilla Y.] Univ Calif San Francisco, San Francisco Gen Hosp, Div Cardiol, San Francisco, CA USA. [Leone, Anna] Oxonon BioAnal, Emeryville, CA USA. [Martin, Jeffrey N.; Deeks, Steven G.] Univ Calif San Francisco, San Francisco Gen Hosp, Posit Hlth Program, San Francisco, CA USA. RP Hsue, PY (reprint author), Room 5G1 Cardiol SFGH,1001 Potrero Ave, San Francisco, CA 94110 USA. EM phsue@medsfgh.ucsf.edu FU SCOPE* [R01HL095130, R01HL095126]; NIAID [RO1 AI087145, K24AI069994]; UCSF/Gladstone Institute of Virology & Immunology CFAR [P30 AI027763]; UCSF Clinical and Translational Research Institute Clinical Research Center [UL1 RR024131]; CFAR Network of Integrated Systems [R24 AI067039] FX The study received grant support from R01HL095130 (P.Y.H.), R01HL095126 (P.Y.H.), SCOPE*.; SCOPE cohort supported by NIAID (RO1 AI087145, K24AI069994), UCSF/Gladstone Institute of Virology & Immunology CFAR (P30 AI027763), UCSF Clinical and Translational Research Institute Clinical Research Center (UL1 RR024131), and CFAR Network of Integrated Systems (R24 AI067039). NR 35 TC 20 Z9 21 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 EI 1473-5571 J9 AIDS JI Aids PD FEB 20 PY 2014 VL 28 IS 4 BP 511 EP 519 DI 10.1097/QAD.0000000000000124 PG 9 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA AC3AI UT WOS:000332387000007 PM 24469026 ER PT J AU Liu, WJ Wang, JQ Weaver, MJ Vrahas, MS Zhou, DS AF Liu Wanjun Wang Junqiang Weaver, Michael J. Vrahas, Mark S. Zhou Dongsheng TI Lateral migration with telescoping of a trochanteric fixation nail in the treatment of an intertrochanteric hip fracture SO CHINESE MEDICAL JOURNAL LA English DT Article DE trochanteric fixation nail; intertrochanteric hip fracture; fracture fixation; helical blade; complications ID TIP-APEX DISTANCE; SCREW; COMPRESSION; OUTCOMES; FAILURE; CUTOUT AB Background The trochanteric fixation nail (TFN) can be used to treat stable and unstable fractures of intertrochanteric hip fractures. We study the common lateral migration that occurs with telescoping of intertrochanteric hip fractures treated with TFN and identify the predictors and relationships to clinical outcomes. Methods Patient demographic information, fracture type (Arbeitsgemeinschaft fur Osteosynthesefragen (AO)/Orthopaedic Trauma Association (OTA) classification), radiographic data, and clinical data were collected. Lateral migration with telescoping was measured. Statistical analyses were performed to determine which variables predicted lateral migration with telescoping. Patient outcome scores were recorded using the Modified Harris Hip Score (MHHS), Hip Outcome Score-Activity of Daily Living (HOS-ADL), and Visual Analog Scale for pain. Results Two hundred and twenty-three patients (67 males, 156 females) fitted the radiographic and follow-up (average 24.6 months) criteria. The average age was 77.2 years. The average lateral migration with telescoping was 4.8 mm. Twenty-one patients (9.4%) had excessive lateral migration with telescoping (>= 10 mm). The quality of calcar reduction (P=0.01) and unstable fracture patterns (P=0.006) were significant predictive factors of lateral migration with telescoping. The mean outcome scores (MHHS and HOS-ADL) were 80.1 points and 78.7 points, respectively. All subjects had no significant relationship to lateral migration with telescoping (P > 0.05). Of all the patients who developed lateral migration with telescoping, only one required removal of the blade for hip pain and all patients went on to uneventful union at an average time of 4.5 months. Conclusions Lateral migration with telescoping is a common mechanical complication of intertrochanteric hip fracture treated with the TFN procedure. It was predicted by the quality of calcar reduction and fracture type. However, this did not affect stable fixation and fracture healing, so rarely leads to clinical problems. C1 [Liu Wanjun; Zhou Dongsheng] Shandong Univ, Shandong Prov Hosp, Dept Orthopaed, Jinan 250021, Shandong, Peoples R China. [Wang Junqiang] Beijing Jishuitan Hosp, Dept Orthopaed, Beijing 100035, Peoples R China. [Weaver, Michael J.; Vrahas, Mark S.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Partners Orthopaed, Boston, MA 02114 USA. RP Vrahas, MS (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Partners Orthopaed, Boston, MA 02114 USA. EM mvrahas@partners.org NR 22 TC 3 Z9 3 U1 0 U2 3 PU CHINESE MEDICAL ASSOC PI BEIJING PA 42 DONGSI XIDAJIE, BEIJING 100710, PEOPLES R CHINA SN 0366-6999 J9 CHINESE MED J-PEKING JI Chin. Med. J. PD FEB 20 PY 2014 VL 127 IS 4 BP 680 EP 684 DI 10.3760/cma.j.issn.0366-6999.20132420 PG 5 WC Medicine, General & Internal SC General & Internal Medicine GA AD8EE UT WOS:000333498500016 PM 24534222 ER PT J AU Yanai, M Rocha, MA Matolek, AZ Chintalacharuvu, A Taira, Y Chintalacharuvu, K Beenhouwer, DO AF Yanai, Machi Rocha, Miguel A. Matolek, Anthony Z. Chintalacharuvu, Archana Taira, Yasuhiko Chintalacharuvu, Koteswara Beenhouwer, David O. TI Separately or Combined, LukG/LukH Is Functionally Unique Compared to Other Staphylococcal Bicomponent Leukotoxins SO PLOS ONE LA English DT Article ID PANTON-VALENTINE LEUKOCIDIN; NF-KAPPA-B; INTERLEUKIN-8 GENE-EXPRESSION; HUMAN NEUTROPHILS; POLYMORPHONUCLEAR LEUKOCYTES; SUBSEQUENT ACTIVATION; GAMMA-HEMOLYSIN; IL-8 PRODUCTION; PORE FORMATION; 2 COMPONENTS AB Staphylococcus aureus is a major human pathogen that elaborates several exotoxins. Among these are the bicomponent leukotoxins (BCLs), which include gamma-hemolysin, Panton-Valentine leukocidin (PVL), and LukDE. The toxin components are classified as either F or S proteins, which are secreted individually and assemble on cell surfaces to form hetero-oligomeric pores resulting in lysis of PMNs and/or erythrocytes. F and S proteins of gamma-hemolysin, PVL and LukDE have similar to 70% sequence homology within the same class and several heterologous combinations of F and S members from these three bicomponent toxin groups are functional. Recently, an additional BCL pair, LukGH (also called LukAB) that has only 30% homology to gamma-hemolysin, PVL and LukDE, has been characterized from S. aureus. Our results showed that LukGH was more cytotoxic to human PMNs than PVL. However, LukGH-induced calcium ion influx in PMNs was markedly attenuated and slower than that induced by PVL and other staphylococcal BCLs. In contrast to other heterologous BCL combinations, LukG in combination with heterologous S components, and LukH in combination with heterologous F components did not induce calcium ion entry or cell lysis in human PMNs or rabbit erythrocytes. Like PVL, LukGH induced IL-8 production by PMNs. While individual components LukG and LukH had no cytolytic or calcium influx activity, they each induced high levels of IL-8 transcription and secretion. IL-8 production induced by LukG or LukH was dependent on NF-kappa B. Therefore, our results indicate LukGH differs functionally from other staphylococcal BCLs. C1 [Yanai, Machi; Rocha, Miguel A.; Matolek, Anthony Z.; Chintalacharuvu, Archana; Chintalacharuvu, Koteswara; Beenhouwer, David O.] Vet Affairs Greater Los Angeles Healthcare Syst, Div Infect Dis, Los Angeles, CA 90073 USA. [Yanai, Machi; Taira, Yasuhiko] St Marianna Univ, Sch Med, Kawasaki, Kanagawa, Japan. [Beenhouwer, David O.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90024 USA. RP Beenhouwer, DO (reprint author), Vet Affairs Greater Los Angeles Healthcare Syst, Div Infect Dis, Los Angeles, CA 90073 USA. EM dbeenhou@ucla.edu FU NIH [AI071025]; Veterans Affairs (Merit Award) FX This work was supported by grants from NIH (AI071025, DOB) and the Veterans Affairs (Merit Award, DOB). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 43 TC 3 Z9 3 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 FEB 20 PY 2014 VL 9 IS 2 AR e89308 DI 10.1371/journal.pone.0089308 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AB3UC UT WOS:000331714700098 PM 24586678 ER PT J AU Lee, SM Yang, S Joo, M Kim, KM Park, CK Ahn, S Min, BH Lee, JH Kim, S Rhee, JC Kim, JJ Lauwers, GY AF Lee, Sun-Mi Yang, Sun Joo, Mee Kim, Kyoung-Mee Park, Cheol Keun Ahn, Soomin Min, Byung-Hoon Lee, Jun Haeng Kim, Seonwoo Rhee, Jong Chul Kim, Jae J. Lauwers, Gregory Y. TI Poorly differentiated component in gastric pinch biopsies predicts submucosal invasion SO DIAGNOSTIC PATHOLOGY LA English DT Article DE Gastric cancer; Biopsy; Histologic; Submucosa; Invasion; Endoscopic resection ID LYMPH-NODE METASTASIS; HIGH-GRADE DYSPLASIA; ENDOSCOPIC MUCOSAL RESECTION; RISK-FACTORS; CANCER; CARCINOMA; ADENOCARCINOMA; HETEROGENEITY; DISSECTION; ESOPHAGUS AB Background: Endoscopic resection has become standard therapy for selected patients with early gastric carcinoma (EGC). However, the preoperative diagnostic accuracy for excluding submucosal (SM) invasion is not precise. Moreover, histologic features predicting SM invasion in gastric carcinomas (SMiGC) have not been studied extensively. Methods: Pre-treatment gastric biopsies from 60 patients with SM invasion who underwent endoscopic resection were reviewed and compared to 58 biopsies of lesions confirmed to be intramucosal carcinomas (IMC). For validation of the results, an independent cohort consisting of 616 gastric biopsies confirmed as EGC were analyzed. For statistical analyses,chi-square test, Fisher's exact test and multiple logistic progression tests were used. Results: In the biopsy specimens of patients with SMiGCs, differentiated histology, poorly differentiated component, wisps of muscularis mucosa, tumor cribriforming, papillary architecture, desmoplasia and intraglandular eosinophilic necrotic debris (IEND) were observed in 96.7%, 36.7%, 16.7%, 16.7%, 23.3%, 40%, and 46.7% of cases, respectively, while the same features were observed in 100%, 5.2%, 0%, 1.7%, 5.2%, 19%, and 22.4% of biopsies with IMC. In multivariate analyses, poorly differentiated component [odds ratio (OR), 9.59, p = 0.002], IEND [OR, 6.23, p = 0.012], tumor cribriforming [OR, 4.66, p = 0.03] and papillary architecture [OR, 5.52, p = 0.018] were significantly associated with the detection of SM invasion. In the validation cohort, poorly differentiated component (p = 0.003) and papillary architecture (p = 0.008) remained significant. Conclusion: Poorly differentiated component and papillary architecture are significant histopathologic predictors of SM invasion in pretreatment gastric biopsies of lesions considered for endoscopic therapy. Additional prospective studies are warranted to confirm our findings. C1 [Lee, Sun-Mi] Univ Texas Hlth Sci Ctr San Antonio, Dept Pathol, San Antonio, TX 78229 USA. [Yang, Sun; Kim, Kyoung-Mee; Min, Byung-Hoon; Lee, Jun Haeng; Rhee, Jong Chul; Kim, Jae J.] Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Dept Med, Seoul 135710, South Korea. [Joo, Mee] Inje Univ, Ilsan Paik Hosp, Coll Med, Dept Pathol, Goyang Si, Gyeonggi Do, South Korea. [Kim, Kyoung-Mee; Park, Cheol Keun; Ahn, Soomin] Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Dept Pathol, Seoul 135710, South Korea. [Kim, Seonwoo] Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Biostat Unit, Seoul 135710, South Korea. [Lauwers, Gregory Y.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. RP Kim, KM (reprint author), Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Dept Med, 50 Ilwon Dong, Seoul 135710, South Korea. EM kkmkys@skku.edu; jjkim@skku.edu FU Samsung Biomedical Research Institute [SBRISP1B20112] FX This work was supported by a grant from the Samsung Biomedical Research Institute (#SBRISP1B20112). NR 30 TC 2 Z9 2 U1 0 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1746-1596 J9 DIAGN PATHOL JI Diagn. Pathol. PD FEB 20 PY 2014 VL 9 AR 34 DI 10.1186/1746-1596-9-34 PG 7 WC Pathology SC Pathology GA AB9MC UT WOS:000332117000001 PM 24555807 ER PT J AU Yoo, B Kavishwar, A Ghosh, SK Barteneva, N Yigit, MV Moore, A Medarova, Z AF Yoo, Byunghee Kavishwar, Amol Ghosh, Subrata K. Barteneva, Natalie Yigit, Mehmet V. Moore, Anna Medarova, Zdravka TI Detection of miRNA Expression in Intact Cells Using Activatable Sensor Oligonucleotides SO CHEMISTRY & BIOLOGY LA English DT Article ID IN-SITU; MICRORNAS; METASTASIS; HYBRIDIZATION; MICROARRAY; CANCER AB We describe a technology for the profiling of miRNA expression in intact cells. The technology is based on sensor oligonucleotides that are cleavable, completely complementary to a target miRNA, and dual-labeled with a fluorescent dye and a quencher. Upon entering the cell, the sensor oligonucleotide binds its specific miRNA target through complementary base-pairing. This triggers assembly of the endogenous RNA Induced Silencing Complex (RISC) around the miRNA-sensor duplex and cleavage of the sensor oligonucleotide, resulting in separation between the dye and quencher, and a fluorescence turn-on. In the presented feasibility studies, we focus on a specific miRNA (miR-10b) implicated in breast cancer metastasis. Using a human breast adenocarcinoma cell line, we illustrate the application of this technology for miRNA detection with nanomolar sensitivity in both a cell-free system and intact cells. C1 [Yoo, Byunghee; Kavishwar, Amol; Ghosh, Subrata K.; Yigit, Mehmet V.; Moore, Anna; Medarova, Zdravka] Massachusetts Gen Hosp, MGH MIT HMS Athinoula A Martinos Ctr Biomed Imagi, Boston, MA 02129 USA. [Yoo, Byunghee; Kavishwar, Amol; Ghosh, Subrata K.; Yigit, Mehmet V.; Moore, Anna; Medarova, Zdravka] Harvard Univ, Sch Med, Boston, MA 02129 USA. [Barteneva, Natalie] Harvard Univ, Sch Med, Boston Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA. RP Moore, A (reprint author), Massachusetts Gen Hosp, MGH MIT HMS Athinoula A Martinos Ctr Biomed Imagi, Boston, MA 02129 USA. EM amoore@helix.mgh.harvard.edu; zmedarova@partners.org OI Kavishwar, Amol/0000-0001-8214-6625 FU NIH; Young Investigator Award; Breast Cancer Alliance; NCI [CA009502]; [NCIR00CA129070]; [NCI-1R01CA163461-01A1] FX This work was supported by grants NCIR00CA129070 and NCI-1R01CA163461-01A1 to Z.M. by the NIH, the Young Investigator Award to Z.M. by the Breast Cancer Alliance, and T32 Cancer Imaging grant CA009502 from NCI to A. M. (B.Y., trainee). NR 23 TC 8 Z9 8 U1 0 U2 16 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-5521 EI 1879-1301 J9 CHEM BIOL JI Chem. Biol. PD FEB 20 PY 2014 VL 21 IS 2 BP 199 EP 204 DI 10.1016/j.chembiol.2013.12.007 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AB4BG UT WOS:000331733500007 PM 24440078 ER PT J AU Sanidas, I Polytarchou, C Hatziapostolou, M Ezell, SA Kottakis, F Hu, L Guo, AL Xie, JX Comb, MJ Iliopoulos, D Tsichlis, PN AF Sanidas, Ioannis Polytarchou, Christos Hatziapostolou, Maria Ezell, Scott A. Kottakis, Filippos Hu, Lan Guo, Ailan Xie, Jianxin Comb, Michael J. Iliopoulos, Dimitrios Tsichlis, Philip N. TI Phosphoproteomics Screen Reveals Akt Isoform-Specific Signals Linking RNA Processing to Lung Cancer SO MOLECULAR CELL LA English DT Article ID POLYMERASE-II; GENOME-WIDE; PROTEIN; COMPLEX; TRANSCRIPTION; BINDING; PATHWAY; DOMAIN; MICE; RESISTANCE AB The three Akt isoforms are functionally distinct. Here we show that their phosphoproteomes also differ, suggesting that their functional differences are due to differences in target specificity. One of the top cellular functions differentially regulated by Akt isoforms is RNA processing. IWS1, an RNA processing regulator, is phosphorylated by Akt3 and Akt1 at Ser720/Thr721. The latter is required for the recruitment of SETD2 to the RNA Pol II complex. SETD2 trimethylates histone H3 at K36 during transcription, creating a docking site for MRG15 and PTB. H3K36me3-bound MRG15 and PTB regulate FGFR-2 splicing, which controls tumor growth and invasiveness downstream of IWS1 phosphorylation. Twenty-one of the twenty-four non-small-cell-lung carcinomas we analyzed express IWS1. More importantly, the stoichiometry of IWS1 phosphorylation in these tumors correlates with the FGFR-2 splicing pattern and with Akt phosphorylation and Akt3 expression. These data identify an Akt isoform-dependent regulatory mechanism for RNA processing and demonstrate its role in lung cancer. C1 [Sanidas, Ioannis; Polytarchou, Christos; Hatziapostolou, Maria; Ezell, Scott A.; Kottakis, Filippos; Tsichlis, Philip N.] Tufts Med Ctr, Mol Oncol Res Inst, Boston, MA 02111 USA. [Polytarchou, Christos; Hatziapostolou, Maria; Iliopoulos, Dimitrios] Univ Calif Los Angeles, David Geffen Sch Med, Div Digest Dis, Ctr Syst Biomed, Los Angeles, CA 90095 USA. [Hu, Lan] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Ctr Canc Computat Biol, Boston, MA 02215 USA. [Guo, Ailan; Xie, Jianxin; Comb, Michael J.] Cell Signaling Technol, Danvers, MA 01923 USA. RP Tsichlis, PN (reprint author), Tufts Med Ctr, Mol Oncol Res Inst, Boston, MA 02111 USA. EM ptsichlis@tuftsmedicalcenter.org RI Hatziapostolou, Maria/N-1820-2015 OI Hatziapostolou, Maria/0000-0003-2493-7028 FU NIH [RO1CA57436] FX We thank numerous colleagues, listed in the Supplemental Experimental Procedures, for providing constructs. Animal experiments were carried out at the Dana-Farber Cancer Institute, the former institutional affiliation of C. P., M. H., and D. I. We thank the Tufts tumor bank for normal and tumor lung specimens. We also thank James Baleja for interesting discussions; Alexandra Touroutoglou for assisting in the statistical analysis of the tumor data; and Philip Hinds, Claire Moore, and Kevin Struhl for reviewing the manuscript prior to submission. This work was supported by NIH grant RO1CA57436 (to P.N.T.). NR 39 TC 20 Z9 21 U1 1 U2 8 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 FEB 20 PY 2014 VL 53 IS 4 BP 577 EP 590 DI 10.1016/j.molcel.2013.12.018 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AB2ZE UT WOS:000331660200007 PM 24462114 ER PT J AU Cox, AG Goessling, W AF Cox, Andrew G. Goessling, Wolfram TI REGENERATIVE BIOLOGY Take the brakes off for liver repair SO NATURE LA English DT Editorial Material ID ANGIOCRINE SIGNALS; ENDOTHELIAL-CELLS; ANGIOPOIETIN-2; INJURY C1 [Cox, Andrew G.; Goessling, Wolfram] Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Genet, Boston, MA 02115 USA. [Cox, Andrew G.; Goessling, Wolfram] Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Gastroenterol, Boston, MA 02115 USA. [Goessling, Wolfram] Dana Farber Canc Inst, Boston, MA USA. [Goessling, Wolfram] Harvard Stem Cell Inst, Cambridge, MA USA. [Goessling, Wolfram] Broad Inst MIT & Harvard, Cambridge, MA USA. RP Cox, AG (reprint author), Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Genet, Boston, MA 02115 USA. EM wgoessling@partners.org FU NIDDK NIH HHS [R01 DK090311] NR 11 TC 1 Z9 2 U1 0 U2 14 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 FEB 20 PY 2014 VL 506 IS 7488 BP 299 EP 300 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AB0JL UT WOS:000331477800024 PM 24553235 ER PT J AU Ojesina, AI Lichtenstein, L Freeman, SS Pedamallu, CS Imaz-Rosshandler, I Pugh, TJ Cherniack, AD Ambrogio, L Cibulskis, K Bertelsen, B Romero-Cordoba, S Trevino, V Vazquez-Santillan, K Guadarrama, AS Wright, AA Rosenberg, MW Duke, F Kaplan, B Wang, R Nickerson, E Walline, HM Lawrence, MS Stewart, C Carter, SL McKenna, A Rodriguez-Sanchez, IP Espinosa-Castilla, M Woie, K Bjorge, L Wik, E Halle, MK Hoivik, EA Krakstad, C Gabino, NB Gomez-Macias, GS Valdez-Chapa, LD Garza-Rodriguez, ML Maytorena, G Vazquez, J Rodea, C Cravioto, A Cortes, ML Greulich, H Crum, CP Neuberg, DS Hidalgo-Miranda, A Escareno, CR Akslen, LA Carey, TE Vintermyr, OK Gabriel, SB Barrera-Saldana, HA Melendez-Zajgla, J Getz, G Salvesen, HB Meyerson, M AF Ojesina, Akinyemi I. Lichtenstein, Lee Freeman, Samuel S. Pedamallu, Chandra Sekhar Imaz-Rosshandler, Ivan Pugh, Trevor J. Cherniack, Andrew D. Ambrogio, Lauren Cibulskis, Kristian Bertelsen, Bjorn Romero-Cordoba, Sandra Trevino, Victor Vazquez-Santillan, Karla Salido Guadarrama, Alberto Wright, Alexi A. Rosenberg, Mara W. Duke, Fujiko Kaplan, Bethany Wang, Rui Nickerson, Elizabeth Walline, Heather M. Lawrence, Michael S. Stewart, Chip Carter, Scott L. McKenna, Aaron Rodriguez-Sanchez, Iram P. Espinosa-Castilla, Magali Woie, Kathrine Bjorge, Line Wik, Elisabeth Halle, Mari K. Hoivik, Erling A. Krakstad, Camilla Belem Gabino, Nayeli Sofia Gomez-Macias, Gabriela Valdez-Chapa, Lezmes D. Lourdes Garza-Rodriguez, Maria Maytorena, German Vazquez, Jorge Rodea, Carlos Cravioto, Adrian Cortes, Maria L. Greulich, Heidi Crum, Christopher P. Neuberg, Donna S. Hidalgo-Miranda, Alfredo Escareno, Claudia Rangel Akslen, Lars A. Carey, Thomas E. Vintermyr, Olav K. Gabriel, Stacey B. Barrera-Saldana, Hugo A. Melendez-Zajgla, Jorge Getz, Gad Salvesen, Helga B. Meyerson, Matthew TI Landscape of genomic alterations in cervical carcinomas SO NATURE LA English DT Article ID SQUAMOUS-CELL CARCINOMA; DNA-SEQUENCING DATA; SOMATIC MUTATIONS; HUMAN CANCER; HUMAN-PAPILLOMAVIRUS; SENSITIVE DETECTION; EXPRESSION; DISCOVERY; SAMPLES; FUSION AB Cervical cancer is responsible for 10-15% of cancer-related deaths in women worldwide(1,2). The aetiological role of infection with high-risk human papilloma viruses (HPVs) in cervical carcinomas is well established(3). Previous studies have also implicated somatic mutations in PIK3CA, PTEN, TP53, STK11 and KRAS(4-7) as well as several copy-number alterations in the pathogenesis of cervical carcinomas(8,9). Here we report whole-exome sequencing analysis of 115 cervical carcinoma-normal paired samples, transcriptome sequencing of 79 cases and whole-genome sequencing of 14 tumour-normal pairs. Previously unknown somatic mutations in 79 primary squamous cell carcinomas include recurrent E322K substitutions in the MAPK1 gene (8%), inactivating mutations in the HLA-B gene (9%), and mutations in EP300 (16%), FBXW7 (15%), NFE2L2 (4%), TP53 (5%) and ERBB2 (6%). We also observe somatic ELF3 (13%) and CBFB (8%) mutations in 24 adenocarcinomas. Squamous cell carcinomas have higher frequencies of somatic nucleotide substitutions occurring at cytosines preceded by thymines (Tp*C sites) than adenocarcinomas. Gene expression levels at HPV integration sites were statistically significantly higher in tumours with HPV integration compared with expression of the same genes in tumours without viral integration at the same site. These data demonstrate several recurrent genomic alterations in cervical carcinomas that suggest new strategies to combat this disease. C1 [Ojesina, Akinyemi I.; Pedamallu, Chandra Sekhar; Pugh, Trevor J.; Wright, Alexi A.; Duke, Fujiko; Kaplan, Bethany; Wang, Rui; Greulich, Heidi; Meyerson, Matthew] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Ojesina, Akinyemi I.; Lichtenstein, Lee; Freeman, Samuel S.; Pedamallu, Chandra Sekhar; Pugh, Trevor J.; Cherniack, Andrew D.; Ambrogio, Lauren; Cibulskis, Kristian; Rosenberg, Mara W.; Kaplan, Bethany; Nickerson, Elizabeth; Lawrence, Michael S.; Stewart, Chip; Carter, Scott L.; McKenna, Aaron; Cortes, Maria L.; Greulich, Heidi; Gabriel, Stacey B.; Getz, Gad; Meyerson, Matthew] Eli & Edythe L Broad Inst Massachusetts Inst Tech, Cambridge, MA 02142 USA. [Imaz-Rosshandler, Ivan; Romero-Cordoba, Sandra; Vazquez-Santillan, Karla; Salido Guadarrama, Alberto; Espinosa-Castilla, Magali; Belem Gabino, Nayeli; Hidalgo-Miranda, Alfredo; Escareno, Claudia Rangel; Melendez-Zajgla, Jorge] Inst Nacl Med Genom, Mexico City 14610, DF, Mexico. [Bertelsen, Bjorn; Akslen, Lars A.; Vintermyr, Olav K.] Haukeland Hosp, Dept Pathol, N-5021 Bergen, Norway. [Trevino, Victor] Tecnol Monterrey, Monterrey 64849, Mexico. [Wright, Alexi A.; Greulich, Heidi] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Wang, Rui] Fudan Univ, Shanghai Canc Ctr, Dept Thorac Surg, Shanghai 200032, Peoples R China. [Walline, Heather M.] Univ Michigan, Rackham Grad Sch, Program Biomed Sci, Canc Biol Program, Ann Arbor, MI 48109 USA. [Rodriguez-Sanchez, Iram P.; Sofia Gomez-Macias, Gabriela; Valdez-Chapa, Lezmes D.; Lourdes Garza-Rodriguez, Maria; Barrera-Saldana, Hugo A.] Univ Autonoma Nuevo Leon, Fac Med, Monterrey 64460, Nuevo Leon, Mexico. [Rodriguez-Sanchez, Iram P.; Sofia Gomez-Macias, Gabriela; Valdez-Chapa, Lezmes D.; Lourdes Garza-Rodriguez, Maria; Barrera-Saldana, Hugo A.] Univ Autonoma Nuevo Leon, Hosp Univ Dr Jose Eluterio Gonzalez, Monterrey 64460, Nuevo Leon, Mexico. [Woie, Kathrine; Bjorge, Line; Wik, Elisabeth; Halle, Mari K.; Hoivik, Erling A.; Krakstad, Camilla; Salvesen, Helga B.] Haukeland Hosp, Dept Obstet & Gynecol, N-5021 Bergen, Norway. [Bjorge, Line; Wik, Elisabeth; Halle, Mari K.; Hoivik, Erling A.; Krakstad, Camilla; Salvesen, Helga B.] Univ Bergen, Ctr Canc Biomarkers, Dept Clin Sci, N-5020 Bergen, Norway. [Maytorena, German; Vazquez, Jorge; Rodea, Carlos; Cravioto, Adrian] Inst Mexicano Seguro Social, Mexico City 06720, DF, Mexico. [Crum, Christopher P.; Meyerson, Matthew] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Neuberg, Donna S.] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02215 USA. [Escareno, Claudia Rangel] Claremont Grad Univ, Claremont, CA 91711 USA. [Akslen, Lars A.; Vintermyr, Olav K.] Univ Bergen, Dept Clin Med, Ctr Canc Biomarkers, N-5020 Bergen, Norway. [Carey, Thomas E.] Univ Michigan, Ctr Comprehens Canc, Head & Neck Oncol Program, Ann Arbor, MI 48109 USA. [Carey, Thomas E.] Univ Michigan, Ctr Comprehens Canc, Dept Otolaryngol, Ann Arbor, MI 48109 USA. [Getz, Gad] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Getz, Gad] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Getz, Gad] Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Meyerson, M (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. EM helga.salvesen@uib.no; matthew_meyerson@dfci.harvard.edu RI Hidalgo-Miranda, Alfredo/B-2123-2010; Trevino, Victor/C-9219-2009; Romero-Cordoba, Sandra Lorena/A-2246-2014; Akslen, Lars /C-1202-2017; Bjorge, Line/C-1307-2017; salvesen, Helga/C-1187-2017; OI Krakstad, Camilla/0000-0002-0174-8139; Carey, Thomas/0000-0002-5202-7518; Hidalgo-Miranda, Alfredo/0000-0003-2315-3977; Trevino, Victor/0000-0002-7472-9844; Romero-Cordoba, Sandra Lorena/0000-0002-5591-696X; Akslen, Lars /0000-0003-2710-9543; Bjorge, Line/0000-0002-0240-2770; salvesen, Helga/0000-0002-4438-8831; Ojesina, Akinyemi/0000-0003-0755-3639; Halle, Mari/0000-0002-2660-8271 FU Carlos Slim Health Institute in Mexico; Rebecca Ridley Kry Fellowship of the Damon Runyon Cancer Research Foundation; MMRF Research Fellow Award; Helse Vest; Research Council of Norway; Norwegian Cancer Society; Harald Andersens legat; CONACyT [SALUD-2008-C01-87625, 161619]; UANL PAICyT [CS1038-1]; Instituto Mexicano del Seguro Social (IMSS) FX This work was conducted as part of the Slim Initiative for Genomic Medicine in the Americas, a project funded by the Carlos Slim Health Institute in Mexico. This work was also partially supported by the Rebecca Ridley Kry Fellowship of the Damon Runyon Cancer Research Foundation (A.I.O.); MMRF Research Fellow Award (A.I.O.); Helse Vest, Research Council of Norway, Norwegian Cancer Society and Harald Andersens legat (H. B. S.); CONACyT grant SALUD-2008-C01-87625 and UANL PAICyT grant CS1038-1 (H.A.B.-S.); and CONACyT grant 161619 (J.M.-Z.). We also thank B. Edvardsen, K. Dahl-Michelsen, A. Mokleiv, K. Madisso, T. Njolstad and E. Valen for technical and programmatic assistance; the staff of the Broad Institute Genomics Platform for their assistance in processing samples and generating the sequencing data used in the analyses; the Instituto Mexicano del Seguro Social (IMSS) for their Support; and L. Gaffney of Broad Institute Communications for figure layout and design. NR 56 TC 162 Z9 169 U1 5 U2 81 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 FEB 20 PY 2014 VL 506 IS 7488 BP 371 EP + DI 10.1038/nature12881 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AB0JL UT WOS:000331477800042 PM 24390348 ER PT J AU Zhu, JM Lee, KP Spencer, TJ Biederman, J Bhide, PG AF Zhu, Jinmin Lee, Kevin P. Spencer, Thomas J. Biederman, Joseph Bhide, Pradeep G. TI Transgenerational Transmission of Hyperactivity in a Mouse Model of ADHD SO JOURNAL OF NEUROSCIENCE LA English DT Article DE ADHD; dopamine; hyperactivity; methylphenidate; nicotine; transgenerational transmission ID ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; PRENATAL NICOTINE EXPOSURE; ORIGIN ALLELIC EXPRESSION; MATERNAL SMOKING; BEHAVIORAL TERATOGENICITY; EPIGENETIC INHERITANCE; CIGARETTE-SMOKING; RISK-FACTOR; PREGNANCY; BRAIN AB Attention deficit hyperactivity disorder (ADHD) is a neurobehavioral disorder affecting children and adults. Genetic and environmental factors are associated with the etiology of ADHD. Among the environmental factors, exposure of the developing brain to nicotine is considered a major risk factor. Recent evidence suggests that environmental influences on the brain and behavior may be transmitted from one generation to the next. We used a prenatal nicotine exposure (PNE) mouse model of ADHD to test the hypothesis that PNE-induced hyperactivity, a proxy for human ADHD phenotype, is transmitted from one generation to the next. Our data reveal transgenerational transmission of PNE-induced hyperactivity in mice via the maternal but not the paternal line of descent. We suggest that transgenerational transmission is a plausible mechanism for propagation of environmentally induced ADHD phenotypes in the population. C1 [Zhu, Jinmin; Lee, Kevin P.; Bhide, Pradeep G.] Florida State Univ, Coll Med, Ctr Brain Repair, Tallahassee, FL 32306 USA. [Spencer, Thomas J.; Biederman, Joseph] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Bhide, PG (reprint author), Florida State Univ, Coll Med, 1115 West Call St, Tallahassee, FL 32306 USA. EM Pradeep.Bhide@med.fsu.edu OI Bhide, Pradeep/0000-0003-4236-9415 FU United States Public Health Service [R21DA027358] FX This work was supported by the United States Public Health Service (Grant R21DA027358). We thank Dr. Michael Schwarzschild for access to equipment and resources in his laboratory at the Massachusetts General Hospital, Boston, Massachusetts. NR 39 TC 15 Z9 15 U1 3 U2 19 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 FEB 19 PY 2014 VL 34 IS 8 BP 2768 EP 2773 DI 10.1523/JNEUROSCI.4402-13.2014 PG 6 WC Neurosciences SC Neurosciences & Neurology GA AB7VE UT WOS:000331998200002 PM 24553919 ER PT J AU Yang, C McKenna, JT Zant, JC Winston, S Basheer, R Brown, RE AF Yang, Chun McKenna, James T. Zant, Janneke C. Winston, Stuart Basheer, Radhika Brown, Ritchie E. TI Cholinergic Neurons Excite Cortically Projecting Basal Forebrain GABAergic Neurons SO JOURNAL OF NEUROSCIENCE LA English DT Article DE brain slices; optostimulation; patch-clamp; transgenic mice ID NUCLEUS BASALIS; ALZHEIMERS-DISEASE; ALLOSTERIC MODULATORS; DISCHARGE PROFILES; GAMMA-OSCILLATIONS; IN-VITRO; RAT; SLEEP; ACETYLCHOLINE; PARVALBUMIN AB The basal forebrain (BF) plays an important role in the control of cortical activation and attention. Understanding the modulation of BF neuronal activity is a prerequisite to treat disorders of cortical activation involving BF dysfunction, such as Alzheimer's disease. Here we reveal the interaction between cholinergic neurons and cortically projecting BF GABAergic neurons using immunohistochemistry and whole-cell recordings in vitro. In GAD67-GFP knock-in mice, BF cholinergic (choline acetyltransferase-positive) neurons were intermingled with GABAergic (GFP (+)) neurons. Immunohistochemistry for the vesicular acetylcholine transporter showed that cholinergic fibers apposed putative cortically projecting GABAergic neurons containing parvalbumin (PV). In coronal BF slices from GAD67-GFP knock-in or PV-tdTomato mice, pharmacological activation of cholinergic receptors with bath application of carbachol increased the firing rate of large (> 20 mu m diameter) BF GFP (+) and PV (tdTomato +) neurons, which exhibited the intrinsic membrane properties of cortically projecting neurons. The excitatory effect of carbachol was blocked by antagonists of M-1 and M-3 muscarinic receptors in two subpopulations of BF GABAergic neurons [large hyperpolarization-activated cation current (I-h) and small I-h, respectively]. Ion substitution experiments and reversal potential measurements suggested that the carbachol-induced inward current was mediated mainly by sodium-permeable cation channels. Carbachol also increased the frequency of spontaneous excitatory and inhibitory synaptic currents. Furthermore, optogenetic stimulation of cholinergic neurons/fibers caused a mecamylamine- and atropine-sensitive inward current in putative GABAergic neurons. Thus, cortically projecting, BF GABAergic/PV neurons are excited by neighboring BF and/or brainstem cholinergic neurons. Loss of cholinergic neurons in Alzheimer's disease may impair cortical activation, in part, through disfacilitation of BF cortically projecting GABAergic/PV neurons. C1 VA Boston Healthcare Syst, Neurosci Lab, Brockton, MA 02301 USA. Harvard Univ, Sch Med, Brockton, MA 02301 USA. RP Brown, RE (reprint author), VA Boston Healthcare Syst, Dept Psychiat, Neurosci Lab, In Vitro Neurophysiol Sect, Res 151C,940 Belmont St, Brockton, MA 02301 USA. EM Ritchie_Brown@hms.harvard.edu FU National Institute of Mental Health [R01 MH039683, R21 MH094803]; National Heart, Lung, and Blood Institute [HL095491]; National Institute of Neurological Disorders and Stroke [R21 NS079866] FX This work was supported by VA Merit Awards to R. W. McCarley and R. B.; and by National Institute of Mental Health Grants R01 MH039683 and R21 MH094803; National Heart, Lung, and Blood Institute Grant HL095491; and National Institute of Neurological Disorders and Stroke Grant R21 NS079866. NR 46 TC 19 Z9 22 U1 3 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 FEB 19 PY 2014 VL 34 IS 8 BP 2832 EP 2844 DI 10.1523/0NEUROSCI.3235-13.2014 PG 13 WC Neurosciences SC Neurosciences & Neurology GA AB7VE UT WOS:000331998200008 PM 24553925 ER PT J AU Ahasic, AM Zhao, Y Su, L Sheu, CC Thompson, BT Christiani, DC AF Ahasic, Amy M. Zhao, Yang Su, Li Sheu, Chau-Chyun Thompson, B. Taylor Christiani, David C. TI Adiponectin Gene Polymorphisms and Acute Respiratory Distress Syndrome Susceptibility and Mortality SO PLOS ONE LA English DT Article ID ACUTE LUNG INJURY; SERUM ADIPONECTIN; CRITICAL ILLNESS; ASSOCIATION; RISK; HORMONE; ADIPOSE; OBESITY; IDENTIFICATION; ACTIVATION AB Rationale: Adiponectin is an anti-inflammatory adipokine that is the most abundant gene product of adipose tissue. Lower levels have been observed in obesity, insulin resistance, and in critical illness. However, elevated levels early in acute respiratory failure have been associated with mortality. Polymorphisms in adiponectin-related genes (ADIPOQ, ADIPOR1, ADIPOR2) have been examined for relationships with obesity, insulin resistance and diabetes, cardiovascular disease, and to circulating adipokine levels, but many gaps in knowledge remain. The current study aims to assess the association between potentially functional polymorphisms in adiponectin-related genes with acute respiratory distress syndrome (ARDS) risk and mortality. Methods: Consecutive patients with risk factors for ARDS admitted to the ICU were enrolled and followed prospectively for development of ARDS. ARDS cases were followed through day 60 for all-cause mortality. 2067 patients were successfully genotyped using the Illumina CVD BeadChip high-density platform. Of these, 567 patients developed ARDS. Forty-four single nucleotide polymorphisms (SNPs) on ADIPOQ, ADIPOR1 and ADIPOR2 were successfully genotyped. Of these, 9 SNPs were hypothesized to be functional based on their location (promoter, exon, or 39 untranslated region). These 9 SNPs were analyzed for association with ARDS case status and mortality among ARDS cases. Results: After multivariable analysis and adjustment for multiple comparisons, no SNPs were significantly associated with ARDS case status. Among ARDS cases, homozygotes for the minor allele of rs2082940 (ADIPOQ) had increased mortality (hazard ratio 2.61, 95% confidence interval 1.36-5.00, p = 0.0039) after adjustment for significant covariates. The significance of this association persisted after adjustment for multiple comparisons (FDR_q = 0.029). Conclusions: A common and potentially functional polymorphism in ADIPOQ may impact survival in ARDS. Further studies are required to replicate these results and to correlate genotype with circulating adiponectin levels. C1 [Ahasic, Amy M.] Yale Univ, Sch Med, Dept Med, Sect Pulm Crit Care & Sleep Med, New Haven, CT 06510 USA. [Zhao, Yang] Nanjing Med Univ, Sch Publ Hlth, Dept Epidemiol & Biostat, Nanjing, Jiangsu, Peoples R China. [Su, Li; Christiani, David C.] Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, Environm & Occupat Med & Epidemiol Program, Boston, MA 02115 USA. [Sheu, Chau-Chyun] Kaohsiung Med Univ, Kaohsiung Med Univ Hosp, Div Pulm & Crit Care Med, Kaohsiung, Taiwan. [Thompson, B. Taylor; Christiani, David C.] Massachusetts Gen Hosp, Dept Med, Pulm & Crit Care Unit, Boston, MA 02114 USA. RP Ahasic, AM (reprint author), Yale Univ, Sch Med, Dept Med, Sect Pulm Crit Care & Sleep Med, New Haven, CT 06510 USA. EM amy.ahasic@yale.edu FU American Heart Association [10FTF3440007]; National Institutes of Health/NIH Heart, Lung and Blood Institute [R01 HL60710] FX This study was funded in part by the following grants: American Heart Association (www.heart.org) 10FTF3440007 (PI: Ahasic); National Institutes of Health/NIH Heart, Lung and Blood Institute (www.nhlbi.nih.gov) R01 HL60710 (PI: Christiani). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 40 TC 4 Z9 4 U1 2 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 FEB 19 PY 2014 VL 9 IS 2 AR e89170 DI 10.1371/journal.pone.0089170 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AB3TA UT WOS:000331711900099 PM 24586568 ER PT J AU Rajamuthiah, R Fuchs, BB Jayamani, E Kim, Y Larkins-Ford, J Conery, A Ausubel, FM Mylonakis, E AF Rajamuthiah, Rajmohan Fuchs, Beth Burgwyn Jayamani, Elamparithi Kim, Younghoon Larkins-Ford, Jonah Conery, Annie Ausubel, Frederick M. Mylonakis, Eleftherios TI Whole Animal Automated Platform for Drug Discovery against Multi-Drug Resistant Staphylococcus aureus SO PLOS ONE LA English DT Article ID 2-COMPONENT SIGNAL-TRANSDUCTION; CAENORHABDITIS-ELEGANS INFECTION; WALL TEICHOIC-ACID; CIPROFLOXACIN-RESISTANT; ANTIBACTERIAL AGENTS; VIRULENCE FACTORS; INVITRO ACTIVITY; MODEL HOST; C-ELEGANS; SUSCEPTIBILITY AB Staphylococcus aureus, the leading cause of hospital-acquired infections in the United States, is also pathogenic to the model nematode Caenorhabditis elegans. The C. elegans-S. aureus infection model was previously carried out on solid agar plates where the bacteriovorous C. elegans feeds on a lawn of S. aureus. However, agar-based assays are not amenable to large scale screens for antibacterial compounds. We have developed a high throughput liquid screening assay that uses robotic instrumentation to dispense a precise amount of methicillin resistant S. aureus (MRSA) and worms in 384-well assay plates, followed by automated microscopy and image analysis. In validation of the liquid assay, an MRSA cell wall defective mutant, MW2 Delta tarO, which is attenuated for killing in the agar-based assay, was found to be less virulent in the liquid assay. This robust assay with a Z'-factor consistently greater than 0.5 was utilized to screen the Biomol 4 compound library consisting of 640 small molecules with well characterized bioactivities. As proof of principle, 27 of the 30 clinically used antibiotics present in the library conferred increased C. elegans survival and were identified as hits in the screen. Surprisingly, the antihelminthic drug closantel was also identified as a hit in the screen. In further studies, we confirmed the antistaphylococcal activity of closantel against vancomycin-resistant S. aureus isolates and other Gram-positive bacteria. The liquid C. elegans - S. aureus assay described here allows screening for anti-staphylococcal compounds that are not toxic to the host. C1 [Rajamuthiah, Rajmohan; Fuchs, Beth Burgwyn; Jayamani, Elamparithi; Mylonakis, Eleftherios] Brown Univ, Rhode Isl Hosp, Div Infect Dis, Alpert Med Sch, Providence, RI 02903 USA. [Rajamuthiah, Rajmohan; Fuchs, Beth Burgwyn; Jayamani, Elamparithi; Larkins-Ford, Jonah; Conery, Annie; Ausubel, Frederick M.; Mylonakis, Eleftherios] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Kim, Younghoon] Chonbuk Natl Univ, Dept Anim Sci, Jeonju, South Korea. RP Mylonakis, E (reprint author), Brown Univ, Rhode Isl Hosp, Div Infect Dis, Alpert Med Sch, Providence, RI 02903 USA. EM Eleftherios_Mylonakis@Brown.edu RI Raja Muthiah, Raj Mohan/D-3932-2014 OI Raja Muthiah, Raj Mohan/0000-0002-6956-3130 FU National Institutes of Health [P01 AI083214, U54 AI057159] FX This study was supported by National Institutes of Health grant P01 AI083214 to EM and FA and grant U54 AI057159 to NERCE. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 74 TC 19 Z9 19 U1 3 U2 20 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD FEB 19 PY 2014 VL 9 IS 2 AR e89189 DI 10.1371/journal.pone.0089189 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AB3TA UT WOS:000331711900102 PM 24586584 ER PT J AU Jena, AB Goldman, D Weaver, L Karaca-Mandic, P AF Jena, Anupam B. Goldman, Dana Weaver, Lesley Karaca-Mandic, Pinar TI Opioid prescribing by multiple providers in Medicare: retrospective observational study of insurance claims SO BMJ-BRITISH MEDICAL JOURNAL LA English DT Article ID PRESCRIPTION MONITORING PROGRAM; ADVERSE DRUG EVENTS; NONCANCER PAIN; UNITED-STATES; OUTPATIENT POPULATION; OLDER-ADULTS; ANALGESICS; RATES; CARE; TRENDS AB Objectives To estimate the frequency and characteristics of opioid prescribing by multiple providers in Medicare and the association with hospital admissions related to opioid use. Design Retrospective cohort study. Setting Database of prescription drugs and medical claims in 20% random sample of Medicare beneficiaries in 2010. Participants 1 808 355 Medicare beneficiaries who filled at least one prescription for an opioid from a pharmacy in 2010. Main outcome measures Proportion of beneficiaries who filled opioid prescriptions from multiple providers; proportion of these prescriptions that were concurrently supplied; adjusted rates of hospital admissions related to opioid use associated with multiple provider prescribing. Results Among 1 208 100 beneficiaries with an opioid prescription, 418 530 (34.6%) filled prescriptions from two providers, 171 420 (14.2%) from three providers, and 143 344 (11.9%) from four or more providers. Among beneficiaries with four or more opioid providers, 110 671 (77.2%) received concurrent opioid prescriptions from multiple providers, and the dominant provider prescribed less than half of the mean total prescriptions per beneficiary (7.9/15.2 prescriptions). Multiple provider prescribing was highest among beneficiaries who were also prescribed stimulants, non-narcotic analgesics, and central nervous system, neuromuscular, and antineoplastic drugs. Hospital admissions related to opioid use increased with multiple provider prescribing: the annual unadjusted rate of admission was 1.63% (95% confidence interval 1.58 to 1.67%) for beneficiaries with one provider, 2.08% (2.03% to 2.14%) for two providers, 2.87% (2.77% to 2.97%) for three providers, and 4.83% (4.70% to 4.96%) for four or more providers. Results were similar after covariate adjustment. Conclusions Concurrent opioid prescribing by multiple providers is common in Medicare patients and is associated with higher rates of hospital admission related to opioid use. C1 [Jena, Anupam B.] Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. [Jena, Anupam B.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Jena, Anupam B.] Natl Bur Econ Res, Cambridge, MA 02138 USA. [Goldman, Dana] Univ So Calif, Leonard D Schaeffer Ctr Hlth Policy & Econ, Los Angeles, CA 90089 USA. [Weaver, Lesley; Karaca-Mandic, Pinar] Univ Minnesota, Sch Publ Hlth, Div Hlth Policy & Management, Minneapolis, MN 55455 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 FU National Institutes of Health; National Institute on Aging; University of Minnesota FX This study was funded by the National Institutes of Health, the National Institute on Aging, and the University of Minnesota. The research conducted was independent of any involvement from the sponsors of the study. Study sponsors were not involved in study design, data interpretation, writing, or the decision to submit the article for publication. NR 47 TC 28 Z9 28 U1 1 U2 6 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 FEB 19 PY 2014 VL 348 AR g1393 DI 10.1136/bmj.g1393 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA AB9ZL UT WOS:000332154200001 PM 24553363 ER PT J AU Li, L Szostak, JW AF Li, Li Szostak, Jack W. TI The Free Energy Landscape of Pseudorotation in 3 '-5 ' and 2 '-5 ' Linked Nucleic Acids SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID MOLECULAR-DYNAMICS; AQUEOUS-SOLUTION; CONFORMATIONAL PROPERTIES; BACKBONE HETEROGENEITY; MAGNETIC-RESONANCE; CHEMICAL ETIOLOGY; CRYSTAL-STRUCTURE; SUGAR RING; RNA; NUCLEOSIDES AB The five-membered furanose ring is a central component of the chemical structure of biological nucleic acids. The conformations of the furanose ring can be analytically described using the concept of pseudorotation, and for RNA and DNA they are dominated by the C-2'-endo and C-3'-endo conformers. While the free energy difference between these two conformers can be inferred from NMR measurements, a free energy landscape of the complete pseudorotation cycle of nucleic acids in solution has remained elusive. Here, we describe a new free energy calculation method for molecular dynamics (MD) simulations using the two pseudorotation parameters directly as the collective variables. To validate our approach, we calculated the free energy surface of ribose pseudorotation in guanosine and 2'-deoxyguanosine. The calculated free energy landscape reveals not only the relative stability of the different pseudorotation conformers, but also the main transition path between the stable conformations. Applying this method to a standard A-form RNA duplex uncovered the expected minimum at the C-3'-endo state. However, at a 2'-5' linkage, the minimum shifts to the C-2'-endo conformation. The free energy of the C-3'-endo conformation is 3 kcal/mol higher due to a weaker hydrogen bond and a reduced base stacking interaction. Unrestrained MD simulations suggest that the conversion from C-3'-endo to C-2'-endo and vice versa is on the nanosecond and microsecond time scale, respectively. These calculations suggest that 2'-5' linkages may enable folded RNAs to sample a wider spectrum of their pseudorotation conformations. C1 [Szostak, Jack W.] Massachusetts Gen Hosp, Howard Hughes Med Inst, Dept Mol Biol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Boston, MA 02114 USA. RP Szostak, JW (reprint author), Massachusetts Gen Hosp, Howard Hughes Med Inst, Dept Mol Biol, Boston, MA 02114 USA. EM szostak@molbio.mgh.harvard.edu FU Simons Foundation FX The authors are grateful for the advice and the high resolution X-ray crystal structures of the RNA duplexes provided by Dr. Jia Sheng and thank Dr. Aaron Engelhart for helpful discussions. Computation time was provided by the Orchestra cluster of Harvard Medical School and the ERIS cluster of Partners Healthcare. J.W.S. is an Investigator, and L.L. is a Research Associate of the Howard Hughes Medical Institute. This work was supported in part by a grant from the Simons Foundation. NR 45 TC 13 Z9 13 U1 3 U2 41 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD FEB 19 PY 2014 VL 136 IS 7 BP 2858 EP 2865 DI 10.1021/ja412079b PG 8 WC Chemistry, Multidisciplinary SC Chemistry GA AB4SI UT WOS:000331779800026 PM 24499340 ER PT J AU Chen, C Ackerly, DC AF Chen, Christopher Ackerly, D. Clay TI Beyond ACOs and Bundled Payments Medicare's Shift Toward Accountability in Fee-for-Service SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material C1 [Chen, Christopher] Washington Univ, Sch Med, St Louis, MO 63130 USA. [Ackerly, D. Clay] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Ackerly, DC (reprint author), Massachusetts Gen Hosp, Nonacute Serv, 55 Fruit St, Boston, MA 02114 USA. EM dackerly@partners.org NR 10 TC 21 Z9 21 U1 0 U2 2 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 FEB 19 PY 2014 VL 311 IS 7 BP 673 EP 674 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA AA8ZO UT WOS:000331383700015 PM 24549543 ER PT J AU Toussaint, RJ Lin, D Ehrlichman, LK Ellington, JK Strasser, N Kwon, JY AF Toussaint, Rull James Lin, Darius Ehrlichman, Lauren K. Ellington, J. Kent Strasser, Nicholas Kwon, John Y. TI Peroneal Tendon Displacement Accompanying Intra-Articular Calcaneal Fractures SO JOURNAL OF BONE AND JOINT SURGERY-AMERICAN VOLUME LA English DT Article ID DISLOCATION; MANAGEMENT; DIAGNOSIS AB Background: Peroneal tendon displacement (subluxation or dislocation) accompanying an intra-articular calcaneal fracture is often undetected and under-treated. The goals of this study were to determine (1) the prevalence of peroneal tendon displacement accompanying intra-articular calcaneal fractures, (2) the association of tendon displacement with fracture classifications, (3) the association of tendon displacement with heel width, and (4) the rate of missed diagnosis of the tendon displacement on radiographs and computed tomography (CT) scans and the resulting treatment rate. Methods: A retrospective radiographic review of all calcaneal fractures presenting at three institutions from June 30, 2006, to June 30, 2011, was performed. CT imaging of 421 intra-articular calcaneal fractures involving the posterior facet was available for review. The prevalence of peroneal tendon displacement was noted and its associations with fracture classification and heel width were evaluated. Results: Peroneal tendon displacement was identified in 118(28.0%) of the 421 calcaneal fracture cases. The presence of tendon displacement was significantly associated with joint-depression fractures compared with tongue-type fractures (p < 0.001). Only twelve (10.2%) of the 118 cases of peroneal tendon displacement had been identified in the radiology reports. Although sixty-five (55.1%) of the fractures with tendon displacement had been treated with internal fixation, the tendon displacement was treated surgically in only seven (10.8%) of these cases. Conclusions: Analysis of CT images showed a 28% prevalence of peroneal tendon displacement accompanying intra-articular calcaneal fractures. Surgeons and radiologists are encouraged to consider this association. C1 [Toussaint, Rull James] Massachusetts Gen Hosp, Boston, MA 02114 USA. Brigham & Womens Hosp, Boston, MA 02115 USA. OrthoCarolina, Foot & Ankle Inst, Charlotte, NC USA. RP Toussaint, RJ (reprint author), Massachusetts Gen Hosp, 55 Fruit St,YAW 3F, Boston, MA 02114 USA. NR 18 TC 13 Z9 14 U1 0 U2 0 PU JOURNAL BONE JOINT SURGERY INC PI NEEDHAM PA 20 PICKERING ST, NEEDHAM, MA 02192 USA SN 0021-9355 J9 J BONE JOINT SURG AM JI J. Bone Joint Surg.-Am. Vol. PD FEB 19 PY 2014 VL 96A IS 4 BP 310 EP 315 DI 10.2106/JBJS.L.01378 PG 6 WC Orthopedics; Surgery SC Orthopedics; Surgery GA AA9RT UT WOS:000331431300007 PM 24553887 ER PT J AU Zhang, B Zhang, B Chen, X Bae, S Singh, K Washington, MK Datta, PK AF Zhang, B. Zhang, B. Chen, X. Bae, S. Singh, K. Washington, M. K. Datta, P. K. TI Loss of Smad4 in colorectal cancer induces resistance to 5-fluorouracil through activating Akt pathway SO BRITISH JOURNAL OF CANCER LA English DT Article DE Smad4; colorectal cancer; 5-fluorouracil; Akt; mouse model; tissue microarray; angiogenesis; Bcl-2; TGF-beta ID MULTICENTER RANDOMIZED-TRIAL; COLON-CANCER; TGF-BETA; 1ST-LINE TREATMENT; SIGNALING PATHWAY; LIVER METASTASIS; CARCINOMA-CELLS; DOWN-REGULATION; EXPRESSION; CHEMORESISTANCE AB Background: Higher frequency of Smad4 inactivation or loss of expression is observed in metastasis of colorectal cancer (CRC) leading to unfavourable survival and contributes to chemoresistance. However, the molecular mechanism of how Smad4 regulates chemosensitivity of CRC is unknown. Methods: We evaluated how the loss of Smad4 in CRC enhanced chemoresistance to 5-fluorouracil (5-FU) using two CRC cell lines in vitro and in vivo. Immunoblotting with cell and tumour lysates and immunohistochemical analyses with tissue microarray were performed. Results: Knockdown or loss of Smad4 induced tumorigenicity, migration, invasion, angiogenesis, metastasis, and 5-FU resistance. Smad4 expression in mouse tumours regulated cell-cycle regulatory proteins leading to Rb phosphorylation. Loss of Smad4 activated Akt pathway that resulted in upregulation of anti-apoptotic proteins, Bcl-2 and Bcl-w, and Survivin. Suppression of phosphatidylinositol-3-kinase (PI3K)/Akt pathway by LY294002 restored chemosensitivity of Smad4-deficient cells to 5-FU. Vascular endothelial growth factor-induced angiogenesis in Smad4-deficient cells might also lead to chemoresistance. Low levels of Smad4 expression in CRC tissues correlated with higher levels of Bcl-2 and Bcl-w and with poor overall survival as observed in immunohistochemical staining of tissue microarrays. Conclusion: Loss of Smad4 in CRC patients induces resistance to 5-FU-based therapy through activation of Akt pathway and inhibitors of this pathway may sensitise these patients to 5-FU. C1 [Zhang, B.; Datta, P. K.] Birmingham Vet Affairs Med Ctr, Birmingham, AL USA. [Zhang, B.; Bae, S.; Singh, K.; Datta, P. K.] Univ Alabama Birmingham, Dept Med, Birmingham, AL 35294 USA. [Zhang, B.; Zhang, B.; Datta, P. K.] Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Dept Surg, Nashville, TN 37212 USA. [Chen, X.] Huazhong Univ Sci & Technol, Tongji Med Coll, Hepat Surg Ctr, Dept Surg,Tongji Hosp, Wuhan 430030, Peoples R China. [Washington, M. K.] Vanderbilt Univ, Sch Med, Dept Pathol, Nashville, TN 37212 USA. RP Chen, X (reprint author), Huazhong Univ Sci & Technol, Tongji Med Coll, Hepat Surg Ctr, Dept Surg,Tongji Hosp, 1095 Jiefang Ave, Wuhan 430030, Peoples R China. EM chenxp@medmail.com.cn; prandatta@uabmc.edu FU NCI SPORE grant in lung cancer [5P50CA90949]; Veterans Affairs Merit Review Award; VDDRC [NIH P30DK058404]; [R01 CA95195] FX This study was supported by R01 CA95195, NCI SPORE grant in lung cancer (5P50CA90949, project#4), and Veterans Affairs Merit Review Award (to PK Datta). We thank VDDRC for supporting core services (NIH P30DK058404). We also thank Dr Frank Revetta for immunohistochemical analyses. NR 40 TC 27 Z9 29 U1 1 U2 13 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 FEB 18 PY 2014 VL 110 IS 4 BP 946 EP 957 DI 10.1038/bjc.2013.789 PG 12 WC Oncology SC Oncology GA AB9FR UT WOS:000332096600016 PM 24384683 ER PT J AU Singleton, O Holzel, BK Vangel, M Brach, N Carmody, J Lazar, SW AF Singleton, Omar Hoelzel, Britta K. Vangel, Mark Brach, Narayan Carmody, James Lazar, Sara W. TI Change in brainstem gray matter concentration following a mindfulness-based intervention is correlated with improvement in psychological well-being SO FRONTIERS IN HUMAN NEUROSCIENCE LA English DT Article DE brain stem; mindfulness; well-being; stress; psychological; raphe nuclei ID PEDUNCULOPONTINE TEGMENTAL NUCLEUS; LONG-TERM MEDITATION; QUALITY-OF-LIFE; GENERALIZED ANXIETY DISORDER; DORSAL RAPHE NUCLEUS; STRESS REDUCTION; LOCUS-COERULEUS; COGNITIVE THERAPY; CANCER OUTPATIENTS; DOPAMINE NEURONS AB Individuals can improve their levels of psychological well-being (PWB) through utilization of psychological interventions, including the practice of mindfulness meditation, which is defined as the non-judgmental awareness of experiences in the present moment. We recently reported that an 8-week-mindfulness-based stress reduction (MBSR) course lead to increases in gray matter concentration in several brain areas, as detected with voxel-based morphometry of magnetization prepared rapid acquisition gradient echo MRI scans, including the pons/raphe/locus coeruleus area of the brainstem. Given the role of the pons and raphe in mood and arousal, we hypothesized that changes in this region might underlie changes in wellbeing. A subset of 14 healthy individuals from a previously published data set completed anatomical MRI and filled out the PWB scale before and after MBSR participation. PWB change was used as the predictive regressor for changes in gray matter density within those brain regions that had previously shown pre- to post-MBSR changes. Results showed that scores on five PWB subscales as well as the PWB total score increased significantly over the MBSR course. The change was positively correlated with gray matter concentration increases in two symmetrically bilateral clusters in the brainstem. Those clusters appeared to contain the area of the pontine tegmentum, locus coeruleus, nucleus raphe pontis, and the sensory trigeminal nucleus. No clusters were negatively correlated with the change in PWB. This preliminary study suggests a neural correlate of enhanced PWB. The identified brain areas include the sites of synthesis and release of the neuro-transmitters, norepinephrine and serotonin, which are involved in the modulation of arousal and mood, and have been related to a variety of affective functions as well as associated clinical dysfunctions. C1 [Singleton, Omar; Vangel, Mark; Lazar, Sara W.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Boston, MA 02129 USA. [Hoelzel, Britta K.] Charite, Inst Med Psychol, D-13353 Berlin, Germany. [Brach, Narayan] Palo Alto Univ, PGSP Stanford PsyD Consortium, Palo Alto, CA USA. [Carmody, James] Univ Massachusetts, Sch Med, Worcester, MA USA. RP Lazar, SW (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, 149,13th St, Boston, MA 02129 USA. EM lazar@nmr.mgh.harvard.edu RI Lazar, Sara/G-3809-2012 OI Lazar, Sara/0000-0003-1126-8363 FU National Institutes of Health-NCCAM [R21-AT003425-01A2]; British Broadcasting Company (BBC); Marie Curie International Outgoing Fellowship; Kusala Foundation; National Institutes of Health [K01AT00694] FX We wish to express our gratitude to all participants for their cooperation. We thank the Center for Mindfulness for conducting the Mindfulness-based stress reduction courses, and Nik Olendzki and Christina Congleton for support in data collection. This research was funded by the National Institutes of Health-NCCAM (R21-AT003425-01A2) and the British Broadcasting Company (BBC). Britta K. Holzel was supported by a Marie Curie International Outgoing Fellowship within the Seventh European Community Framework Programme and the Kusala Foundation. Sara W. Lazar was supported by National Institutes of Health funding K01AT00694. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 81 TC 18 Z9 18 U1 13 U2 89 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1662-5161 J9 FRONT HUM NEUROSCI JI Front. Hum. Neurosci. PD FEB 18 PY 2014 VL 8 AR 33 DI 10.3389/fnhum.2014.00033 PG 7 WC Neurosciences; Psychology SC Neurosciences & Neurology; Psychology GA AB9AO UT WOS:000332081700001 PM 24600370 ER PT J AU Kotton, CN AF Kotton, Camille Nelson TI Life-Saving Organ Transplants Accompanied by Stealthy and Unexpected Pathogens SO ANNALS OF INTERNAL MEDICINE LA English DT Editorial Material ID SOLID-ORGAN; MICROSPORIDIOSIS; INFECTIONS C1 [Kotton, Camille Nelson] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Kotton, Camille Nelson] Harvard Univ, Sch Med, Boston, MA USA. RP Kotton, CN (reprint author), Massachusetts Gen Hosp, Div Infect Dis, 55 Fruit St,Cox 5, Boston, MA 02114 USA. EM ckotton@partners.org NR 8 TC 0 Z9 0 U1 0 U2 0 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 EI 1539-3704 J9 ANN INTERN MED JI Ann. Intern. Med. PD FEB 18 PY 2014 VL 160 IS 4 BP 282 EP 283 DI 10.7326/M13-2906 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA AB3BO UT WOS:000331666500008 PM 24727844 ER PT J AU Rowe, GC Safdar, A Arany, Z AF Rowe, Glenn C. Safdar, Adeel Arany, Zolt TI Running Forward New Frontiers in Endurance Exercise Biology SO CIRCULATION LA English DT Editorial Material ID ACTIVATED PROTEIN-KINASE; TRANSCRIPTIONAL COACTIVATOR PGC-1-ALPHA; HUMAN SKELETAL-MUSCLE; INCREASES MITOCHONDRIAL BIOGENESIS; IN-HOUSE MICE; OXIDATIVE-METABOLISM; NEUROTROPHIC FACTOR; VOLUNTARY EXERCISE; ENERGY-METABOLISM; PHYSICAL-ACTIVITY C1 Beth Israel Deaconess Med Ctr, Cardiovasc Inst, Boston, MA 02215 USA. Beth Israel Deaconess Med Ctr, Vasc Biol Res Ctr, Boston, MA 02215 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Arany, Z (reprint author), BIDMC, ECLS906, 330 Brookline Ave, Boston, MA 02215 USA. EM zarany@bidmc.harvard.edu OI Rowe, Glenn/0000-0002-8195-9605; Safdar, Adeel/0000-0003-2469-0467 FU NHLBI NIH HHS [HL094499, R01 HL094499]; NIAMS NIH HHS [AR062128, K01 AR062128] NR 179 TC 18 Z9 18 U1 2 U2 17 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 FEB 18 PY 2014 VL 129 IS 7 BP 798 EP 810 PG 13 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA AA8PX UT WOS:000331358500013 PM 24550551 ER PT J AU Gostissa, M Schwer, B Chang, A Dong, JC Meyers, RM Marecki, GT Choi, VW Chiarle, R Zarrin, AA Alt, FW AF Gostissa, Monica Schwer, Bjoern Chang, Amelia Dong, Junchao Meyers, Robin M. Marecki, Gregory T. Choi, Vivian W. Chiarle, Roberto Zarrin, Ali A. Alt, Frederick W. TI IgH class switching exploits a general property of two DNA breaks to be joined in cis over long chromosomal distances SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE intrachromosomal joining; topological domains; double-strand break synapsis ID ACUTE LYMPHOBLASTIC-LEUKEMIA; DOUBLE-STRAND BREAKS; HUMAN GENOME; B-CELLS; RECOMBINATION; ENDONUCLEASE; 53BP1; ORGANIZATION; MECHANISMS; LANDSCAPE AB Antibody class switch recombination (CSR) in B lymphocytes joins two DNA double-strand breaks (DSBs) lying 100-200 kb apart within switch (S) regions in the immunoglobulin heavy-chain locus (IgH). CSR-activated B lymphocytes generate multiple S-region DSBs in the donor S mu and in a downstream acceptor S region, with a DSB in S mu being joined to a DSB in the acceptor S region at sufficient frequency to drive CSR in a large fraction of activated B cells. Such frequent joining of widely separated CSR DSBs could be promoted by IgH-specific or B-cell-specific processes or by general aspects of chromosome architecture and DSB repair. Previously, we found that B cells with two yeast I-SceI endonuclease targets in place of S gamma 1 undergo I-SceI-dependent class switching from IgM to IgG1 at 5-10% of normal levels. Now, we report that B cells in which S gamma 1 is replaced with a 28 I-SceI target array, designed to increase I-SceI DSB frequency, undergo I-SceI-dependent class switching at almost normal levels. High-throughput genome-wide translocation sequencing revealed that I-SceI-generated DSBs introduced in cis at S mu and S gamma 1 sites are joined together in T cells at levels similar to those of B cells. Such high joining levels also occurred between I-SceI-generated DSBs within c-myc and I-SceI- or CRISPR/Cas9-generated DSBs 100 kb downstream within Pvt1 in B cells or fibroblasts, respectively. We suggest that CSR exploits a general propensity of intrachromosomal DSBs separated by several hundred kilobases to be frequently joined together and discuss the relevance of this finding for recurrent interstitial deletions in cancer. C1 [Gostissa, Monica; Schwer, Bjoern; Chang, Amelia; Dong, Junchao; Meyers, Robin M.; Marecki, Gregory T.; Choi, Vivian W.; Chiarle, Roberto; Zarrin, Ali A.; Alt, Frederick W.] Boston Childrens Hosp, Howard Hughes Med Inst, Boston, MA 02115 USA. [Gostissa, Monica; Schwer, Bjoern; Chang, Amelia; Dong, Junchao; Meyers, Robin M.; Marecki, Gregory T.; Choi, Vivian W.; Chiarle, Roberto; Zarrin, Ali A.; Alt, Frederick W.] Boston Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA. [Gostissa, Monica; Schwer, Bjoern; Chang, Amelia; Dong, Junchao; Meyers, Robin M.; Marecki, Gregory T.; Choi, Vivian W.; Chiarle, Roberto; Zarrin, Ali A.; Alt, Frederick W.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. RP Alt, FW (reprint author), Boston Childrens Hosp, Howard Hughes Med Inst, Boston, MA 02115 USA. EM alt@enders.tch.harvard.edu RI Dong, Junchao/G-5719-2016; OI Dong, Junchao/0000-0001-7404-3562; CHIARLE, Roberto/0000-0003-1564-8531 FU National Institute of Allergy and Infectious Diseases [R01AI077595]; National Cancer Institute of the National Institutes of Health [R01CA098285, P01CA109901]; Eleanor and Miles Shore/Boston Children's Hospital Career Development Fellowship Award; FP7 ERC-StG [242965, AIRC IG-12023, AICR 12-0216]; Associazione Italiana per la Ricerca sul Cancro FX This work was supported by grants from the National Institute of Allergy and Infectious Diseases (Grant R01AI077595) and the National Cancer Institute (Grants R01CA098285 and P01CA109901) of the National Institutes of Health (to F. W. A.). F. W. A. is an Investigator of the Howard Hughes Medical Institute. M. G. was a V Foundation Scholar and is supported by an Eleanor and Miles Shore/Boston Children's Hospital Career Development Fellowship Award. R. C. was supported by Grants FP7 ERC-2009-StG (Proposal 242965, "Lunely"), AIRC IG-12023, and AICR 12-0216. NR 33 TC 16 Z9 16 U1 0 U2 11 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 18 PY 2014 VL 111 IS 7 BP 2644 EP 2649 DI 10.1073/pnas.1324176111 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AA9EL UT WOS:000331396500053 PM 24550291 ER PT J AU Maertens, GN Cook, NJ Wang, WF Hare, S Gupta, SS Oztop, I Lee, KE Pye, VE Cosnefroy, O Snijders, AP KewalRamani, VN Fassati, A Engelman, A Cherepanov, P AF Maertens, Goedele N. Cook, Nicola J. Wang, Weifeng Hare, Stephen Gupta, Saumya Shree Oeztop, Ilker Lee, KyeongEun Pye, Valerie E. Cosnefroy, Ophelie Snijders, Ambrosius P. KewalRamani, Vineet N. Fassati, Ariberto Engelman, Alan Cherepanov, Peter TI Structural basis for nuclear import of splicing factors by human Transportin 3 SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE SR protein; Transportin-SR; importin; host factor ID SR PROTEIN; HIV-1 REPLICATION; RS DOMAIN; PROCESSIVE PHOSPHORYLATION; MAMMALIAN-CELLS; TNPO3; REGULATORS; INFECTION; MECHANISM; COMPLEX AB Transportin 3 (Tnpo3, Transportin-SR2) is implicated in nuclear import of splicing factors and HIV-1 replication. Herein, we show that the majority of cellular Tnpo3 binding partners contain arginine-serine (RS) repeat domains and present crystal structures of human Tnpo3 in its free as well as GTPase Ran- and alternative splicing factor/splicing factor 2 (ASF/SF2)-bound forms. The flexible beta-karyopherin fold of Tnpo3 embraces the RNA recognition motif and RS domains of the cargo. A constellation of charged residues on and around the arginine-rich helix of Tnpo3 HEAT repeat 15 engage the phosphorylated RS domain and are critical for the recognition and nuclear import of ASF/SF2. Mutations in the same region of Tnpo3 impair its interaction with the cleavage and polyadenylation specificity factor 6 (CPSF6) and its ability to support HIV-1 replication. Steric incompatibility of the RS domain and RanGTP engagement by Tnpo3 provides the mechanism for cargo release in the nucleus. Our results elucidate the structural bases for nuclear import of splicing factors and the Tnpo3-CPSF6 nexus in HIV-1 biology. C1 [Maertens, Goedele N.; Hare, Stephen; Gupta, Saumya Shree; Cherepanov, Peter] Univ London Imperial Coll Sci Technol & Med, Div Infect Dis, London W2 1PG, England. [Cook, Nicola J.; Pye, Valerie E.; Cosnefroy, Ophelie; Snijders, Ambrosius P.; Cherepanov, Peter] Canc Res UK, London Res Inst, Clare Hall Labs, Potters Bar EN6 3LD, Herts, England. [Wang, Weifeng; Oeztop, Ilker; Engelman, Alan] Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. [Lee, KyeongEun; KewalRamani, Vineet N.] Natl Canc Inst, HIV Drug Resistance Program, Frederick, MD 21702 USA. [Fassati, Ariberto] UCL, Wohl Vir Ctr, London WC1E 6BT, England. [Fassati, Ariberto] UCL, Med Res Council Ctr Med & Mol Virol, Div Infect & Immun, London WC1E 6BT, England. RP Cherepanov, P (reprint author), Univ London Imperial Coll Sci Technol & Med, Div Infect Dis, St Marys Campus, London W2 1PG, England. EM peter.cherepanov@cancer.org.uk RI wang, weifeng/N-4140-2013; Maertens, Goedele/D-8628-2015; Cherepanov, Peter/F-6859-2010; OI Maertens, Goedele/0000-0002-1963-8026; Cherepanov, Peter/0000-0002-0634-538X; Hare, Stephen/0000-0003-2951-1595; Pye, Valerie E/0000-0001-9616-2992; Snijders, Bram/0000-0002-5416-8592 FU US National Institute of General Medical Sciences [GM082251-06]; National Institute of Allergies and Infectious Disease [AI052014-11]; European Union [305137]; National Institutes of Health, National Cancer Institute, Center for Cancer Research FX We thank the staff of European Synchrotron Radiation Facility ID14-4 and ID23-1 and Diamond I03 beam lines for assistance with X-ray data collection, D. Frith for excellent technical assistance with mass spectrometry, L. Sansregret for help with fluorescent microscopy, and Jonathan Stoye for critical reading of the manuscript. This work was supported by US National Institute of General Medical Sciences P50 Grant GM082251-06 (to A. E. and P. C.), National Institute of Allergies and Infectious Disease R01 Grant AI052014-11 (to A. E.), and European Union FP7 HIVINNOV Consortium Grant 305137 (to A. F.). V.N.K. is supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. NR 54 TC 20 Z9 20 U1 0 U2 6 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 18 PY 2014 VL 111 IS 7 BP 2728 EP 2733 DI 10.1073/pnas.1320755111 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AA9EL UT WOS:000331396500067 PM 24449914 ER PT J AU Perl, L Lerman-Shivek, H Rechavia, E Vaduganathan, M Leshem-Lev, D Zemer-Wassercug, N Dadush, O Codner, P Bental, T Battler, A Kornowski, R Lev, EI AF Perl, Leor Lerman-Shivek, Hila Rechavia, Eldad Vaduganathan, Muthiah Leshem-Lev, Dorit Zemer-Wassercug, Noa Dadush, Oshrat Codner, Pablo Bental, Tamir Battler, Alexander Kornowski, Ran Lev, Eli I. TI Response to Prasugrel and Levels of Circulating Reticulated Platelets in Patients With ST-Segment Elevation Myocardial Infarction SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE antiplatelet therapy; pharmacology; ST-segment elevation myocardial infarction ID CORONARY-ARTERY-DISEASE; ASPIRIN-TREATED PATIENTS; CLOPIDOGREL; REACTIVITY; HETEROGENEITY; INTERVENTION; INHIBITION; TICAGRELOR; OUTCOMES; IMPACT AB Objectives The aim of this study was to determine whether response to prasugrel is associated with the proportion of circulating reticulated platelets (RPs) in patients with ST-segment elevation myocardial infarction (STEMI). Background Despite better pharmacodynamic properties and clinical efficacy of prasugrel compared with clopidogrel, antiplatelet responses to prasugrel are not uniform. The mechanism of this variability in response is not clear. RPs, young hyperactive forms, are increased during situations of enhanced platelet turnover. Methods Patients with STEMI treated with primary percutaneous intervention (PCI) and prasugrel were tested for platelet reactivity using purinergic receptor P2Y, G-protein coupled, 12 (P2Y12) assay and multiple electrode aggregometry (MEA). RP levels were determined using flow cytometry with thiazole orange staining. Tests were performed at 2 to 4 days and 30 days post-PCI. Platelet function was compared by varying levels of RPs, analyzed as continuous (regression analysis) and categorical (tertiles) variables. Results Sixty-two patients were included (mean age: 57.5 +/- 8 years; 21.2% women; 27.7% diabetes). At the early time point, RP levels were strongly correlated with platelet reactivity when evaluated by the P2Y12 assay (Spearman's correlation coefficient: 0.55 for P2Y12 reaction units, -0.49 for percent inhibition) and MEA (Spearman's: 0.50). The upper tertile of RPs displayed higher platelet reactivity compared with the middle and lower tertiles, according to P2Y12 assay and MEA. Similar results with strong correlations between RP and platelet reactivity were noted at 30 days post-PCI. Conclusions The proportion of circulating RPs strongly correlates with response to prasugrel in patients with STEMI treated with PCI. High levels of RPs are associated with increased platelet reactivity despite prasugrel treatment. (C) 2014 by the American College of Cardiology Foundation C1 [Perl, Leor; Lerman-Shivek, Hila; Rechavia, Eldad; Zemer-Wassercug, Noa; Codner, Pablo; Bental, Tamir; Battler, Alexander; Kornowski, Ran; Lev, Eli I.] Rabin Med Ctr, Dept Cardiol, Petah Tiqwa, Israel. [Perl, Leor; Lerman-Shivek, Hila; Rechavia, Eldad; Zemer-Wassercug, Noa; Codner, Pablo; Bental, Tamir; Battler, Alexander; Kornowski, Ran; Lev, Eli I.] Tel Aviv Univ, Sackler Fac Med, IL-69978 Tel Aviv, Israel. [Lerman-Shivek, Hila] Hebrew Univ Jerusalem, Sch Pharm, Dept Clin Pharm, IL-91120 Jerusalem, Israel. [Vaduganathan, Muthiah] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med, Boston, MA USA. [Leshem-Lev, Dorit; Dadush, Oshrat] Rabin Med Ctr, Felsenstein Med Res Inst, Petah Tiqwa, Israel. RP Lev, EI (reprint author), Tel Aviv Univ, Dept Cardiol, Rabin Med Ctr, Jabotinsky St, IL-49100 Tel Aviv, Israel. EM elil@clalit.org.il FU Rabin Medical Center FX This study was financially supported by the Grant for Young Investigators, Rabin Medical Center (Dr. Perl). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. NR 18 TC 25 Z9 25 U1 0 U2 6 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 FEB 18 PY 2014 VL 63 IS 6 BP 513 EP 517 DI 10.1016/j.jacc.2013.07.110 PG 5 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AA4QT UT WOS:000331081700004 PM 24148715 ER PT J AU O'Donoghue, ML Morrow, DA Tsimikas, S Sloan, S Ren, AF Hoffman, EB Desai, NR Solomon, SD Domanski, M Arai, K Chiuve, SE Cannon, CP Sacks, FM Sabatine, MS AF O'Donoghue, Michelle L. Morrow, David A. Tsimikas, Sotirios Sloan, Sarah Ren, Angela F. Hoffman, Elaine B. Desai, Nihar R. Solomon, Scott D. Domanski, Michael Arai, Kiyohito Chiuve, Stephanie E. Cannon, Christopher P. Sacks, Frank M. Sabatine, Marc S. TI Lipoprotein(a) for Risk Assessment in Patients With Established Coronary Artery Disease SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE biomarkers; lipoprotein(a); risk stratification; secondary prevention ID ISCHEMIC-HEART-DISEASE; MYOCARDIAL-INFARCTION; CARDIOVASCULAR RISK; MONOCLONAL-ANTIBODY; CHOLESTEROL LEVELS; CLINICAL-TRIALS; STATIN THERAPY; PLASMA-LEVELS; EVENTS; METAANALYSIS AB Objectives The purpose of this study was to assess the prognostic utility of lipoprotein(a) [Lp(a)] in individuals with coronary artery disease (CAD). Background Data regarding an association between Lp(a) and cardiovascular (CV) risk in secondary prevention populations are sparse. Methods Plasma Lp(a) was measured in 6,708 subjects with CAD from 3 studies; data were then combined with 8 previously published studies for a total of 18,978 subjects. Results Across the 3 studies, increasing levels of Lp(a) were not associated with the risk of CV events when modeled as a continuous variable (odds ratio [OR]: 1.03 per log-transformed SD, 95% confidence interval [CI]: 0.96 to 1.11) or by quintile (Q5:Q1 OR: 1.05, 95% CI: 0.83 to 1.34). When data were combined with previously published studies of Lp(a) in secondary prevention, subjects with Lp(a) levels in the highest quantile were at increased risk of CV events (OR: 1.40, 95% CI: 1.15 to 1.71), but with significant between-study heterogeneity (p = 0.001). When stratified on the basis of low-density lipoprotein (LDL) cholesterol, the association between Lp(a) and CV events was significant in studies in which average LDL cholesterol was >= 130 mg/dl (OR: 1.46, 95% CI: 1.23 to 1.73, p < 0.001), whereas this relationship did not achieve statistical significance for studies with an average LDL cholesterol < 130 mg/dl (OR: 1.20, 95% CI: 0.90 to 1.60, p = 0.21). Conclusions Lp(a) is significantly associated with the risk of CV events in patients with established CAD; however, there exists marked heterogeneity across trials. In particular, the prognostic value of Lp(a) in patients with low cholesterol levels remains unclear. (C) 2014 by the American College of Cardiology Foundation C1 [O'Donoghue, Michelle L.; Morrow, David A.; Tsimikas, Sotirios; Sloan, Sarah; Ren, Angela F.; Hoffman, Elaine B.; Cannon, Christopher P.; Sabatine, Marc S.] Brigham & Womens Hosp, Div Cardiovasc, TIMI Study Grp, Boston, MA 02115 USA. [Tsimikas, Sotirios; Arai, Kiyohito] Univ Calif San Diego, Div Cardiovasc Dis, La Jolla, CA 92093 USA. [Desai, Nihar R.] Yale Univ, Sch Med, Dept Med, Sect Cardiovasc Med, New Haven, CT 06510 USA. [Desai, Nihar R.] Yale New Haven Hlth Syst, Ctr Outcomes Res & Evaluat, New Haven, CT USA. [Solomon, Scott D.] Brigham & Womens Hosp, Div Cardiovasc, Boston, MA 02115 USA. [Domanski, Michael] Mt Sinai Sch Med, Div Cardiovasc, New York, NY USA. [Arai, Kiyohito] Tokyo Womens Med Univ, Div Cardiol, Tokyo, Japan. [Chiuve, Stephanie E.] Brigham & Womens Hosp, Dept Med, Div Prevent Med, Boston, MA 02115 USA. [Chiuve, Stephanie E.; Sacks, Frank M.] Harvard Univ, Sch Med, Boston, MA USA. [Sacks, Frank M.] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA. [Sacks, Frank M.] Brigham & Womens Hosp, Dept Med, Div Cardiol, Boston, MA USA. RP O'Donoghue, ML (reprint author), Brigham & Womens Hosp, Div Cardiovasc, TIMI Study Grp, 350 Longwood Ave,1st Floor, Boston, MA 02115 USA. EM modonoghue@partners.org FU National Heart, Lung, and Blood Institute; Knoll Pharmaceuticals; Abbott Laboratories; Bristol-Myers Squibb; Sankyo; Pfizer, Inc.; National Heart, Lung, and Blood Institute of the National Institutes of Health [R01HL094390, R01HL096738]; GlaxoSmithKline; AstraZeneca; Genzyme; Aegerion; Abbott; Amgen; Athera; Beckman Coulter; BG Medicine; Buhlmann Laboratories; Daiichi Sankyo; Eisai; Eli Lilly; Merck; Nanosphere; Novartis; Ortho-Clinical Diagnostics; Pfizer; Randox; Roche Diagnostics; Sanofi-Aventis; Singulex; Johnson Johnson; Fondation Leducq; Accumetrics; CSL Behring; Essentialis; Regeneron; Sanofi; Takeda; ISIS; AstraZeneca/Bristol-Myers Squibb Alliance; Bristol-Myers Squibb/sanofi-aventis Joint Venture; Daiichi-Sankyo; Intarcia; Critical Diagnostics; Diasorin; Vertex FX The PEACE trial was supported by a contract from the National Heart, Lung, and Blood Institute and by Knoll Pharmaceuticals and Abbott Laboratories. The PROVE IT-TIMI 22 study was supported by Bristol-Myers Squibb and Sankyo. The CARE trial was supported by a grant from Bristol-Myers Squibb. The assay for Lp(a) in PEACE was conducted at diaDexus. The assay for Lp(a) in PROVE IT-TIMI 22 was supported by an investigator-initiated research grant (Advances in Atorvastatin Research Grant) from Pfizer, Inc. (to Dr. Tsimikas). Research reported in this publication was supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health under award numbers R01HL094390 and R01HL096738 to Dr. Sabatine. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Dr. O'Donoghue has received grant funding from GlaxoSmithKline, AstraZeneca, and Genzyme; and has received consulting fees from Aegerion. Dr. Morrow reports that the TIMI Study Group has received research grants from Abbott, AstraZeneca, Amgen, Athera, Beckman Coulter, BG Medicine, Bristol-Myers Squibb, Buhlmann Laboratories, Daiichi Sankyo, Eisai, Eli Lilly, GlaxoSmithKline, Merck, Nanosphere, Novartis, Ortho-Clinical Diagnostics, Pfizer, Randox, Roche Diagnostics, Sanofi-Aventis, Singulex, and Johnson & Johnson; he has also served as a consultant for BG Medicine, Critical Diagnostics, Eli Lilly, Genentech, Gilead, Instrumentation Laboratory, Johnson & Johnson, Konica/Minolta, Merck, Novartis, Roche Diagnostics, and Servier. Dr. Tsimikas is supported in part by grants from the Fondation Leducq and by an investigator-initiated research grant (Advances in Atorvastatin Research Grant) from Pfizer, Inc.; is a coinventor and receives royalties from patents owned by the University of California for the commercial use of oxidation-specific antibodies; is a consultant to Quest, Sanofi, Genzyme, Regeneron, and ISIS; and has received investigator-initiated grants from Pfizer and Merck. Dr. Cannon has received grant funding from Accumetrics, AstraZeneca, CSL Behring, Essentialis, GlaxoSmithKline, Merck, Regeneron, Sanofi, and Takeda; he has served on the advisory board for Alnylam, Bristol-Myers Squibb, Lipimedix, and Pfizer; and he is a clinical advisor and has equity in Automedics Medical Systems. Dr. Sacks has served as a consultant to Amgen, Eli Lilly, Merck, Roche, and sanofi-aventis; has received funding from ISIS and Aegerion; and he has received lecture fees from AstraZeneca. Dr. Sabatine has received grants from Amgen, AstraZeneca, AstraZeneca/Bristol-Myers Squibb Alliance, Bristol-Myers Squibb/sanofi-aventis Joint Venture, Daiichi-Sankyo, Eisai, Genzyme, GlaxoSmithKline, Intarcia, Merck, sanofi-aventis, Takeda, Abbott Laboratories, Accumetrics, Critical Diagnostics, Nanosphere, and Roche Diagnostics; and he has received consulting fees from Aegerion, Amgen, AstraZeneca/Bristol-Myers Squibb Alliance, Diasorin, GlaxoSmithKline, Intarcia, Merck, Pfizer, sanofi-aventis, and Vertex. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. John J. Kastelein, MD, served as Guest Editor for this paper. NR 46 TC 27 Z9 29 U1 1 U2 10 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 FEB 18 PY 2014 VL 63 IS 6 BP 520 EP 527 DI 10.1016/j.jacc.2013.09.042 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AA4QT UT WOS:000331081700006 PM 24161323 ER PT J AU Harrison, J Rentz, DM McLaughlin, T Niecko, T Gregg, KM Black, RS Buchanan, J Liu, E Grundman, M AF Harrison, John Rentz, Dorene M. McLaughlin, Trent Niecko, Timothy Gregg, Keith M. Black, Ronald S. Buchanan, Jacqui Liu, Enchi Grundman, Michael CA ELN-AIP-901 Study Investigator Grp TI Cognition in MCI and Alzheimer's Disease: Baseline Data from a Longitudinal Study of the NTB SO CLINICAL NEUROPSYCHOLOGIST LA English DT Article DE Alzheimer's disease; Cognition; MCI; Neuropsychological Test Battery; Psychometric properties ID CONTROLLED-TRIAL; CLINICAL-TRIALS; A-BETA; IMPAIRMENT; EFFICACY; SAFETY; PBT2 AB Baseline data are summarized from a study examining the psychometric properties of the Neuropsychological Test Battery (NTB) and its subtests, and correlating the NTB with other cognitive and functional assessments. A multicenter, longitudinal, non-interventional study included mild to moderate Alzheimer's disease (AD, n = 196), mild cognitive impairment (MCI, n = 70), or normal cognition participants (NC, n = 75). The NTB, other cognitive assessment tools, functional/behavioral questionnaires, and health outcome assessments were administered. At baseline composite NTB, NTB memory, and NTB executive function z-scores were significantly lower for participants with AD compared with MCI, and for participants with MCI compared with NC. The composite NTB z-score had high test-retest reliability between screening and baseline. The results of this study suggest that NTB exhibits good reliability in patients with mild to moderate AD and MCI. C1 [Harrison, John] Metis Cognit Ltd, Warminster BA12 6QY, Wilts, England. [Harrison, John] Univ London Imperial Coll Sci Technol & Med, Dept Med, London, England. [Rentz, Dorene M.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Neurol, Boston, MA 02115 USA. [Rentz, Dorene M.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA 02115 USA. [McLaughlin, Trent; Gregg, Keith M.; Buchanan, Jacqui; Liu, Enchi] Janssen Alzheimer Immunotherapy Res & Dev LLC, San Francisco, CA USA. [Niecko, Timothy] Niecko Hlth Econ LLC, Naples, FL USA. [Black, Ronald S.] Pfizer Inc, Collegeville, PA USA. [Grundman, Michael] Global R&D Partners Inc, San Diego, CA USA. RP Harrison, J (reprint author), Metis Cognit Ltd, Pk House, Warminster BA12 6QY, Wilts, England. EM john@metiscog.com FU Janssen Alzheimer Immunotherapy Research & Development, LLC; Pfizer Inc. FX This study was sponsored by Janssen Alzheimer Immunotherapy Research & Development, LLC, and Pfizer Inc. Medical writing support was provided by Benjamin R. Houghtaling, PhD, and Lisette T. Arnaud, PhD, at Phase Five Communications Inc., and was funded by Pfizer Inc. and Janssen Alzheimer Immunotherapy Research & Development, LLC. John Harrison has received consultancy payments from Pfizer Inc. and Janssen Alzheimer Immunotherapy Research & Development, LLC. John Harrison does not own any of the tests that comprise the NTB and has received no payment from the tests' owners for recommending the use of these measures. Trent McLaughlin was an employee of Janssen Alzheimer Immunotherapy and Ronald Black was an employee of Pfizer at the time this research was conducted. Tim Niecko and Jacqui Buchanan were paid contractors to Janssen Alzheimer Immunotherapy Research & Development, LLC, in the development of this manuscript. Michael Grundman was a paid consultant to Janssen Alzheimer Immunotherapy Research & Development, LLC, in the development of this manuscript. NR 14 TC 0 Z9 0 U1 0 U2 7 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 520 CHESTNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 1385-4046 EI 1744-4144 J9 CLIN NEUROPSYCHOL JI Clin. Neuropsychol. PD FEB 17 PY 2014 VL 28 IS 2 BP 252 EP 268 DI 10.1080/13854046.2013.875595 PG 17 WC Psychology, Clinical; Clinical Neurology; Psychology SC Psychology; Neurosciences & Neurology GA AB7TU UT WOS:000331994400006 PM 24521259 ER PT J AU Lemon, CM Curtin, PN Somers, RC Greytak, AB Lanning, RM Jain, RK Bawendi, MG Nocera, DG AF Lemon, Christopher M. Curtin, Peter N. Somers, Rebecca C. Greytak, Andrew B. Lanning, Ryan M. Jain, Rakesh K. Bawendi, Moungi G. Nocera, Daniel G. TI Metabolic Tumor Profiling with pH, Oxygen, and Glucose Chemosensors on a Quantum Dot Scaffold SO INORGANIC CHEMISTRY LA English DT Article ID RESONANCE ENERGY-TRANSFER; EXCITATION CROSS-SECTIONS; PRESSURE-SENSITIVE PAINTS; CANCER STEM-CELLS; IN-VIVO; BORONIC ACID; 2-PHOTON ABSORPTION; CHEMICAL SENSORS; DRUG-DELIVERY; SEMICONDUCTOR NANOCRYSTALLITES AB Acidity, hypoxia, and glucose levels characterize the tumor microenvironment rendering pH, pO(2), and pGlucose, respectively, important indicators of tumor health. To this end, understanding how these parameters change can be a powerful tool for the development of novel and effective therapeutics. We have designed optical chemosensors that feature a quantum dot and an analyte-responsive dye. These noninvasive chemosensors permit pH, oxygen, and glucose to be monitored dynamically within the tumor microenvironment by using multiphoton imaging. C1 [Lemon, Christopher M.; Nocera, Daniel G.] Harvard Univ, Dept Chem & Chem Biol, Cambridge, MA 02138 USA. [Curtin, Peter N.; Somers, Rebecca C.; Greytak, Andrew B.; Bawendi, Moungi G.] MIT, Dept Chem, Cambridge, MA 02139 USA. [Lanning, Ryan M.; Jain, Rakesh K.] Massachusetts Gen Hosp, Dept Radiat Oncol, Edwin L Steele Lab Tumor Biol, Boston, MA 02114 USA. [Lanning, Ryan M.; Jain, Rakesh K.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Greytak, Andrew B.] Univ S Carolina, Dept Chem & Biochem, Columbia, SC 29208 USA. RP Nocera, DG (reprint author), Harvard Univ, Dept Chem & Chem Biol, 12 Oxford St, Cambridge, MA 02138 USA. EM dnocera@fas.harvard.edu OI Greytak, Andrew/0000-0001-8978-6457 FU U.S. National Cancer Institute [R01-CA126642] FX C.M.L. acknowledges the National Science Foundation's Graduate Research Fellowship Program. We thank Dr. Oliver Bruns and Dr. Xiaoxing Han for assistance in collecting the two-photon brain images of Figure 8. This research was supported by U.S. National Cancer Institute Grant R01-CA126642. NR 286 TC 25 Z9 26 U1 3 U2 58 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0020-1669 EI 1520-510X J9 INORG CHEM JI Inorg. Chem. PD FEB 17 PY 2014 VL 53 IS 4 BP 1900 EP 1915 DI 10.1021/ic401587r PG 16 WC Chemistry, Inorganic & Nuclear SC Chemistry GA AB9VP UT WOS:000332144100010 PM 24143874 ER PT J AU Nihal, M Ahmad, N Wood, GS AF Nihal, Minakshi Ahmad, Nihal Wood, Gary S. TI SIRT1 is upregulated in cutaneous T-cell lymphoma, and its inhibition induces growth arrest and apoptosis SO CELL CYCLE LA English DT Article DE CTCL; SIRT1; HDACI; p53; apoptosis ID HISTONE DEACETYLASE INHIBITOR; TUMOR-SUPPRESSOR; ROMIDEPSIN; EXPRESSION; P53; VORINOSTAT; MECHANISM; CANCER; SAHA; LOCALIZATION AB Silent information regulator type-1 (SIRT1) is the best-studied member of the Sirtuin (Sir2) family of nicotinamide dinucleotide (NAD)-dependent class III histone deacetylases (HDACs), but has not yet been explored in cutaneous T-cell lymphoma (CTCL). We analyzed five CTCL cell lines and lesional tissues using flow cytometry, immunostaining, immunoblotting, cell death, viability, and apoptosis assays, small-molecule inhibitors, and shRNA knockdown. We found strong SIRT1 expression among CTCL lines relative to normal lymphocytes. CTCL cells in lesional tissues also expressed SIRT1 strongly. SIRT1 knockdown resulted in reduced cellular metabolism and proliferation, increased apoptosis, and PARP cleavage products. Tenovin-1, which reversibly inhibits class III HDACs (SIRT1 and SIRT2), reduced SIRT enzymatic activity and SIRT1 expression and led to increased apoptosis. These alterations were accompanied by increased forkhead box O3 (FoxO3) in several cell lines and increased nuclear p53, as well as acetylated p53 in wtp53 MyLa CTCL line. A combination of class I/II and class III HDACIs (vorinostat and tenovin-1) produced significantly greater growth inhibition, cell death via apoptosis, as well as superior p53 promoter upregulation in wtp53 MyLa cells as compared with either agent alone. This occurred in a partially p53-dependent manner, as these effects were blunted by p53 knockdown. Our results indicate that SIRT1 is strongly expressed in CTCL. Its inhibition results in reduced growth and increased apoptosis of CTCL cells. Furthermore, our findings suggest that some CTCL patients, such as those with wtp53, might benefit more from treatment with a combination of different classes of HDACIs than with a single agent. C1 [Nihal, Minakshi; Ahmad, Nihal; Wood, Gary S.] Univ Wisconsin, Dept Dermatol, Sch Med & Publ Hlth, Madison, WI 53706 USA. [Nihal, Minakshi; Ahmad, Nihal; Wood, Gary S.] Univ Wisconsin, Sch Med & Publ Hlth, Paul P Carbone Comprehens Canc Ctr, Madison, WI USA. [Ahmad, Nihal; Wood, Gary S.] William S Middleton Mem Vet Adm Med Ctr, Madison, WI USA. RP Wood, GS (reprint author), Univ Wisconsin, Dept Dermatol, Sch Med & Publ Hlth, Madison, WI 53706 USA. EM gwood@dermatology.wisc.edu FU Department of Veterans Affairs; NCI [P30CA014520, CA164417] FX Supported by Merit Review funding from the Department of Veterans Affairs (GSW and NA) and NCI (P30CA014520 and CA164417). NR 50 TC 15 Z9 18 U1 0 U2 5 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 FEB 15 PY 2014 VL 13 IS 4 BP 632 EP 640 DI 10.4161/cc.27523 PG 9 WC Cell Biology SC Cell Biology GA AF0RY UT WOS:000334422900021 PM 24343700 ER PT J AU Karst, AM Jones, PM Vena, N Ligon, AH Liu, JF Hirsch, MS Etemadmoghadam, D Bowtell, DDL Drapkin, R AF Karst, Alison M. Jones, Paul M. Vena, Natalie Ligon, Azra H. Liu, Joyce F. Hirsch, Michelle S. Etemadmoghadam, Dariush Bowtell, David D. L. Drapkin, Ronny TI Cyclin E1 Deregulation Occurs Early in Secretory Cell Transformation to Promote Formation of Fallopian Tube-Derived High-Grade Serous Ovarian Cancers SO CANCER RESEARCH LA English DT Article ID COMPARATIVE GENOMIC HYBRIDIZATION; INTRAEPITHELIAL CARCINOMA; EPITHELIAL-CELLS; MAMMARY-GLAND; COPY NUMBER; DNA-DAMAGE; P53; INSTABILITY; TUMORIGENESIS; AMPLIFICATION AB The fallopian tube is now generally considered the dominant site of origin for high-grade serous ovarian carcinoma. However, the molecular pathogenesis of fallopian tube-derived serous carcinomas is poorly understood and there are few experimental studies examining the transformation of human fallopian tube cells. Prompted by recent genomic analyses that identified cyclin E1 (CCNE1) gene amplification as a candidate oncogenic driver in high-grade serous ovarian carcinoma, we evaluated the functional role of cyclin E1 in serous carcinogenesis. Cyclin E1 was expressed in early- and late-stage human tumor samples. In primary human fallopian tube secretory epithelial cells, cyclin E1 expression imparted malignant characteristics to untransformed cells if p53 was compromised, promoting an accumulation of DNA damage and altered transcription of DNA damage response genes related to DNA replication stress. Together, our findings corroborate the hypothesis that cyclin E1 dysregulation acts to drive malignant transformation in fallopian tube secretory cells that are the site of origin of high-grade serous ovarian carcinomas. (C)2013 AACR. C1 [Karst, Alison M.; Jones, Paul M.; Vena, Natalie; Liu, Joyce F.; Drapkin, Ronny] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Vena, Natalie; Ligon, Azra H.] Dana Farber Canc Inst, Ctr Mol Oncol Pathol, Boston, MA 02215 USA. [Karst, Alison M.; Ligon, Azra H.; Liu, Joyce F.; Hirsch, Michelle S.; Drapkin, Ronny] Harvard Univ, Sch Med, Boston, MA USA. [Ligon, Azra H.] Brigham & Womens Hosp, Dept Pathol, Cytogenet Div, Boston, MA 02115 USA. [Hirsch, Michelle S.; Drapkin, Ronny] Brigham & Womens Hosp, Dept Pathol, Div Womens & Perinatal Pathol, Boston, MA 02115 USA. [Etemadmoghadam, Dariush; Bowtell, David D. L.] Peter MacCallum Canc Inst, Melbourne, Vic, Australia. [Etemadmoghadam, Dariush; Bowtell, David D. L.] Peter MacCallum Canc Inst, Dept Oncol, Melbourne, Vic 3000, Australia. [Etemadmoghadam, Dariush; Bowtell, David D. L.] Univ Melbourne, Dept Pathol, Melbourne, Vic, Australia. [Bowtell, David D. L.] Univ Melbourne, Dept Biochem & Mol Biol, Melbourne, Vic, Australia. RP Drapkin, R (reprint author), Dana Farber Canc Inst, Jimmy Fund Bldg,Room 215D,450 Brookline Ave, Boston, MA 02215 USA. EM ronny_drapkin@dfci.harvard.edu RI Drapkin, Ronny/E-9944-2016; Bowtell, David/H-1007-2016 OI Drapkin, Ronny/0000-0002-6912-6977; Bowtell, David/0000-0001-9089-7525 FU National Cancer Institute [NIH P50-CA105009, NIH U01 CA-152990, NIH R21 CA-156021]; Honorable Tina Brozman 'Tina's Wish' Foundation; Dr. Miriam and Sheldon G. Adelson Medical Research Foundation; Robert and Debra First Fund; Gamel Family Fund; Canadian Institutes of Health Research Fellowship; Kaleidoscope of Hope Foundation Young Investigator Research Grant; National Health and Medical Research Council [APP 1042358] FX This work was supported by grants from the National Cancer Institute at the NIH P50-CA105009 (R. Drapkin), NIH U01 CA-152990 (R. Drapkin), NIH R21 CA-156021 (R. Drapkin); the Honorable Tina Brozman 'Tina's Wish' Foundation (R. Drapkin), the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (R. Drapkin), the Robert and Debra First Fund (R. Drapkin), the Gamel Family Fund (R. Drapkin), a Canadian Institutes of Health Research Fellowship (A. M. Karst), a Kaleidoscope of Hope Foundation Young Investigator Research Grant (A. M. Karst), and a National Health and Medical Research Council project grant (APP 1042358; D. D. L. Bowtell). NR 49 TC 28 Z9 30 U1 0 U2 4 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 FEB 15 PY 2014 VL 74 IS 4 BP 1141 EP 1152 DI 10.1158/0008-5472.CAN-13-2247 PG 12 WC Oncology SC Oncology GA AB6DA UT WOS:000331876600014 PM 24366882 ER PT J AU Allmendinger, AM Mallery, RM Magro, CM Wang, N Egan, RA Samuels, MA Callahan, A Viswanadhan, N Klufas, RA Hsu, LG Prasad, S AF Allmendinger, Andrew M. Mallery, Robert M. Magro, Cynthia M. Wang, Nancy Egan, Robert A. Samuels, Martin A. Callahan, Alison Viswanadhan, Narayan Klufas, Roman A. Hsu, Liangge Prasad, Sashank TI Cauda equina involvement in Susac's syndrome SO JOURNAL OF THE NEUROLOGICAL SCIENCES LA English DT Article DE Susac's syndrome; Cauda equina syndrome; Corpus callosum; MRI; Endotheliopathy; Microangiopathy; Retinal artery occlusion; Antiendothelial cell antibodies ID MICROANGIOPATHY; RETINA; BRAIN; ENDOTHELIOPATHY; MRI AB Susac's syndrome is a rare autoimmune microangiopathy characterized by the clinical triad of encephalopathy, branch retinal artery occlusions, and sensorineural hearing loss. In many cases, the clinical triad. is not fully present at the onset of symptoms. MRI studies often show characteristic punched out lesions of the central fibers of the corpus callosum, and leptomeningeal enhancement and deep gray matter lesions may also be seen. Here we present a case of Susac's syndrome in a middle aged man with the unique clinical finding of cauda equina syndrome and spinal MM showing diffuse lumbosacral nerve root enhancement. Biopsy specimens of the brain, leptomeninges, and skin showed evidence of a pauci-immune endotheliopathy, consistent with pathology described in previous cases of Susac's syndrome. This case is important not only because it expands the clinical features of Susac's syndrome but also because it clarifies the mechanism of a disorder of the endothelium, an important target for many disorders of the nervous system. (C) 2013 Elsevier B.V. All rights reserved. C1 [Allmendinger, Andrew M.; Viswanadhan, Narayan; Klufas, Roman A.; Hsu, Liangge] Brigham & Womens Hosp, Dept Radiol, Boston, MA 02115 USA. [Mallery, Robert M.] Univ Penn, Dept Neurol, Philadelphia, PA 19104 USA. [Mallery, Robert M.] Univ Penn, Dept Ophthalmol, Philadelphia, PA 19104 USA. [Magro, Cynthia M.] Cornell Univ, Weill Med Coll, Dept Pathol & Lab Med, New York, NY 10021 USA. [Wang, Nancy; Samuels, Martin A.; Prasad, Sashank] Brigham & Womens Hosp, Dept Neurol, Boston, MA 02115 USA. [Egan, Robert A.] Oregon Neurol, Tualatin, OR USA. [Callahan, Alison] Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Boston, MA 02114 USA. RP Mallery, RM (reprint author), 51 N 39th St Suite 501, Philadelphia, PA 19104 USA. EM robert.mallery@uphs.upenn.edu NR 15 TC 1 Z9 2 U1 1 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0022-510X EI 1878-5883 J9 J NEUROL SCI JI J. Neurol. Sci. PD FEB 15 PY 2014 VL 337 IS 1-2 BP 91 EP 96 DI 10.1016/j.jns.2013.11.023 PG 6 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA AC8TW UT WOS:000332808700016 PM 24290499 ER PT J AU Zhao, X Chen, F Feng, ZJ Li, XS Zhou, XH AF Zhao, Xing Chen, Fei Feng, Zijian Li, Xiaosong Zhou, Xiao-Hua TI The temporal lagged association between meteorological factors and malaria in 30 counties in south-west China: a multilevel distributed lag non-linear analysis SO MALARIA JOURNAL LA English DT Article ID EAST-AFRICAN HIGHLANDS; CLIMATE-CHANGE; YUNNAN PROVINCE; SPATIOTEMPORAL DISTRIBUTION; INFECTIOUS-DISEASES; FALCIPARUM-MALARIA; BORNE DISEASES; MODELS; EPIDEMIC; TRANSMISSION AB Background: The association between malaria and meteorological factors is complex due to the lagged and non-linear pattern. Without fully considering these characteristics, existing studies usually concluded inconsistent findings. Investigating the lagged correlation pattern between malaria and climatic variables may improve the understanding of the association and generate possible better prediction models. This is especially beneficial to the south-west China, which is a high-incidence area in China. Methods: Thirty counties in south-west China were selected, and corresponding weekly malaria cases and four weekly meteorological variables were collected from 2004 to 2009. The Multilevel Distributed Lag Non-linear Model (MDLNM) was used to study the temporal lagged correlation between weekly malaria and weekly meteorological factors. The counties were divided into two groups, hot and cold weathers, in order to compare the difference under different climatic conditions and improve reliability and generalizability within similar climatic conditions. Results: Rainfall was associated with malaria cases in both hot and cold weather counties with a lagged correlation, and the lag range was relatively longer than those of other meteorological factors. Besides, the lag range was longer in hot weather counties compared to cold weather counties. Relative humidity was correlated with malaria cases at early and late lags in hot weather counties. Minimum temperature had a longer lag range and larger correlation coefficients for hot weather counties compared to cold weather counties. Maximum temperature was only associated with malaria cases at early lags. Conclusion: Using weekly malaria cases and meteorological information, this work studied the temporal lagged association pattern between malaria cases and meteorological information in south-west China. The results suggest that different meteorological factors show distinct patterns and magnitudes for the lagged correlation, and the patterns will depend on the climatic condition. Existing inconsistent findings for climatic factors' lags could be due to either the invalid assumption of a single fixed lag or the distinct temperature conditions from different study sites. The lag pattern for meteorological factors should be considered in the development of malaria early warning system. C1 [Zhao, Xing; Chen, Fei; Li, Xiaosong] Sichuan Univ, West China Sch Publ Hlth, Chengdu 610041, Peoples R China. [Zhao, Xing; Zhou, Xiao-Hua] Univ Washington, Sch Publ Hlth, Dept Biostat, Seattle, WA 98195 USA. [Feng, Zijian] Chinese Ctr Dis Control & Prevent, Off Dis Control & Emergency Response, Beijing 102206, Peoples R China. [Zhou, Xiao-Hua] VA Puget Sound Hlth Care Syst, HSR&D Ctr Excellence, Seattle, WA 98101 USA. RP Li, XS (reprint author), Sichuan Univ, West China Sch Publ Hlth, 17 Sect 3,South Renmin Rd, Chengdu 610041, Peoples R China. EM lixiaosong1101@126.com; azhou@u.washington.edu FU Natural Science Foundation of China [30571618]; Ministry of Health, China [200802133]; China Scholarship Council FX The reviewer's comments has greatly improved the explanation and discussion of Figure 5. This study was supported by the Natural Science Foundation of China (No.30571618), Grants of the Ministry of Health, China (No.200802133), China Scholarship Council (http://en.csc.edu.cn/). NR 57 TC 11 Z9 12 U1 1 U2 7 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1475-2875 J9 MALARIA J JI Malar. J. PD FEB 15 PY 2014 VL 13 AR 57 DI 10.1186/1475-2875-13-57 PG 12 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA AC8HN UT WOS:000332774200002 PM 24528891 ER PT J AU Minder, CM Shaya, GE Michos, ED Keenan, TE Blumenthal, RS Nasir, K Carvalho, JAM Conceicao, RD Santos, RD Blaha, MJ AF Minder, Camille Michael Shaya, Gabriel E. Michos, Erin D. Keenan, Tanya E. Blumenthal, Roger S. Nasir, Khurram Carvalho, Jose A. M. Conceicao, Raquel D. Santos, Raul D. Blaha, Michael J. TI Relation Between Self-Reported Physical Activity Level, Fitness, and Cardiometabolic Risk SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID CARDIORESPIRATORY FITNESS; ACTIVITY QUESTIONNAIRE; CARDIOVASCULAR-DISEASE; METABOLIC SYNDROME; EXERCISE CAPACITY; TREADMILL; VALIDITY; ASSOCIATION; MORTALITY; ADULTS AB Physical activity and cardiorespiratory fitness are associated with improved cardiovascular health and reduced all-cause mortality. The relation between self-reported physical activity, objective physical fitness, and the association of each with cardiometabolic risk has not been fully described. We studied 2,800 healthy Brazilian subjects referred for an employer-sponsored health screening. Physical activity level was determined as "low," "moderate," or "high" with the International Physical Activity Questionnaire: Short Form (IPAQ-SF). Fitness was measured as METs achieved on a maximal, symptom-limited, treadmill stress test. Using multivariate linear regression analysis, we calculated age, gender, and smoking-adjusted correlation coefficients among IPAQ-SF, fitness, and cardiometabolic risk factors. Mean age of study participants was 43 +/- 9 years; 81% were men, and 43% were highly active. Mean METs achieved was 12 +/- 2. IPAQ-SF category and fitness were moderately correlated (r = 0.377). Compared with IPAQ-SF category, fitness was better correlated with cardiometabolic risk factors including anthropomorphic measurements, blood pressure, fasting blood glucose, dyslipidemia, high-sensitivity C-reactive protein, and hepatic steatosis (all p <0.01). Among these, anthropomorphic measurements, blood pressure, high-sensitivity C-reactive protein, and hepatic steatosis had the largest discrepancies in correlation, whereas lipid factors had the least discrepant correlation. When IPAQ-SF and fitness were discordant, poor fitness drove associations with elevated cardiometabolic risk. In conclusion, self-reported physical activity level and directly measured fitness are moderately correlated, and the latter is more strongly associated with a protective cardiovascular risk profile. (C) 2014 Elsevier Inc. All rights reserved. C1 [Minder, Camille Michael; Shaya, Gabriel E.; Michos, Erin D.; Keenan, Tanya E.; Blumenthal, Roger S.; Nasir, Khurram; Blaha, Michael J.] Johns Hopkins Ciccarone Ctr Prevent Heart Dis, Baltimore, MD 21287 USA. [Shaya, Gabriel E.] Univ Miami, Miller Sch Med, Miami, FL 33136 USA. [Keenan, Tanya E.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Nasir, Khurram] Baptist Hlth South Florida, Miami, FL USA. [Carvalho, Jose A. M.; Conceicao, Raquel D.; Santos, Raul D.] Hosp Israelita Albert Einstein, Prevent Med Ctr, Sao Paulo, Brazil. [Santos, Raul D.] Univ Sao Paulo, Med Sch Hosp, Lipid Clin Heart Inst InCor, Sao Paulo, Brazil. RP Blaha, MJ (reprint author), Johns Hopkins Ciccarone Ctr Prevent Heart Dis, Baltimore, MD 21287 USA. EM mblaha1@jhmi.edu RI Santos, Raul/A-1170-2010 OI Santos, Raul/0000-0002-9860-6582 NR 27 TC 19 Z9 20 U1 1 U2 19 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 FEB 15 PY 2014 VL 113 IS 4 BP 637 EP 643 DI 10.1016/j.amjcard.2013.11.010 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AB4PQ UT WOS:000331772800011 PM 24360775 ER PT J AU Kostis, WJ Cabrera, J Messerli, FH Cheng, JQ Sedjro, JE Cosgrove, NM Swerdel, JN Deng, YZ Davis, BR Kostis, JB AF Kostis, William J. Cabrera, Javier Messerli, Franz H. Cheng, Jerry Q. Sedjro, Jeanine E. Cosgrove, Nora M. Swerdel, Joel N. Deng, Yingzi Davis, Barry R. Kostis, John B. TI Competing Cardiovascular and Noncardiovascular Risks and Longevity in the Systolic Hypertension in the Elderly Program SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID ANTIHYPERTENSIVE DRUG-TREATMENT; CLINICAL-TRIALS; LIFE EXPECTANCY; OLDER PERSONS; OUTCOMES; THERAPY; RANDOMIZATION; PREVENTION; ADHERENCE; MORTALITY AB We examined the effect of chlorthalidone-based stepped care on the competing risks of cardiovascular (CV) versus non-CV death in the Systolic Hypertension in the Elderly Program (SHEP). Participants were randomly assigned to chlorthalidone-based stepped-care therapy (n = 2,365) or placebo (n = 2,371) for 4.5 years, and all participants were advised to take active therapy thereafter. At the 22-year follow-up, the gain in life expectancy free from CV death in the active treatment group was 145 days (95% confidence interval [CI] 23 to 260, p = 0.012). The gain in overall life expectancy was smaller (105 days, 95% CI 39 to 242, p = 0.073) because of a 40-day (95% CI 87 to 161) decrease in survival from non-CV death. Compared with an age- and gender-matched cohort, participants had markedly higher overall life expectancy (Wilcoxon p = 0.00001) and greater chance of reaching the ages of 80 (81.3% vs 57.6%), 85 (58.1% vs 37.4%), 90 (30.5% vs 22.0%), 95 (11.9% vs 8.8%), and 100 years (3.7% vs 2.8%). In conclusion, Systolic Hypertension in the Elderly Program participants had higher overall life expectancy than actuarial controls and those randomized to active therapy had longer life expectancy free from CV death but had a small increase in the competing risk of non-CV death. (C) 2014 Elsevier Inc. All rights reserved. C1 [Kostis, William J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol, Boston, MA USA. [Cabrera, Javier] Rutgers State Univ, Dept Stat, Piscataway, NJ USA. [Cabrera, Javier; Cheng, Jerry Q.; Sedjro, Jeanine E.; Cosgrove, Nora M.; Swerdel, Joel N.; Deng, Yingzi; Kostis, John B.] Rutgers Robert Wood Johnson Med Sch, Cardiovasc Inst, New Brunswick, NJ 08901 USA. [Messerli, Franz H.] Columbia Univ Coll Phys & Surg, St Lukes Roosevelt Hosp Ctr, Div Cardiol, New York, NY 10032 USA. [Davis, Barry R.] Univ Texas Hlth Sci Ctr Houston, Houston, TX 77030 USA. RP Kostis, JB (reprint author), Rutgers Robert Wood Johnson Med Sch, Cardiovasc Inst, New Brunswick, NJ 08901 USA. EM kostis@rwjms.rutgers.edu FU National Institutes of Health, National Institute on Aging (Bethesda, Maryland); Robert Wood Johnson Foundation (Princeton, New Jersey) FX This work was supported in part by the National Institutes of Health, National Institute on Aging (Bethesda, Maryland), and the Robert Wood Johnson Foundation (Princeton, New Jersey). NR 21 TC 7 Z9 7 U1 1 U2 4 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 FEB 15 PY 2014 VL 113 IS 4 BP 676 EP 681 DI 10.1016/j.amjcard.2013.11.013 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AB4PQ UT WOS:000331772800017 PM 24388619 ER PT J AU Bandopadhayay, P Bergthold, G Nguyen, B Schubert, S Gholamin, S Tang, YJ Bolin, S Schumacher, SE Zeid, R Masoud, S Yu, FR Vue, N Gibson, WJ Paolella, BR Mitra, SS Cheshier, SH Qi, J Liu, KW Wechsler-Reya, R Weiss, WA Swartling, FJ Kieran, MW Bradner, JE Beroukhim, R Cho, YJ AF Bandopadhayay, Pratiti Bergthold, Guillaume Nguyen, Brian Schubert, Simone Gholamin, Sharareh Tang, Yujie Bolin, Sara Schumacher, Steven E. Zeid, Rhamy Masoud, Sabran Yu, Furong Vue, Nujsaubnusi Gibson, William J. Paolella, Brenton R. Mitra, Siddhartha S. Cheshier, Samuel H. Qi, Jun Liu, Kun-Wei Wechsler-Reya, Robert Weiss, William A. Swartling, Fredrik J. Kieran, Mark W. Bradner, James E. Beroukhim, Rameen Cho, Yoon-Jae TI BET Bromodomain Inhibition of MYC-Amplified Medulloblastoma SO CLINICAL CANCER RESEARCH LA English DT Article ID CIRCULAR BINARY SEGMENTATION; N-MYC; ADJUVANT CHEMOTHERAPY; HISTONE H3.3; BRAIN-TUMORS; C-MYC; SUBGROUPS; PROLIFERATION; CANCER; PRECURSORS AB Purpose: MYC-amplified medulloblastomas are highly lethal tumors. Bromodomain and extraterminal (BET) bromodomain inhibition has recently been shown to suppress MYC-associated transcriptional activity in other cancers. The compound JQ1 inhibits BET bromodomain-containing proteins, including BRD4. Here, we investigate BET bromodomain targeting for the treatment of MYC-amplified medulloblastoma. Experimental Design: We evaluated the effects of genetic and pharmacologic inhibition of BET bromodomains on proliferation, cell cycle, and apoptosis in established and newly generated patient- and genetically engineered mouse model (GEMM)-derived medulloblastoma cell lines and xenografts that harbored amplifications of MYC orMYCN. We also assessed the effect of JQ1 on MYC expression and global MYC-associated transcriptional activity. We assessed the in vivo efficacy of JQ1 in orthotopic xenografts established in immunocompromised mice. Results: Treatment of MYC-amplified medulloblastoma cells with JQ1 decreased cell viability associated with arrest at G(1) and apoptosis. We observed downregulation of MYC expression and confirmed the inhibition of MYC-associated transcriptional targets. The exogenous expression of MYC from a retroviral promoter reduced the effect of JQ1 on cell viability, suggesting that attenuated levels of MYC contribute to the functional effects of JQ1. JQ1 significantly prolonged the survival of orthotopic xenograft models of MYC-amplified medulloblastoma (P < 0.001). Xenografts harvested from mice after five doses of JQ1 had reduced the expression of MYC mRNA and a reduced proliferative index. Conclusion: JQ1 suppresses MYC expression and MYC-associated transcriptional activity in medulloblastomas, resulting in an overall decrease in medulloblastoma cell viability. These preclinical findings highlight the promise of BET bromodomain inhibitors as novel agents for MYC-amplified medulloblastoma. (C)2013 AACR. C1 [Bandopadhayay, Pratiti; Bergthold, Guillaume; Schumacher, Steven E.; Gibson, William J.; Paolella, Brenton R.; Beroukhim, Rameen] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Zeid, Rhamy; Qi, Jun; Bradner, James E.; Beroukhim, Rameen] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA 02215 USA. [Bandopadhayay, Pratiti; Kieran, Mark W.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Bandopadhayay, Pratiti; Kieran, Mark W.] Boston Childrens Hosp, Div Pediat Hematol Oncol, Boston, MA USA. [Beroukhim, Rameen] Dana Farber Canc Inst, Ctr Canc Genome Characterizat, Boston, MA 02115 USA. [Bandopadhayay, Pratiti; Bergthold, Guillaume; Schumacher, Steven E.; Gibson, William J.; Paolella, Brenton R.; Bradner, James E.; Beroukhim, Rameen] Broad Inst MIT & Harvard, Cambridge, MA USA. [Nguyen, Brian; Schubert, Simone; Tang, Yujie; Masoud, Sabran; Yu, Furong; Vue, Nujsaubnusi; Cho, Yoon-Jae] Stanford Univ, Sch Med, Dept Neurol & Neurol Sci, Stanford, CA 94305 USA. [Gholamin, Sharareh; Mitra, Siddhartha S.; Cheshier, Samuel H.; Cho, Yoon-Jae] Stanford Univ, Sch Med, Dept Neurosurg, Stanford, CA 94305 USA. [Cho, Yoon-Jae] Stanford Univ, Med Ctr, Stanford Canc Inst, Stanford, CA 94305 USA. [Liu, Kun-Wei; Wechsler-Reya, Robert] Sanford Burnham Med Res Inst, NCI Designated Canc Ctr, Tumor Initiat & Maintenance Program, La Jolla, CA USA. [Weiss, William A.] Univ Calif San Francisco, Dept Neurol Pediat & Neurosurg, San Francisco, CA 94143 USA. [Bolin, Sara; Swartling, Fredrik J.] Uppsala Univ, Rudbeck Lab, Sci Life Lab, Dept Immunol Genet & Pathol, Uppsala, Sweden. RP Cho, YJ (reprint author), Stanford Univ, Sch Med, Dept Neurol & Neurol Sci, 1201 Welch Rd,MSLS Bldg,Room P213, Stanford, CA 94305 USA. EM Rameen_Beroukhim@dfci.harvard.edu; yjcho1@stanford.edu OI Swartling, Fredrik/0000-0002-8460-4367; Kieran, Mark/0000-0003-2184-7692; Weiss, William/0000-0003-2230-9132 FU St. Baldrick's Foundation Scholar Award; Beirne Faculty Scholar Endowment; NIH [U01-CA176287, R01-CA148699]; Stanford Center for Children's Brain Tumors; Pediatric Low-Grade Astrocytoma Foundation; Friends of DFCI; Sontag Foundation; Gray Matters Foundation; Stop&Shop Pediatric Brain Tumor Program; Mill Foundation for Kids; Men's Collaborative for Women's Cancers; Damon-Runyon Cancer Research Foundation; Nuovo-Soldati Foundation; Philippe Foundation; Swedish Childhood Cancer Foundation; Swedish Cancer Society; Swedish Research Council; Swedish Society of Medicine; Swedish Brain Foundation; eke Wiberg's Foundation; Association for International Cancer Research; California Institute of Regenerative Medicine (San Francisco, CA) [LA1-01747]; [R01-CA159859]; [R01-CA133091] FX This work was financially supported by the following sources: St. Baldrick's Foundation Scholar Award (Y.-J. Cho); Beirne Faculty Scholar Endowment (Y.-J. Cho); NIH U01-CA176287 (Y.-J. Cho and W. A. Weiss); Stanford Center for Children's Brain Tumors (Y.-J. Cho and S. Cheshier); Pediatric Low-Grade Astrocytoma Foundation (P. Bandopadhayay, G. Bergthold, M. W. Kieran, and R. Beroukhim); Friends of DFCI (P. Bandopadhayay); the Sontag Foundation (R. Beroukhim); Gray Matters Foundation (R. Beroukhim); Stop&Shop Pediatric Brain Tumor Program (P. Bandopadhayay and M. W. Kieran); the Mill Foundation for Kids (M. W. Kieran); Men's Collaborative for Women's Cancers (J.E. Bradner and R. Beroukhim); Damon-Runyon Cancer Research Foundation (J. Qi and J. E. Bradner); Nuovo-Soldati Foundation (G. Bergthold); Philippe Foundation (G. Bergthold); R01-CA159859 (W. A. Weiss and R. Wechsler-Reya); NIH R01-CA148699 (W. A. Weiss); R01-CA133091 (W. A. Weiss); Swedish Childhood Cancer Foundation (S. Bolin and F. J. Swartling); the Swedish Cancer Society (S. Bolin and F. J. Swartling); the Swedish Research Council (S. Bolin and F. J. Swartling); the Swedish Society of Medicine (S. Bolin and F. J. Swartling); the Swedish Brain Foundation (S. Bolin and F. J. Swartling); eke Wiberg's Foundation (S. Bolin and F. J. Swartling); and the Association for International Cancer Research (S. Bolin and F. J. Swartling). R. Wechsler-Reya is the recipient of a Leadership Award (LA1-01747) from the California Institute of Regenerative Medicine (San Francisco, CA). NR 46 TC 78 Z9 78 U1 2 U2 22 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 FEB 15 PY 2014 VL 20 IS 4 BP 912 EP 925 DI 10.1158/1078-0432.CCR-13-2281 PG 14 WC Oncology SC Oncology GA AB6CP UT WOS:000331875500015 PM 24297863 ER PT J AU Geldres, C Savoldo, B Hoyos, V Caruana, I Zhang, M Yvon, E Del Vecchio, M Creighton, CJ Ittmann, M Ferrone, S Dotti, G AF Geldres, Claudia Savoldo, Barbara Hoyos, Valentina Caruana, Ignazio Zhang, Ming Yvon, Eric Del Vecchio, Michele Creighton, Chad J. Ittmann, Michael Ferrone, Soldano Dotti, Gianpietro TI T Lymphocytes Redirected against the Chondroitin Sulfate Proteoglycan-4 Control the Growth of Multiple Solid Tumors both In Vitro and In Vivo SO CLINICAL CANCER RESEARCH LA English DT Article ID MELANOMA-ASSOCIATED ANTIGEN; ACUTE LYMPHOBLASTIC-LEUKEMIA; MONOCLONAL-ANTIBODY; HMW-MAA; CELLS; RECEPTOR; ACTIVATION; IMMUNOGLOBULIN; DOMAIN; IMMUNOTHERAPY AB Purpose: Because of its high expression on various types of tumors and its restricted distribution in normal tissues, chondroitin sulfate proteoglycan-4 (CSPG4) represents an attractive target for the antibody-based therapy of several solid tumors. We tested whether T cells transduced with a CSPG4-specific chimeric antigen receptor (CAR) inhibited the growth of CSPG4-expressing tumor cells both in vitro and in vivo. Experimental Design: We first independently validated by immunohistochemistry (IHC) the expression of CSPG4 in an extensive panel of tumor arrays and normal tissues as well as queried public gene expression profiling datasets of human tumors. We constructed a second-generation CSPG4-specific CAR also encoding the CD28 costimulatory endodomain (CAR. CSPG4). We then evaluated human T lymphocytes expressing this CAR for their ex vivo and in vivo antitumor activity against a broad panel of solid tumors. Results: IHC showed that CSPG4 is highly expressed in melanoma, breast cancer, head and neck squamous cell carcinoma (HNSCC), and mesothelioma. In addition, in silico analysis of microarray expression data identified other important potential tumors expressing this target, including glioblastoma, clear cell renal carcinoma, and sarcomas. T lymphocytes genetically modified with a CSPG4-CAR controlled tumor growth in vitro and in vivo in NSG mice engrafted with human melanoma, HNSCC, and breast carcinoma cell lines. Conclusions: CAR. CSPG4-redirected T cells should provide an effective treatment modality for a variety of solid tumors. (C)2013 AACR. C1 [Geldres, Claudia; Savoldo, Barbara; Hoyos, Valentina; Caruana, Ignazio; Zhang, Ming; Yvon, Eric; Del Vecchio, Michele; Dotti, Gianpietro] Baylor Coll Med, Ctr Cell & Gene Therapy, Houston, TX 77030 USA. [Savoldo, Barbara] Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA. [Ittmann, Michael; Dotti, Gianpietro] Baylor Coll Med, Dept Pathol & Immunol, Houston, TX 77030 USA. [Dotti, Gianpietro] Baylor Coll Med, Dept Med, Houston, TX 77030 USA. [Geldres, Claudia; Ittmann, Michael; Dotti, Gianpietro] Baylor Coll Med, Interdept Program Translat Biol & Mol Med, Houston, TX 77030 USA. [Dotti, Gianpietro] Houston Methodist Hosp, Houston, TX USA. [Dotti, Gianpietro] Texas Childrens Hosp, Houston, TX 77030 USA. [Ferrone, Soldano] Baylor Coll Med, Dept Surg, Houston, TX 77030 USA. [Ittmann, Michael] Baylor Coll Med, Michael E DeBakey Dept Vet Affairs Med Ctr, Houston, TX 77030 USA. [Creighton, Chad J.] Baylor Coll Med, Dan L Duncan Canc Ctr, Div Biostat, Houston, TX 77030 USA. [Ferrone, Soldano] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. RP Dotti, G (reprint author), Baylor Coll Med, Ctr Cell & Gene Therapy, 6621 Fannin St MC3-3320, Houston, TX 77030 USA. EM gdotti@bcm.edu RI Del Vecchio, Michele/K-1584-2016; OI Del Vecchio, Michele/0000-0001-9060-2512; Caruana, Ignazio/0000-0002-9250-0605 FU CPRIT Cellular Therapy of Cancer [RP110553]; NCI supporting the Human Tissue Acquisition and Pathology [P30 CA125123]; Statistics and Bioinformatics Core Resources of the Dan L. Duncan Cancer; NIHCA 138188 [CA 138188] FX This work was supported in part by RP110553 CPRIT Cellular Therapy of Cancer, P30 CA125123 NCI supporting the Human Tissue Acquisition and Pathology, and Statistics and Bioinformatics Core Resources of the Dan L. Duncan Cancer and NIH CA 138188. NR 37 TC 13 Z9 13 U1 0 U2 12 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 FEB 15 PY 2014 VL 20 IS 4 BP 962 EP 971 DI 10.1158/1078-0432.CCR-13-2218 PG 10 WC Oncology SC Oncology GA AB6CP UT WOS:000331875500019 PM 24334762 ER PT J AU Jang, I Park, S Cho, JW Yigitkanli, K van Leyen, K Roth, J AF Jang, Insook Park, Sujin Cho, Jin Won Yigitkanli, Kazim van Leyen, Klaus Roth, Jurgen TI Genetic ablation and short-duration inhibition of lipoxygenase results in increased macroautophagy SO EXPERIMENTAL CELL RESEARCH LA English DT Article DE Lipoxygenase; Lipoxygenase knockout; Lipoxygenase inhibition; Liver; Brain; Autophagy; Mitophagy; Oxidative stress ID PLATELET-TYPE 12-LIPOXYGENASE; E-DEFICIENT MICE; TRANSIENT FOCAL ISCHEMIA; BRAIN OXIDATIVE STRESS; ALZHEIMERS-DISEASE; RETICULOCYTE LIPOXYGENASE; INDUCED ATHEROSCLEROSIS; ORGANELLE DEGRADATION; GLUTATHIONE DEPLETION; SELECTIVE AUTOPHAGY AB 12/15-lipoxygenase (12/15-LOX) is involved in organelle homeostasis by degrading mitochondria in maturing red blood cells and by eliminating excess peroxisomes in liver. Furthermore, 12/15-LOX contributes to diseases by exacerbating oxidative stress-related injury, notably in stroke. Nonetheless, it is unclear what the consequences are of abolishing 12/15-LOX activity. Mice in which the alox15 gene has been ablated do not show an obvious phenotype, and LOX enzyme inhibition is not overtly detrimental. We show here that liver histology is also unremarkable. However, electron microscopy demonstrated that 12/15-LOX knockout surprisingly leads to increased macroautophagy in the liver. Not only macroautophagy but also mitophagy and pexophagy were increased in hepatocytes, which otherwise showed unaltered fine structure and organelle morphology. These findings were substantiated by immunofluorescence showing significantly increased number of LC3 puncta and by Western blotting demonstrating a significant increase for LC3-II protein in both liver and brain homogenates of 12/15-LOX knockout mice. Inhibition of 12/15-LOX activity by treatment with four structurally different inhibitors had similar effects in cultured HepG2 hepatoma cells and SH-SY5Y neuroblastoma cells with significantly increased autophagy discernable already after 2 hours. Hence, our study reveals a link between ablation or inhibition of 12/15-LOX and stimulation of macroautophagy. The enhanced macroautophagy may be related to the known tissue-protective effects of LOX ablation or inhibition under various diseased conditions caused by oxidative stress and ischemia. This could provide an important cleaning mechanism of cells and tissues to prevent accumulation of damaged mitochondria and other cellular components. (C) 2013 Elsevier Inc. All rights reserved. C1 [Jang, Insook; Park, Sujin; Cho, Jin Won; Roth, Jurgen] Yonsei Univ, Grad Sch, WCU Program, Dept Integrated OMICS Biomed Sci, Seoul 120749, South Korea. [Yigitkanli, Kazim; van Leyen, Klaus] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Neuroprotect Res Lab, Boston, MA 02129 USA. RP Roth, J (reprint author), Yonsei Univ, Grad Sch, WCU Program, Dept Integrated OMICS Biomed Sci, 50 Yonsei Ro, Seoul 120749, South Korea. EM jurgen.roth@bluewin.ch FU Korean Research WCU [R31-10086]; Basic Science Research Program through the National Research Foundation of Korea (NRF); Ministry of Education, Science and Technology Grant [NRF-2013R1A2A1A01008067]; NIH [R01 NS049430, R01NS069939]; Brain Korea21 fellowship FX This work was supported by Korean Research WCU grant R31-10086 (to J.R. and J.W.C), the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology Grant NRF-2013R1A2A1A01008067 (to J.W.C.) and NIH Grants R01 NS049430 and R01NS069939 (to K.v.L.). I.J.is a recipient of a Brain Korea21 fellowship. NR 77 TC 4 Z9 4 U1 0 U2 5 PU ELSEVIER INC PI SAN DIEGO PA 525 B STREET, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4827 EI 1090-2422 J9 EXP CELL RES JI Exp. Cell Res. PD FEB 15 PY 2014 VL 321 IS 2 BP 276 EP 287 DI 10.1016/j.yexcr.2013.11.017 PG 12 WC Oncology; Cell Biology SC Oncology; Cell Biology GA AA9ND UT WOS:000331419300018 PM 24291223 ER PT J AU He, KH Juhl, K Karadimos, M El Khattabi, I Fitzpatrick, C Bonner-Weir, S Sharma, A AF He, KaiHui Hu Juhl, Kirstine Karadimos, Michael El Khattabi, Ilham Fitzpatrick, Connor Bonner-Weir, Susan Sharma, Arun TI Differentiation of pancreatic endocrine progenitors reversibly blocked by premature induction of MafA (vol 385, pg 2, 2014) SO DEVELOPMENTAL BIOLOGY LA English DT Correction C1 [He, KaiHui Hu; Juhl, Kirstine; Karadimos, Michael; El Khattabi, Ilham; Fitzpatrick, Connor; Bonner-Weir, Susan; Sharma, Arun] Harvard Univ, Sch Med, Joslin Diabet Ctr, Sect Islet Cell & Regenerat Biol, Boston, MA 02215 USA. RP Sharma, A (reprint author), Harvard Univ, Sch Med, Joslin Diabet Ctr, Sect Islet Cell & Regenerat Biol, 1 Joslin Pl, Boston, MA 02215 USA. EM arun.sharma@joslin.harvard.edu NR 1 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 EI 1095-564X J9 DEV BIOL JI Dev. Biol. PD FEB 15 PY 2014 VL 386 IS 2 BP 484 EP 485 DI 10.1016/j.ydbio.2013.12.029 PG 2 WC Developmental Biology SC Developmental Biology GA AA3UF UT WOS:000331019000019 ER PT J AU Shi, CH Schisler, JC Rubel, CE Tan, S Song, B McDonough, H Xu, L Portbury, AL Mao, CY True, C Wang, RH Wang, QZ Sun, SL Seminara, SB Patterson, C Xu, YM AF Shi, Chang-He Schisler, Jonathan C. Rubel, Carrie E. Tan, Song Song, Bo McDonough, Holly Xu, Lei Portbury, Andrea L. Mao, Cheng-Yuan True, Cadence Wang, Rui-Hao Wang, Qing-Zhi Sun, Shi-Lei Seminara, Stephanie B. Patterson, Cam Xu, Yu-Ming TI Ataxia and hypogonadism caused by the loss of ubiquitin ligase activity of the U box protein CHIP SO HUMAN MOLECULAR GENETICS LA English DT Article ID SHORT READ ALIGNMENT; HEAT-SHOCK PROTEINS; PROTEASOMAL DEGRADATION; CHAPERONE FUNCTIONS; CEREBELLAR-ATAXIA; HAPLOTYPE MAP; HUMAN GENOME; MUTATIONS; STRESS; UBIQUITYLATION AB Gordon Holmes syndrome (GHS) is a rare Mendelian neurodegenerative disorder characterized by ataxia and hypogonadism. Recently, it was suggested that disordered ubiquitination underlies GHS though the discovery of exome mutations in the E3 ligase RNF216 and deubiquitinase OTUD4. We performed exome sequencing in a family with two of three siblings afflicted with ataxia and hypogonadism and identified a homozygous mutation in STUB1 (NM_005861) c.737CT, p.Thr246Met, a gene that encodes the protein CHIP (C-terminus of HSC70-interacting protein). CHIP plays a central role in regulating protein quality control, in part through its ability to function as an E3 ligase. Loss of CHIP function has long been associated with protein misfolding and aggregation in several genetic mouse models of neurodegenerative disorders; however, a role for CHIP in human neurological disease has yet to be identified. Introduction of the Thr246Met mutation into CHIP results in a loss of ubiquitin ligase activity measured directly using recombinant proteins as well as in cell culture models. Loss of CHIP function in mice resulted in behavioral and reproductive impairments that mimic human ataxia and hypogonadism. We conclude that GHS can be caused by a loss-of-function mutation in CHIP. Our findings further highlight the role of disordered ubiquitination and protein quality control in the pathogenesis of neurodegenerative disease and demonstrate the utility of combining whole-exome sequencing with molecular analyses and animal models to define causal disease polymorphisms. C1 [Shi, Chang-He; Tan, Song; Song, Bo; Mao, Cheng-Yuan; Wang, Rui-Hao; Wang, Qing-Zhi; Sun, Shi-Lei; Xu, Yu-Ming] Zhengzhou Univ, Affiliated Hosp 1, Dept Neurol, Zhengzhou 450000, Henan, Peoples R China. [Schisler, Jonathan C.; Rubel, Carrie E.; McDonough, Holly; Xu, Lei; Patterson, Cam] Univ N Carolina, McAllister Heart Inst, Chapel Hill, NC 27514 USA. [Schisler, Jonathan C.; Portbury, Andrea L.; Patterson, Cam] Univ N Carolina, Dept Cardiol, Chapel Hill, NC 27514 USA. [Xu, Lei] Shandong Univ, Dept Cardiac Surg, Shandong Prov Hosp, Jinan 250012, Shandong, Peoples R China. [True, Cadence; Seminara, Stephanie B.] Massachusetts Gen Hosp, Dept Reprod Endocrine, Boston, MA 02115 USA. RP Patterson, C (reprint author), Univ N Carolina, 8200 Med Biomol Res Bldg,103 Mason Farm Rd, Chapel Hill, NC 27599 USA. EM cpatters@med.unc.edu; xuyuming@zzu.edu.cn OI Schisler, Jonathan/0000-0001-7382-2783; Wang, Ruihao/0000-0003-4792-5572 FU National Natural Science Foundation of China [81070920]; National Institutes of Health [R01-GM061728]; Fondation Leducq FX This work was supported in part by the National Natural Science Foundation of China grant 81070920 (to Y.X.) and the National Institutes of Health grant R01-GM061728 and Fondation Leducq (to C. P.). NR 46 TC 27 Z9 29 U1 0 U2 7 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 FEB 15 PY 2014 VL 23 IS 4 BP 1013 EP 1024 DI 10.1093/hmg/ddt497 PG 12 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA AA1FO UT WOS:000330842100015 PM 24113144 ER PT J AU McFarland, KN Huizenga, MN Darnell, SB Sangrey, GR Berezovska, O Cha, JHJ Outeiro, TF Sadri-Vakili, G AF McFarland, Karen N. Huizenga, Megan N. Darnell, Shayna B. Sangrey, Gavin R. Berezovska, Oksana Cha, Jang-Ho J. Outeiro, Tiago F. Sadri-Vakili, Ghazaleh TI MeCP2: a novel Huntingtin interactor SO HUMAN MOLECULAR GENETICS LA English DT Article ID NEUROTROPHIC FACTOR TRANSCRIPTION; LIFETIME IMAGING MICROSCOPY; BINDING PROTEIN MECP2; MUTANT HUNTINGTIN; DNA METHYLATION; RETT-SYNDROME; REPRESSES TRANSCRIPTION; ALZHEIMERS-DISEASE; BDNF TRANSCRIPTION; GENE-EXPRESSION AB Transcriptional dysregulation has been proposed to play a major role in the pathology of Huntingtons disease (HD). However, the mechanisms that cause selective downregulation of target genes remain unknown. Previous studies have shown that mutant huntingtin (Htt) protein interacts with a number of transcription factors thereby altering transcription. Here we report that Htt directly interacts with methyl-CpG binding protein 2 (MeCP2) in mouse and cellular models of HD using complimentary biochemical and Fluorescent Lifetime Imaging to measure Frster Resonance Energy Transfer approaches. HttMeCP2 interactions are enhanced in the presence of the expanded polyglutamine (polyQ) tract and are stronger in the nucleus compared with the cytoplasm. Furthermore, we find increased binding of MeCP2 to the promoter of brain-derived neurotrophic factor (BDNF), a gene that is downregulated in HD, in the presence of mutant Htt. Finally, decreasing MeCP2 levels in mutant Htt-expressing cells using siRNA increases BDNF levels, suggesting that MeCP2 downregulates BDNF expression in HD. Taken together, these findings suggest that aberrant interactions between Htt and MeCP2 contribute to transcriptional dysregulation in HD. C1 [McFarland, Karen N.] Univ Florida, Dept Neurol, Gainesville, FL 32610 USA. [McFarland, Karen N.] Univ Florida, McKnight Brain Inst, Gainesville, FL 32610 USA. [Huizenga, Megan N.; Darnell, Shayna B.; Sangrey, Gavin R.; Berezovska, Oksana; Sadri-Vakili, Ghazaleh] Massachusetts Gen Hosp, MassGen Inst Neurodegenerat Dis, Charlestown, MA 02129 USA. [Cha, Jang-Ho J.] Merck & Co Inc, N Wales, PA 19454 USA. [Outeiro, Tiago F.] Univ Med Goettingen, Dept NeuroDegenerat & Restorat Res, Ctr Mol Physiol Brain, D-37073 Gottingen, Germany. RP Sadri-Vakili, G (reprint author), Massachusetts Gen Hosp, MassGen Inst Neurodegenerat Dis, 114 16th St, Charlestown, MA 02129 USA. EM gsadrivakili@partners.org FU Hereditary Disease Foundation; HDSA Coalition for the Cure; National Institutes of Health [AG15379] FX This work was supported by the Hereditary Disease Foundation (G.S.V.) and HDSA Coalition for the Cure (J.-H.J.C.) and National Institutes of Health AG15379 (O.B.). NR 54 TC 9 Z9 9 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 FEB 15 PY 2014 VL 23 IS 4 BP 1036 EP 1044 DI 10.1093/hmg/ddt499 PG 9 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA AA1FO UT WOS:000330842100017 PM 24105466 ER PT J AU April, MD Wood, R Berkowitz, BK Paltiel, AD Anglaret, X Losina, E Freedberg, KA Walensky, RP AF April, Michael D. Wood, Robin Berkowitz, Bethany K. Paltiel, A. David Anglaret, Xavier Losina, Elena Freedberg, Kenneth A. Walensky, Rochelle P. TI The Survival Benefits of Antiretroviral Therapy in South Africa SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE HIV; South Africa; highly active antiretroviral therapy ID SUB-SAHARAN AFRICA; HIV-INFECTED ADULTS; COST-EFFECTIVENESS; COTE-DIVOIRE; TREATMENT PROGRAMS; TREATMENT SERVICE; CLINICAL IMPACT; FOLLOW-UP; SCALE-UP; MORTALITY AB Background. We sought to quantify the survival benefits attributable to antiretroviral therapy (ART) in South Africa since 2004. Methods. We used the Cost-Effectiveness of Preventing AIDS Complications-International model (CEPAC) to simulate 8 cohorts of human immunodeficiency virus (HIV)-infected patients initiating ART each year during 2004-2011. Model inputs included cohort-specific mean CD4(+) T-cell count at ART initiation (112-178 cells/mu L), 24-week ART suppressive efficacy (78%), second-line ART availability (2.4% of ART recipients), and cohort-specific 36-month retention rate (55%-71%). CEPAC simulated survival twice for each cohort, once with and once without ART. The sum of the products of per capita survival differences and the total numbers of persons initiating ART for each cohort yielded the total survival benefits. Results. Lifetime per capita survival benefits ranged from 9.3 to 10.2 life-years across the 8 cohorts. Total estimated population lifetime survival benefit for all persons starting ART during 2004-2011 was 21.7 million life-years, of which 2.8 million life-years (12.7%) had been realized by December 2012. By 2030, benefits reached 17.9 million life-years under current policies, 21.7 million life-years with universal second-line ART, 23.3 million life-years with increased linkage to care of eligible untreated patients, and 28.0 million life-years with both linkage to care and universal second-line ART. Conclusions. We found dramatic past and potential future survival benefits attributable to ART, justifying international support of ART rollout in South Africa. C1 [April, Michael D.] San Antonio Uniformed Serv Hlth Educ Consortium, Dept Emergency Med, San Antonio, TX USA. [April, Michael D.; Freedberg, Kenneth A.; Walensky, Rochelle P.] Harvard Univ, Sch Med, Boston, MA USA. [Losina, Elena; Freedberg, Kenneth A.; Walensky, Rochelle P.] Harvard Univ, Harvard Sch Publ Hlth, Ctr AIDS Res, Boston, MA USA. [Freedberg, Kenneth A.] Harvard Univ, Harvard Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA USA. [April, Michael D.; Berkowitz, Bethany K.; Freedberg, Kenneth A.; Walensky, Rochelle P.] Massachusetts Gen Hosp, Med Practice Evaluat Ctr, Boston, MA 02114 USA. [Freedberg, Kenneth A.; Walensky, Rochelle P.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA USA. [Freedberg, Kenneth A.; Walensky, Rochelle P.] Massachusetts Gen Hosp, Div Gen Med, Boston, MA USA. [Losina, Elena] Boston Univ, Dept Biostat, Boston, MA 02215 USA. [Freedberg, Kenneth A.] Boston Univ, Dept Epidemiol, Boston, MA 02215 USA. [Losina, Elena] Brigham & Womens Hosp, Dept Orthoped Surg, Boston, MA 02115 USA. [Walensky, Rochelle P.] Brigham & Womens Hosp, Div Infect Dis, Boston, MA 02115 USA. [Paltiel, A. David] Yale Univ, Sch Publ Hlth, New Haven, CT USA. [Wood, Robin] Univ Cape Town, Desmond Tutu HIV Ctr, Inst Infect Dis & Mol Med, ZA-7925 Cape Town, South Africa. [Wood, Robin] Univ Cape Town, Dept Med, ZA-7925 Cape Town, South Africa. [Anglaret, Xavier] INSERM, Ctr 897, Bordeaux, France. [Anglaret, Xavier] Univ Bordeaux Segalen, Bordeaux, France. [Anglaret, Xavier] Programme PAC CI ANRS Res Site Abidjan, Abidjan, Cote Ivoire. RP April, MD (reprint author), Massachusetts Gen Hosp, Med Practice Evaluat Ctr, 50 Staniford St,9th Fl, Boston, MA 02114 USA. EM michael.d.april@post.harvard.edu RI Anglaret, Xavier/F-7333-2013; OI Walensky, Rochelle P./0000-0002-8795-379X FU National Institute of Allergy and Infectious Diseases [R01 AI058736, P30 AI060354, R01 AI093269]; Infectious Diseases Society of America FX This work was supported by the National Institute of Allergy and Infectious Diseases (grants R01 AI058736, P30 AI060354, and R01 AI093269) and the Infectious Diseases Society of America (Medical Scholars Program). NR 48 TC 16 Z9 16 U1 0 U2 10 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 FEB 15 PY 2014 VL 209 IS 4 BP 491 EP 499 DI 10.1093/infdis/jit584 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA AA2BD UT WOS:000330899200004 PM 24307741 ER PT J AU Musher, DM Bebko, SP Roig, IL AF Musher, Daniel M. Bebko, Serge P. Roig, Ingrid L. TI Serum Procalcitonin Level, Viral Polymerase Chain Reaction Analysis, and Lower Respiratory Tract Infection SO JOURNAL OF INFECTIOUS DISEASES LA English DT Letter ID COMMUNITY-ACQUIRED PNEUMONIA; ANTIBIOTIC-THERAPY; ACUTE EXACERBATIONS C1 [Musher, Daniel M.; Bebko, Serge P.; Roig, Ingrid L.] Baylor Coll Med, Michael E DeBakey Vet Affairs Med Ctr, Infect Dis Sect, Houston, TX 77030 USA. [Musher, Daniel M.; Bebko, Serge P.; Roig, Ingrid L.] Baylor Coll Med, Dept Med, Houston, TX 77030 USA. [Musher, Daniel M.] Baylor Coll Med, Dept Mol Virol & Microbiol, Houston, TX 77030 USA. RP Musher, DM (reprint author), Vet Affairs Med Ctr, Infect Dis Sect, 2002 Holcombe Blvd,Rm 4B-370, Houston, TX 77030 USA. EM daniel.musher@med.va.gov NR 9 TC 6 Z9 6 U1 0 U2 0 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 FEB 15 PY 2014 VL 209 IS 4 BP 631 EP U155 DI 10.1093/infdis/jit579 PG 3 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA AA2BD UT WOS:000330899200023 PM 24218499 ER PT J AU Bright, MG Bianciardi, M de Zwart, JA Murphy, K Duyn, JH AF Bright, Molly G. Bianciardi, Marta de Zwart, Jacco A. Murphy, Kevin Duyn, Jeff H. TI Early anti-correlated BOLD signal changes of physiologic origin SO NEUROIMAGE LA English DT Article DE fMRI; Negative BOLD; Anti-correlated BOLD; Physiology; Respiratory challenge; Deactivation ID PRIMARY SOMATOSENSORY CORTEX; SENSORY STIMULATION; FMRI SIGNALS; BLOOD-FLOW; BRAIN; FLUCTUATIONS; HYPERCAPNIA; ACTIVATION; DYNAMICS; CONTRAST AB Negative BOLD signals that are synchronous with resting state fluctuations have been observed in large vessels in the cortical sulci and surrounding the ventricles. In this study, we investigated the origin of these negative BOLD signals by applying a Cued Deep Breathing (COB) task to create transient hypocapnia and a resultant global fMRI signal decrease. We hypothesized that a global stimulus would amplify the effect in large vessels and that using a global negative (vasoconstrictive) stimulus would test whether these voxels exhibit either inherently negative or simply anti-correlated BOLD responses. Significantly anti-correlated, but positive, BOLD signal changes during respiratory challenges were identified in voxels primarily located near edges of brain spaces containing CSF. These positive BOLD responses occurred earlier than the negative COB response across most of gray matter voxels. These findings confirm earlier suggestions that in some brain regions, local, fractional changes in CSF volume may overwhelm BOLD-related signal changes, leading to signal anti-correlation. We show that regions with CDB anti-correlated signals coincide with most, but not all, of the regions with negative BOLD signal changes observed during a visual and motor stimulus task. Thus, the addition of a physiological challenge to fMRI experiments can help identify which negative BOLD signals are passive physiological anti-correlations and which may have a putative neuronal origin. Published by Elsevier Inc. C1 [Bright, Molly G.; Bianciardi, Marta; de Zwart, Jacco A.; Duyn, Jeff H.] NINDS, Adv MRI Sect, LFMI, NIH, Bethesda, MD 20892 USA. [Bright, Molly G.; Murphy, Kevin] Cardiff Univ, Sch Psychol, CUBRIC, Cardiff CF10 3AT, S Glam, Wales. [Bianciardi, Marta] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol,Athinoula A Martinos Ctr Biomed Imagi, Boston, MA USA. RP Bright, MG (reprint author), Cardiff Univ, Sch Psychol, CUBRIC, Cardiff CF10 3AT, S Glam, Wales. EM BrightMG@cardiff.ac.uk RI Murphy, Kevin/A-1581-2010; OI Murphy, Kevin/0000-0002-6516-313X; Bright, Molly/0000-0001-7257-9646 FU Intramural Research Program of NINDS/NIH; Wellcome Trust FX We thank Susan Fulton Guttman for her assistance in the data acquisition. This research was supported by the Intramural Research Program of NINDS/NIH and the Wellcome Trust. NR 35 TC 4 Z9 4 U1 1 U2 9 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 EI 1095-9572 J9 NEUROIMAGE JI Neuroimage PD FEB 15 PY 2014 VL 87 BP 287 EP 296 DI 10.1016/j.neuroimage.2013.10.055 PG 10 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 301TC UT WOS:000330554000028 PM 24211818 ER PT J AU Babadi, B Obregon-Henao, G Lamus, C Hamalainen, MS Brown, EN Purdon, PL AF Babadi, Behtash Obregon-Henao, Gabriel Lamus, Camilo Haemaelaeinen, Matti S. Brown, Emery N. Purdon, Patrick L. TI A Subspace Pursuit-based Iterative Greedy Hierarchical solution to the neuromagnetic inverse problem SO NEUROIMAGE LA English DT Article DE MEG; EEG; Source localization; Sparse representations; Compressed sensing; Greedy algorithms; Evoked fields analysis ID SOURCE RECONSTRUCTION; MEG INVERSE; SIGNAL RECONSTRUCTION; ELECTRICAL-ACTIVITY; SOURCE LOCALIZATION; BAYESIAN FRAMEWORK; MATCHING PURSUIT; MAGNETIC-FIELDS; EEG GENERATION; MCMC METHODS AB Magnetoencephalography (MEG) is an important non-invasive method for studying activity within the human brain. Source localization methods can be used to estimate spatiotemporal activity from MEG measurements with high temporal resolution, but the spatial resolution of these estimates is poor due to the ill-posed nature of the MEG inverse problem. Recent developments in source localization methodology have emphasized temporal as well as spatial constraints to improve source localization accuracy, but these methods can be computationally intense. Solutions emphasizing spatial sparsity hold tremendous promise, since the underlying neurophysiological processes generating MEG signals are often sparse in nature, whether in the form of focal sources, or distributed sources representing large-scale functional networks. Recent developments in the theory of compressed sensing (CS) provide a rigorous framework to estimate signals with sparse structure. In particular, a class of CS algorithms referred to as greedy pursuit algorithms can provide both high recovery accuracy and low computational complexity. Greedy pursuit algorithms are difficult to apply directly to the MEG inverse problem because of the high-dimensional structure of the MEG source space and the high spatial correlation in MEG measurements. In this paper, we develop a novel greedy pursuit algorithm for sparse MEG source localization that overcomes these fundamental problems. This algorithm, which we refer to as the Subspace Pursuit-based Iterative Greedy Hierarchical (SPIGH) inverse solution, exhibits very low computational complexity while achieving very high localization accuracy. We evaluate the performance of the proposed algorithm using comprehensive simulations, as well as the analysis of human MEG data during spontaneous brain activity and somatosensory stimuli. These studies reveal substantial performance gains provided by the SPIGH algorithm in terms of computational complexity, localization accuracy, and robustness. (C) 2013 Elsevier Inc All rights reserved. C1 [Babadi, Behtash; Obregon-Henao, Gabriel; Lamus, Camilo; Brown, Emery N.; Purdon, Patrick L.] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. [Babadi, Behtash; Lamus, Camilo; Brown, Emery N.] MIT, Dept Brain & Cognit Sci, Cambridge, MA 02139 USA. [Haemaelaeinen, Matti S.] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Boston, MA 02114 USA. [Haemaelaeinen, Matti S.; Brown, Emery N.] Harvard Mit Div Hlth Sci & Technol, Cambridge, MA USA. [Brown, Emery N.] MIT, Inst Med Engn & Sci, Cambridge, MA 02139 USA. RP Babadi, B (reprint author), Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. EM behtash@nmr.mgh.harvard.edu; patrickp@nmr.mgh.harvard.edu OI Obregon-Henao, Gabriel/0000-0003-1622-6090 FU National Institutes of Health (NIH) New Innovator Award [DP2-OD006454, R01-EB006385, P41-RR014075-11] FX This work was supported by the National Institutes of Health (NIH) New Innovator Award DP2-OD006454 (to P.L.P.), R01-EB006385 (to E.N.B., M.S.H., and P.L.P.), and P41-RR014075-11 (to M.S.H.). We would like to thank Simona Temereanca for providing us with the mu-rhythm data used in this paper, and Alexandre Gramfort for constructive discussions regarding the SEFs experiment. NR 63 TC 8 Z9 8 U1 0 U2 18 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 EI 1095-9572 J9 NEUROIMAGE JI Neuroimage PD FEB 15 PY 2014 VL 87 BP 427 EP 443 DI 10.1016/j.neuroimage.2013.09.008 PG 17 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 301TC UT WOS:000330554000040 PM 24055554 ER PT J AU Erdogan, SB Yucel, MA Akin, A AF Erdogan, Sinem B. Yucel, Meryem A. Akin, Ata TI Analysis of task-evoked systemic interference in fNIRS measurements: Insights from fMRI SO NEUROIMAGE LA English DT Article DE Hemodynamic response; Systemic interference; Functional near infrared spectroscopy; Magnetic resonance imaging; Physiological artifact removal; Cognitive task ID NEAR-INFRARED SPECTROSCOPY; DIFFUSE OPTICAL TOMOGRAPHY; NIRS HEMODYNAMIC-RESPONSES; FUNCTIONAL BRAIN; BOLD SIGNAL; IN-VIVO; CEREBRAL HEMODYNAMICS; PHOTON MIGRATION; ADULT HUMANS; OXYGEN-SATURATION AB Functional near infrared spectroscopy (fNIRS) is a promising method for monitoring cerebral hemodynamics with a wide range of clinical applications. INIRS signals are contaminated with systemic physiological interferences from both the brain and superficial tissues, resulting in a poor estimation of the task related neuronal activation. In this study, we use the anatomical resolution of functional magnetic resonance imaging (fMRI) to extract scalp and brain vascular signals separately and construct an optically weighted spatial average of the fMRI blood oxygen level-dependent (BOLD) signal for characterizing the scalp signal contribution to fNIRS measurements. We introduce an extended superficial signal regression (ESSR) method for canceling physiology-based systemic interference where the effects of cerebral and superficial systemic interference are treated separately. We apply and validate our method on the optically weighted BOLD signals, which are obtained by projecting the fMRI image onto optical measurement space by use of the optical forward problem. The performance of ESSR method in removing physiological artifacts is compared to i) a global signal regression (GSR) method and ii) a superficial signal regression (SSR) method. The retrieved signals from each method are compared with the neural signals that represent the 'ground truth' brain activation cleaned from cerebral systemic fluctuations. We report significant improvements in the recovery of task induced neural activation with the ESSR method when compared to the other two methods as reflected in the Pearson R2 coefficient and mean square error (MSE) metrics (two tailed paired t-tests, p <0.05). The signal quality is enhanced most when ESSR method is applied with higher spatial localization, lower inter-trial variability, a clear canonical waveform and higher contrast-to-noise (CNR) improvement (60%). Our findings suggest that, during a cognitive task i) superficial scalp signal contribution to fNIRS signals varies significantly among different regions on the forehead and ii) using an average scalp measurement together with a local measure of superficial hemodynamics better accounts for the systemic interference inherent in the brain as well as superficial scalp tissue. We conclude that maximizing the overlap between the optical pathlength of superficial and deeper penetration measurements is of crucial importance for accurate recovery of the evoked hemodynamic response in (NIRS recordings. (C) 2013 Elsevier Inc. All rights reserved. C1 [Erdogan, Sinem B.] Bogazici Univ, Inst Biomed Engn, TR-34684 Istanbul, Turkey. [Yucel, Meryem A.] Harvard Univ, Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Dept Radiol,Sch Med, Charlestown, MA USA. [Akin, Ata] Istanbul Bilgi Univ, Dept Genet & Bioengn, TR-34060 Istanbul, Turkey. RP Erdogan, SB (reprint author), Bogazici Univ, Inst Biomed Engn, TR-34684 Istanbul, Turkey. EM burcu.erdogan@boun.edu.tr OI Akin, Ata/0000-0002-1773-0857 FU BURF [11XD4]; TUBITAK [112E034] FX This study is sponsored in part by BURF Project No.: 11XD4 and in part by TUBITAK Project No.: 112E034. Authors would like to thank Deniz Nevsehirli, Yasemin Keskin Ergen and Ali Bayram for their help in fMRI data collection, and the Photon Migration Imaging Laboratory at Massachusetts General Hospital for the Monte Carlo simulation code. NR 97 TC 15 Z9 15 U1 1 U2 24 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 EI 1095-9572 J9 NEUROIMAGE JI Neuroimage PD FEB 15 PY 2014 VL 87 BP 490 EP 504 DI 10.1016/j.neuroimage.2013.10.024 PG 15 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 301TC UT WOS:000330554000044 PM 24148922 ER PT J AU Curie, A Nazir, T Brun, A Paulignan, Y Reboul, A Delange, K Cheylus, A Bertrand, S Rochefort, F Bussy, G Marignier, S Lacombe, D Chiron, C Cossee, M Leheup, B Philippe, C Laugel, V De St Martin, A Sacco, S Poirier, K Bienvenu, T Souville, I Gilbert-Dussardier, B Bieth, E Kauffmann, D Briot, P de Freminville, B Prieur, F Till, M Rooryck-Thambo, C Mortemousque, I Bobillier-Chaumont, I Toutain, A Touraine, R Sanlaville, D Chelly, J Freeman, S Kong, J Hadjikhani, N Gollub, RL Roy, A des Portes, V AF Curie, Aurore Nazir, Tatjana Brun, Amandine Paulignan, Yves Reboul, Anne Delange, Karine Cheylus, Anne Bertrand, Sophie Rochefort, Fanny Bussy, Gerald Marignier, Stephanie Lacombe, Didier Chiron, Catherine Cossee, Mireille Leheup, Bruno Philippe, Christophe Laugel, Vincent De St Martin, Anne Sacco, Silvia Poirier, Karine Bienvenu, Thierry Souville, Isabelle Gilbert-Dussardier, Brigitte Bieth, Eric Kauffmann, Didier Briot, Philippe de Freminville, Benedicte Prieur, Fabienne Till, Michel Rooryck-Thambo, Caroline Mortemousque, Isabelle Bobillier-Chaumont, Isabelle Toutain, Annick Touraine, Renaud Sanlaville, Damien Chelly, Jamel Freeman, Sonya Kong, Jian Hadjikhani, Nouchine Gollub, Randy L. Roy, Alice des Portes, Vincent TI The c.429_452 duplication of the ARX gene: a unique developmental-model of limb kinetic apraxia SO ORPHANET JOURNAL OF RARE DISEASES LA English DT Article DE ARX gene mutation; Kinematic study; Limb-kinetic apraxia; X-linked intellectual disability; Partington syndrome ID LINKED MENTAL-RETARDATION; MOTOR DEVELOPMENT SCALE; ABSENT CORPUS-CALLOSUM; BEHAVIOR RATING FORM; INFANTILE SPASMS; HOMEOBOX GENE; CORTICOBASAL DEGENERATION; POLYALANINE EXPANSION; PREHENSION MOVEMENTS; ABNORMAL GENITALIA AB Background: The c.429_452dup24 of the ARX gene is a rare genetic anomaly, leading to X-Linked Intellectual Disability without brain malformation. While in certain cases c. 429_452dup24 has been associated with specific clinical patterns such as Partington syndrome, the consequence of this mutation has been also often classified as "non-specific Intellectual Disability". The present work aims at a more precise description of the clinical features linked to the c.429_452dup24 mutation. Methods: We clinically reviewed all affected patients identified in France over a five-year period, i.e. 27 patients from 12 different families. Detailed cognitive, behavioural, and motor evaluation, as well as standardized videotaped assessments of oro-lingual and gestural praxis, were performed. In a sub-group of 13 ARX patients, kinematic and MRI studies were further accomplished to better characterize the motor impairment prevalent in the ARX patients group. To ensure that data were specific to the ARX gene mutation and did not result from low-cognitive functioning per se, a group of 27 age-and IQ-matched Down syndrome patients served as control. Results: Neuropsychological and motor assessment indicated that the c.429_452dup24 mutation constitutes a recognizable clinical syndrome: ARX patients exhibiting Intellectual Disability, without primary motor impairment, but with a very specific upper limb distal motor apraxia associated with a pathognomonic hand-grip. Patients affected with the so-called Partington syndrome, which involves major hand dystonia and orolingual apraxia, exhibit the most severe symptoms of the disorder. The particular "reach and grip" impairment which was observed in all ARX patients, but not in Down syndrome patients, was further characterized by the kinematic data: (i) loss of preference for the index finger when gripping an object, (ii) major impairment of fourth finger deftness, and (iii) a lack of pronation movements. This lack of distal movement coordination exhibited by ARX patients is associated with the loss of independent digital dexterity and is similar to the distortion of individual finger movements and posture observed in Limb Kinetic Apraxia. Conclusion: These findings suggest that the ARX c.429_452dup24 mutation may be a developmental model for Limb Kinetic Apraxia. C1 [Curie, Aurore; Brun, Amandine; Delange, Karine; Bussy, Gerald; Marignier, Stephanie; des Portes, Vincent] Hosp Civils Lyon, Hop Femme Mere Enfant, Ctr Reference Deficiences Intellectuelles Causes, F-69677 Bron, France. [Curie, Aurore; Nazir, Tatjana; Brun, Amandine; Paulignan, Yves; Reboul, Anne; Delange, Karine; Cheylus, Anne; Bertrand, Sophie; Rochefort, Fanny; Bussy, Gerald; Bobillier-Chaumont, Isabelle; Roy, Alice; des Portes, Vincent] Inst Cognit Sci, CNRS UMR 5304, L2C2, F-69675 Bron, France. [Curie, Aurore; des Portes, Vincent] Univ Lyon, Fac Med Lyon Sud Charles Merieux, F-69008 Lyon, France. [Curie, Aurore; Freeman, Sonya; Kong, Jian; Hadjikhani, Nouchine; Gollub, Randy L.] Massachusetts Gen Hosp, Athinoula Martinos Ctr Biomedial Imaging A, Charlestown, MA USA. [Chiron, Catherine] Hop Necker Enfants Malad, INSERM UMR 663, Paris, France. [Sacco, Silvia] Hop Trousseau, F-75571 Paris, France. [Delange, Karine; Bienvenu, Thierry; Souville, Isabelle; Chelly, Jamel] Hop Cochin, F-75674 Paris, France. [Kauffmann, Didier] Fdn Sonnenhof, Bischwiller, France. [Briot, Philippe] MAS Courcouronnes, Courcouronnes, France. [Till, Michel] Hop St Luc St Joseph, Lyon, France. [Sanlaville, Damien] Univ Lyon 1, INSERM U1028, CRNL,CNRS UMR5292, Serv Genet,Hop Femme Mere Enfant,Hosp Civils Lyon, F-69365 Lyon, France. RP Curie, A (reprint author), Hosp Civils Lyon, Hop Femme Mere Enfant, Ctr Reference Deficiences Intellectuelles Causes, F-69677 Bron, France. EM aurorecurie@yahoo.fr RI lacombe, didier/K-7967-2014; ROORYCK, Caroline/M-4565-2014; sanlaville, damien/M-4716-2014; Chiron, Catherine/E-8506-2016; Chelly, Jamel/J-7528-2015; OI sanlaville, damien/0000-0001-9939-2849; Chelly, Jamel/0000-0002-0939-8719; Cheylus, Anne/0000-0002-4243-3686; Gollub, Randy L./0000-0002-9434-4044; Hadjikhani, Nouchine/0000-0003-4075-3106 FU French Ministry of Health [PHRC]; CNRS/Hospice Civils de Lyon; Clinical Investigation Center of the Hospices Civils de Lyon (HCL); Fondation Jerome-Lejeune; Fondation pour la Recherche Medicale (FRM); Air France company FX Authors are indebted to patients and their families and caregivers, especially those who cheerfully welcomed the clinical team in their own homes. Special thanks for the support of the french XLMR parents' association "Xtraordinaire" and Amanda Cook. We would also like to thank Pr Claude Morraine and Pr Gerard Ponsot for their help and encouragement. Financial support from the French Ministry of Health (grant PHRC 2003 and 2008), the CNRS/Hospice Civils de Lyon (research fellow post-graduate grant for AC), the Clinical Investigation Center of the Hospices Civils de Lyon (HCL), the Fondation Jerome-Lejeune (grant for AC), the Fondation pour la Recherche Medicale (FRM), Air France company. NR 59 TC 1 Z9 1 U1 2 U2 11 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1750-1172 J9 ORPHANET J RARE DIS JI Orphanet J. Rare Dis. PD FEB 14 PY 2014 VL 9 AR 25 DI 10.1186/1750-1172-9-25 PG 16 WC Genetics & Heredity; Medicine, Research & Experimental SC Genetics & Heredity; Research & Experimental Medicine GA AG2NI UT WOS:000335252800001 PM 24528893 ER PT J AU Pauli, A Norris, ML Valen, E Chew, GL Gagnon, JA Zimmerman, S Mitchell, A Ma, J Dubrulle, J Reyon, D Tsai, SQ Joung, JK Saghatelian, A Schier, AF AF Pauli, Andrea Norris, Megan L. Valen, Eivind Chew, Guo-Liang Gagnon, James A. Zimmerman, Steven Mitchell, Andrew Ma, Jiao Dubrulle, Julien Reyon, Deepak Tsai, Shengdar Q. Joung, J. Keith Saghatelian, Alan Schier, Alexander F. TI Toddler: An Embryonic Signal That Promotes Cell Movement via Apelin Receptors SO SCIENCE LA English DT Article ID ZEBRAFISH GASTRULATION; CARDIOVASCULAR DEVELOPMENT; DROSOPHILA GASTRULATION; DEFICIENT MICE; BLOOD-VESSELS; APJ RECEPTOR; STEM-CELLS; IN-VIVO; MIGRATION; PROTEIN AB It has been assumed that most, if not all, signals regulating early development have been identified. Contrary to this expectation, we identified 28 candidate signaling proteins expressed during zebrafish embryogenesis, including Toddler, a short, conserved, and secreted peptide. Both absence and overproduction of Toddler reduce the movement of mesendodermal cells during zebrafish gastrulation. Local and ubiquitous production of Toddler promote cell movement, suggesting that Toddler is neither an attractant nor a repellent but acts globally as a motogen. Toddler drives internalization of G protein-coupled APJ/Apelin receptors, and activation of APJ/Apelin signaling rescues toddler mutants. These results indicate that Toddler is an activator of APJ/Apelin receptor signaling, promotes gastrulation movements, and might be the first in a series of uncharacterized developmental signals. C1 [Pauli, Andrea; Norris, Megan L.; Valen, Eivind; Chew, Guo-Liang; Gagnon, James A.; Zimmerman, Steven; Dubrulle, Julien; Schier, Alexander F.] Harvard Univ, Dept Mol & Cellular Biol, Cambridge, MA 02138 USA. [Mitchell, Andrew; Ma, Jiao; Saghatelian, Alan] Harvard Univ, Dept Chem & Chem Biol, Cambridge, MA 02138 USA. [Reyon, Deepak; Tsai, Shengdar Q.; Joung, J. Keith] Massachusetts Gen Hosp, Mol Pathol Unit, Ctr Computat & Integrat Biol, Charlestown, MA 02129 USA. [Reyon, Deepak; Tsai, Shengdar Q.; Joung, J. Keith] Massachusetts Gen Hosp, Ctr Canc Res, Charlestown, MA 02129 USA. [Reyon, Deepak; Tsai, Shengdar Q.; Joung, J. Keith] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Joung, J. Keith; Schier, Alexander F.] Broad Inst Massachusetts Inst Technol & Harvard, Cambridge, MA 02142 USA. [Schier, Alexander F.] Harvard Univ, FAS Ctr Syst Biol, Cambridge, MA 02138 USA. [Schier, Alexander F.] Harvard Univ, Ctr Brain Sci, Cambridge, MA 02138 USA. [Schier, Alexander F.] Harvard Univ, Harvard Stem Cell Inst, Cambridge, MA 02138 USA. RP Pauli, A (reprint author), Harvard Univ, Dept Mol & Cellular Biol, Cambridge, MA 02138 USA. EM pauli@fas.harvard.edu; schier@fas.harvard.edu OI Gagnon, James/0000-0003-3978-6058; Chew, Guo-Liang/0000-0003-4357-1404; Valen, Eivind/0000-0003-1840-6108 FU Editas Medicine; NIH; Human Frontier Science Program; Howard Hughes Medical Institute; American Cancer Society FX We thank D. Richardson and C. Kraft from the Harvard Center for Biological Imaging for technical support; F. Merkle for providing human and mouse embryonic stem cell RNA; M. Lin for the initial PhyloCSF analysis; L. Solnica-Krezel, E. Raz, C. Houart, members of the 2013 MBL Zebrafish Course, and the Schier laboratory for helpful discussions; and S. Mango, W. Talbot, R. Losick, J. Farrell, and K. Rogers for comments on the manuscript. Obtaining the TALEN plasmids will require the completion of a Uniform Biological Material Transfer Agreement with the Massachusetts General Hospital. The Massachusetts General Hospital has applied for a patent that covers the FLASH method used to make the TALENs and J. K. J. is an inventor on this patent. J. K. J. has financial interests in Editas Medicine and Transposagen Biopharmaceuticals. J. K. J. is a member of the Scientific Advisory Board of Transposagen Biopharmaceuticals and is a co-founder and paid consultant of Editas Medicine and holds equity in both companies. 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. This research was supported by NIH (A. F. S., A. P., and A. S.), Human Frontier Science Program (A. P. and E. V.), Howard Hughes Medical Institute (G.-L. C.), and the American Cancer Society (J.A.G.). NR 56 TC 86 Z9 90 U1 4 U2 35 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 FEB 14 PY 2014 VL 343 IS 6172 BP 746 EP + AR 1248636 DI 10.1126/science.1248636 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AB1NB UT WOS:000331557800032 PM 24407481 ER PT J AU Roderick, JE Tesell, J Shultz, LD Brehm, MA Greiner, DL Harris, MH Silverman, LB Sallan, SE Gutierrez, A Look, AT Qi, J Bradner, JE Kelliher, MA AF Roderick, Justine E. Tesell, Jessica Shultz, Leonard D. Brehm, Michael A. Greiner, Dale L. Harris, Marian H. Silverman, Lewis B. Sallan, Stephen E. Gutierrez, Alejandro Look, A. Thomas Qi, Jun Bradner, James E. Kelliher, Michelle A. TI c-Myc inhibition prevents leukemia initiation in mice and impairs the growth of relapsed and induction failure pediatric T-ALL cells SO BLOOD LA English DT Article ID ACUTE LYMPHOBLASTIC-LEUKEMIA; BET BROMODOMAIN INHIBITION; PEST DOMAIN MUTATION; TUMOR-SUPPRESSOR; NOTCH1 MUTATIONS; SELF-RENEWAL; STEM-CELL; B-CLL; EXPRESSION; TARGETS AB Although prognosis has improved for children with T-cell acute lymphoblastic leukemia (T-ALL), 20% to 30% of patients undergo induction failure (IF) or relapse. Leukemia-initiating cells (LICs) are hypothesized to be resistant to chemotherapy and to mediate relapse. We and others have shown that Notch1 directly regulates c-Myc, a known regulator of quiescence in stem and progenitor populations, leading us to examine whether c-Myc inhibition results in efficient targeting of T-ALL-initiating cells. We demonstrate that c-Myc suppression by small hairpin RNA or pharmacologic approaches prevents leukemia initiation in mice by eliminating LIC activity. Consistent with its anti-LIC activity in mice, treatment with the BET bromodomain BRD4 inhibitor JQ1 reduces C-MYC expression and inhibits the growth of relapsed and IF pediatric T-ALL samples in vitro. These findings demonstrate a critical role for c-Myc in LIC maintenance and provide evidence that MYC inhibition may be an effective therapy for relapsed/IF T-ALL patients. C1 [Roderick, Justine E.; Tesell, Jessica; Kelliher, Michelle A.] Univ Massachusetts, Sch Med, Dept Canc Biol, Worcester, MA 01605 USA. [Shultz, Leonard D.] Jackson Lab, Bar Harbor, ME 04609 USA. [Brehm, Michael A.; Greiner, Dale L.] Univ Massachusetts, Sch Med, Program Mol Med, Worcester, MA 01605 USA. [Harris, Marian H.; Gutierrez, Alejandro; Look, A. Thomas] Harvard Univ, Sch Med, Div Hematol Oncol, Boston Childrens Hosp, Boston, MA USA. [Silverman, Lewis B.; Sallan, Stephen E.; Gutierrez, Alejandro; Look, A. Thomas] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Qi, Jun; Bradner, James E.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Jerome Lipper Multiple Myeloma Ctr, Boston, MA 02115 USA. RP Kelliher, MA (reprint author), Univ Massachusetts, Sch Med, Dept Canc Biol, Worcester, MA 01605 USA. EM Michelle.Kelliher@umassmed.edu OI Gutierrez, Alejandro/0000-0002-0249-9007 FU National Institutes of Health (National Cancer Institute) [CA096899, CA034196]; National Institutes of Health (National Institute of Allergy and Infectious Diseases) [AI04669]; National Institutes of Health (National Cancer Institute) T32 training grant [CA130807]; American Cancer Society Postdoctoral Fellowship [125087-PF-13-247-01-LIB] FX This work was supported by National Institutes of Health (National Cancer Institute) grants CA096899 (M. A. K.), CA034196 (L. D. S.), and (National Institute of Allergy and Infectious Diseases) grant AI04669 (D. L. G., L. D. S., and M. A. B.). J.R. was supported by a National Institutes of Health (National Cancer Institute) T32 training grant CA130807 to the Department of Cancer Biology at the University of Massachusetts Medical School and the American Cancer Society Postdoctoral Fellowship 125087-PF-13-247-01-LIB. NR 50 TC 46 Z9 49 U1 0 U2 7 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD FEB 13 PY 2014 VL 123 IS 7 BP 1040 EP 1050 DI 10.1182/blood-2013-08-522698 PG 11 WC Hematology SC Hematology GA AH0US UT WOS:000335836700019 PM 24394663 ER PT J AU Wu, RR Himmel, TL Buchanan, AH Powell, KP Hauser, ER Ginsburg, GS Henrich, VC Orlando, LA AF Wu, R. Ryanne Himmel, Tiffany L. Buchanan, Adam H. Powell, Karen P. Hauser, Elizabeth R. Ginsburg, Geoffrey S. Henrich, Vincent C. Orlando, Lori A. TI Quality of family history collection with use of a patient facing family history assessment tool SO BMC FAMILY PRACTICE LA English DT Article DE Family history; Data quality; Patient-centered ID GENETICALLY COMPLEX TRAITS; AMERICAN-CANCER-SOCIETY; AFFECTED RELATIVE PAIRS; PRIMARY-CARE PHYSICIANS; RISK-ASSESSMENT; LINKAGE STRATEGIES; COMMON DISEASES; HEALTH HISTORY; HEART-ASSOCIATION; COLORECTAL-CANCER AB Background: Studies have shown that the quality of family health history (FHH) collection in primary care is inadequate to assess disease risk. To use FHH for risk assessment, collected data must have adequate detail. To address this issue, we developed a patient facing FHH assessment tool, MeTree. In this paper we report the content and quality of the FHH collected using MeTree. Methods: Design: A hybrid implementation-effectiveness study. Patients were recruited from 2009 to 2012. Setting: Two community primary care clinics in Greensboro, NC. Participants: All non-adopted adult English speaking patients with upcoming appointments were invited to participate. Intervention: Education about and collection of FHH with entry into MeTree. Measures: We report the proportion of pedigrees that were high-quality. High-quality pedigrees are defined as having all the following criteria: (1) three generations of relatives, (2) relatives' lineage, (3) relatives' gender, (4) an up-to-date FHH, (5) pertinent negatives noted, (6) age of disease onset in affected relatives, and for deceased relatives, (7) the age and (8) cause of death (Prim Care 31:479-495, 2004.). Results: Enrollment: 1,184. Participant demographics: age range 18-92 (mean 58.8, SD 11.79), 56% male, and 75% white. The median pedigree size was 21 (range 8-71) and the FHH entered into MeTree resulted in a database of 27,406 individuals. FHHs collected by MeTree were found to be high quality in 99.8% (N = 1,182/1,184) as compared to <4% at baseline. An average of 1.9 relatives per pedigree (range 0-50, SD 4.14) had no data reported. For pedigrees where at least one relative has no data (N = 497/1,184), 4.97 relatives per pedigree (range 1-50, SD 5.44) had no data. Talking with family members before using MeTree significantly decreased the proportion of relatives with no data reported (4.98% if you talked to your relative vs. 10.85% if you did not, p-value < 0.001.). Conclusion: Using MeTree improves the quantity and quality of the FHH data that is collected and talking with relatives prior to the collection of FHH significantly improves the quantity and quality of the data provided. This allows more patients to be accurately risk stratified and offered appropriate preventive care guided by their risk level. C1 [Wu, R. Ryanne] US Dept Vet Affairs, Med Ctr, Hlth Serv Res & Dev, Durham, NC 27701 USA. [Wu, R. Ryanne; Himmel, Tiffany L.; Ginsburg, Geoffrey S.; Orlando, Lori A.] Duke Univ, Inst Genome Sci & Policy, Duke Ctr Personalized & Precis Med, Durham, NC 27708 USA. [Wu, R. Ryanne; Orlando, Lori A.] Duke Univ Hlth Syst, Duke Dept Internal Med, Durham, NC USA. [Buchanan, Adam H.] Duke Univ Hlth Syst, Duke Canc Inst, Durham, NC 27710 USA. [Powell, Karen P.; Henrich, Vincent C.] UNC Greensboro, Ctr Biotechnol Genom & Hlth Res, Greensboro, NC 27412 USA. [Hauser, Elizabeth R.] US Dept Vet Affairs, Med Ctr, CSP Epidemiol Ctr, Durham, NC 27701 USA. [Hauser, Elizabeth R.] Duke Univ, Ctr Human Genet, DUMC, Durham, NC 27710 USA. RP Wu, RR (reprint author), US Dept Vet Affairs, Med Ctr, Hlth Serv Res & Dev, 411 W Chapel Hill St,Ste 600, Durham, NC 27701 USA. EM ryanne.wu@duke.edu FU DoD FX This study is funded by the DoD. All authors are funded by the study as was time for manuscript preparation. The funding body provided IRB approval and ethical oversight of the study but did not have a role in the study design, data collection, analysis, interpretation, or in the writing of this manuscript. This material is also the result of work supported with resources and the use of facilities at the Durham, NC VA medical center by RW. NR 40 TC 8 Z9 8 U1 0 U2 0 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 FEB 13 PY 2014 VL 15 AR 31 DI 10.1186/1471-2296-15-31 PG 8 WC Primary Health Care; Medicine, General & Internal SC General & Internal Medicine GA AB8YT UT WOS:000332076800001 PM 24520818 ER PT J AU Mora-Blanco, EL Mishina, Y Tillman, EJ Cho, YJ Thom, CS Pomeroy, SL Shao, W Roberts, CWM AF Mora-Blanco, E. L. Mishina, Y. Tillman, E. J. Cho, Y-J Thom, C. S. Pomeroy, S. L. Shao, W. Roberts, C. W. M. TI Activation of beta-catenin/TCF targets following loss of the tumor suppressor SNF5 SO ONCOGENE LA English DT Article DE chromatin remodeling; tumor suppressor; Swi/Snf; beta-catenin; epigenetics ID CHROMATIN REMODELING COMPLEXES; GENOMIC INSTABILITY; BINDING REGIONS; RHABDOID TUMORS; MULTIPLE ROLES; CANCER; DIFFERENTIATION; TUMORIGENESIS; MUTATIONS; CELLS AB The SWI/SNF chromatin remodeling complex is a master regulator of developmental cell-fate decisions, although the key target pathways are poorly characterized. Here, we interrogated the contribution of the SWI/SNF subunit and tumor suppressor SNF5 to the regulation of developmental pathways using conditional mouse and cell culture models. We find that loss of SNF5 phenocopies beta-catenin hyperactivation and that SNF5 is essential for regulating Wnt/beta-catenin pathway target expression. These data provide insight into chromatin-based mechanisms that underlie developmental regulation and elucidate the emerging theme that mutation of this tumor suppressor complex can activate developmental pathways by uncoupling them from upstream control. C1 [Mora-Blanco, E. L.; Tillman, E. J.; Thom, C. S.; Roberts, C. W. M.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Mora-Blanco, E. L.; Tillman, E. J.; Thom, C. S.; Roberts, C. W. M.] Harvard Univ, Sch Med, Dept Pediat, Div Hematol Oncol,Childrens Hosp Boston, Boston, MA 02115 USA. [Mishina, Y.; Shao, W.] Novartis Inst Biomed Res, Cambridge, MA USA. [Cho, Y-J; Pomeroy, S. L.] Childrens Hosp Boston, Dept Neurol, Boston, MA USA. RP Roberts, CWM (reprint author), Dana Farber Canc Inst, Dept Pediat Oncol, 450 Brookline Ave, Boston, MA 02115 USA. EM Charles_Roberts@dfci.harvard.edu FU National Cancer Institute, National Institutes of Health [1F31CA130553, R01CA113794, U01-1156106]; Stand Up 2 Cancer Innovative Research Grant; The Garrett B Smith Foundation; Cure AT/RT; Miles for Mary FX We thank ES McKenna for critical reading of the manuscript and A Lassar for helpful discussions. The in situ probe constructs were generously provided by C Tabin (Harvard Medical School). This work was supported in part by National Cancer Institute, National Institutes of Health Pre-Doctoral NRSA award 1F31CA130553 (ELMB), R01CA113794 (CWMR) and U01-1156106 (Stuart H Orkin). CWM R is a recipient of a Stand Up 2 Cancer Innovative Research Grant. Miles for Mary, The Garrett B Smith Foundation and Cure AT/RT Now provided additional support. NR 38 TC 17 Z9 18 U1 1 U2 6 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 FEB 13 PY 2014 VL 33 IS 7 BP 933 EP 938 DI 10.1038/onc.2013.37 PG 6 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA AB2MN UT WOS:000331626900015 PM 23435428 ER PT J AU Croci, DO Cerliani, JP Dalotto-Moreno, T Mendez-Huergo, SP Mascanfroni, ID Dergan-Dylon, S Toscano, MA Caramelo, JJ Garcia-Vallejo, JJ Ouyang, J Mesri, EA Junttila, MR Bais, C Shipp, MA Salatino, M Rabinovich, GA AF Croci, Diego O. Cerliani, Juan P. Dalotto-Moreno, Tomas Mendez-Huergo, Santiago P. Mascanfroni, Ivan D. Dergan-Dylon, Sebastian Toscano, Marta A. Caramelo, Julio J. Garcia-Vallejo, Juan J. Ouyang, Jing Mesri, Enrique A. Junttila, Melissa R. Bais, Carlos Shipp, Margaret A. Salatino, Mariana Rabinovich, Gabriel A. TI Glycosylation-Dependent Lectin-Receptor Interactions Preserve Angiogenesis in Anti-VEGF Refractory Tumors SO CELL LA English DT Article ID HUMAN ENDOTHELIAL-CELLS; IMMUNE PRIVILEGE; INHIBITS GROWTH; GALECTIN-1; DISEASE; THERAPY; PROGRESSION; ACTIVATION; MECHANISMS; RESISTANCE AB The clinical benefit conferred by vascular endothelial growth factors (VEGF)-targeted therapies is variable, and tumors from treated patients eventually reinitiate growth. Here, we identify a glycosylation-dependent pathway that compensates for the absence of cognate ligand and preserves angiogenesis in response to VEGF blockade. Remodeling of the endothelial cell (EC) surface glycome selectively regulated binding of galectin-1 (Gal1), which upon recognition of complex N-glycans on VEGFR2, activated VEGF-like signaling. Vessels within anti-VEGF-sensitive tumors exhibited high levels of alpha 2-6-linkedsialic acid, which prevented Gal1 binding. In contrast, anti-VEGF refractory tumors secreted increased Gal1 and their associated vasculature displayed glycosylation patterns that facilitated Gal1-EC interactions. Interruption of beta 1-6GlcNAc branching in ECs or silencing of tumor-derived Gal1 converted refractory into anti-VEGF-sensitive tumors, whereas elimination of alpha 2-6-linked sialic acid conferred resistance to anti-VEGF. Disruption of the Gal1-N-glycan axis promoted vascular remodeling, immune cell influx and tumor growth inhibition. Thus, targeting glycosylation-dependent lectin-receptor interactions may increase the efficacy of anti-VEGF treatment. C1 [Croci, Diego O.; Cerliani, Juan P.; Dalotto-Moreno, Tomas; Mendez-Huergo, Santiago P.; Mascanfroni, Ivan D.; Dergan-Dylon, Sebastian; Toscano, Marta A.; Salatino, Mariana; Rabinovich, Gabriel A.] Consejo Nacl Invest Cient & Tecn, IBYME, Lab Immunopatol, RA-1428 Buenos Aires, DF, Argentina. [Caramelo, Julio J.] Consejo Nacl Invest Cient & Tecn, Fdn Inst Leloir, Lab Biol Estruct & Celular, RA-1405 Buenos Aires, DF, Argentina. [Garcia-Vallejo, Juan J.] Vrije Univ Amsterdam, Med Ctr, Dept Mol Cell Biol & Immunol, NL-1081 BT Amsterdam, Netherlands. [Ouyang, Jing] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Mesri, Enrique A.] Univ Miami, Miller Sch Med, Sylvester Comprehens Canc Ctr, Dept Microbiol & Immunol,Miami Ctr AIDS Res, Miami, FL 33136 USA. [Junttila, Melissa R.; Bais, Carlos] Genencor Inc, San Francisco, CA 94080 USA. [Rabinovich, Gabriel A.] Univ Buenos Aires, Fac Ciencias Exactas & Nat, Dept Quim Biol, Lab Glicom, RA-1428 Buenos Aires, DF, Argentina. RP Rabinovich, GA (reprint author), Consejo Nacl Invest Cient & Tecn, IBYME, Lab Immunopatol, RA-1428 Buenos Aires, DF, Argentina. EM gabyrabi@gmail.com RI Garcia-Vallejo, Juan/H-4162-2012 OI Garcia-Vallejo, Juan/0000-0001-6238-7069 FU Argentinean Agency for Promotion of Science and Technology; CONICET; University of Buenos Aires; Sales Foundation FX We thank J. Dennis for Mgat5-/- mice; J. Paulson for St6gal1-/- mice; F. Poirier for Lgals1 / mice; J. Wang for Gal1N46D; C. Tran for PDAC tumors; J. Stupirski, H. Kalay, C. Leishman, and R. Morales for technical assistance; and J. Ilarregui and A. Gongora for advice. Supported by the Argentinean Agency for Promotion of Science and Technology, CONICET, University of Buenos Aires, Sales Foundation, and donations from Ferioli and Ostry families (to G.A.R.). NR 50 TC 122 Z9 127 U1 11 U2 70 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 FEB 13 PY 2014 VL 156 IS 4 BP 744 EP 758 DI 10.1016/j.cell.2014.01.043 PG 15 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AA8YB UT WOS:000331379800013 PM 24529377 ER PT J AU Foley, MH Forcier, T McAndrew, E Gonzalez, M Chen, HB Juelg, B Walker, BD Irvine, DJ AF Foley, Maria Hottelet Forcier, Talitha McAndrew, Elizabeth Gonzalez, Michael Chen, Huabiao Juelg, Boris Walker, Bruce D. Irvine, Darrell J. TI High Avidity CD8(+) T Cells Efficiently Eliminate Motile HIV-Infected Targets and Execute a Locally Focused Program of Anti-Viral Function SO PLOS ONE LA English DT Article ID SIMIAN IMMUNODEFICIENCY VIRUS; IMMUNOLOGICAL SYNAPSE; IN-VIVO; ANTIGEN SENSITIVITY; LYMPHOCYTE RESPONSE; TYPE-1 REPLICATION; SECRETORY DOMAIN; VIRAL-INFECTION; RHESUS MACAQUES; ACTIVATION AB The dissemination of HIV from an initial site of infection is facilitated by motile HIV-infected CD4(+) T-cells. However, the impact of infected target cell migration on antigen recognition by HIV-specific CD8(+) T-cells is unclear. Using a 3D in vitro model of tissue, we visualized dynamic interactions between HIV-infected or peptide-pulsed CD4(+) T-cells and HIV-specific CD8(+) T-cells. CTLs engaged motile HIV-infected targets, but similar to 50% of targets broke contact and escaped. In contrast, immobilized target cells were readily killed, indicating target motility directly inhibits CD8(+) T-cell function. Strong calcium signals occurred in CTLs killing a motile target but calcium signaling was weak or absent in CTLs which permitted target escape. Neutralization of adhesion receptors LFA-1 and CD58 inhibited CD8(+) T-cell function within the 3D matrix, demonstrating that efficient motile target lysis as dependent on adhesive engagement of targets. Antigen sensitivity (a convolution of antigen density, TCR avidity and CD8 coreceptor binding) is also critical for target recognition. We modulated this parameter (known as functional avidity but referred to here as "avidity'' for the sake of simplicity) by exploiting common HIV escape mutations and measured their impact on CTL function at the single-cell level. Targets pulsed with low avidity mutant antigens frequently escaped while CTLs killed targets bearing high avidity antigen with near-perfect efficiency. CTLs engaged, arrested, and killed an initial target bearing high avidity antigen within minutes, but serial killing was surprisingly rare. CD8 cells remained committed to their initial dead target for hours, accumulating TCR signals that sustained secretion of soluble antiviral factors. These data indicate that high-avidity CD8(+) T-cells execute an antiviral program in the precise location where antigen has been sensed: CTL effector functions are spatiotemporally coordinated with an early lytic phase followed by a sustained stationary secretory phase to control local viral infection. C1 [Foley, Maria Hottelet; Irvine, Darrell J.] MIT, Dept Biol Engn, Cambridge, MA 02139 USA. [Foley, Maria Hottelet; Forcier, Talitha; McAndrew, Elizabeth; Chen, Huabiao; Juelg, Boris; Walker, Bruce D.; Irvine, Darrell J.] MIT, Massachusetts Gen Hosp, Ragon Inst, Cambridge, MA 02139 USA. [Foley, Maria Hottelet; Forcier, Talitha; McAndrew, Elizabeth; Chen, Huabiao; Juelg, Boris; Walker, Bruce D.; Irvine, Darrell J.] Harvard Univ, Cambridge, MA 02138 USA. [Foley, Maria Hottelet; Irvine, Darrell J.] MIT, Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA. [Forcier, Talitha; Irvine, Darrell J.] MIT, Dept Mat Sci & Engn, Cambridge, MA 02139 USA. [Gonzalez, Michael; Walker, Bruce D.; Irvine, Darrell J.] Howard Hughes Med Inst, Chevy Chase, MD USA. RP Irvine, DJ (reprint author), MIT, Dept Biol Engn, 77 Massachusetts Ave, Cambridge, MA 02139 USA. EM djirvine@mit.edu FU Ragon Institute; NIH [AI030914, AI074415, AI060354]; Harvard Center for AIDS Research FX This work was supported by the Ragon Institute and the NIH (AI030914; AI074415; and AI060354), as well as the Harvard Center for AIDS Research. DJI and BDW are investigators of the HHMI. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 63 TC 15 Z9 15 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 FEB 13 PY 2014 VL 9 IS 2 AR e87873 DI 10.1371/journal.pone.0087873 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AA7GP UT WOS:000331266000019 PM 24551068 ER PT J AU Xia, Z Chen, HB Kang, SG Huynh, T Fang, JW Lamothe, PA Walker, BD Zhou, RH AF Xia, Zhen Chen, Huabiao Kang, Seung-gu Tien Huynh Fang, Justin W. Lamothe, Pedro A. Walker, Bruce D. Zhou, Ruhong TI The complex and specific pMHC interactions with diverse HIV-1 TCR clonotypes reveal a structural basis for alterations in CTL function SO SCIENTIFIC REPORTS LA English DT Article ID T-CELL RESPONSES; FREE-ENERGY SIMULATIONS; RECEPTOR CROSS-REACTIVITY; VIRAL LOAD; LYMPHOCYTE ESCAPE; SINGLE MUTATION; PEPTIDE-MHC; PROTEIN; INFECTION; HEMAGGLUTININ AB Immune control of viral infections is modulated by diverse T cell receptor (TCR) clonotypes engaging peptide-MHC class I complexes on infected cells, but the relationship between TCR structure and antiviral function is unclear. Here we apply in silico molecular modeling with in vivo mutagenesis studies to investigate TCR-pMHC interactions from multiple CTL clonotypes specific for a well-defined HIV-1 epitope. Our molecular dynamics simulations of viral peptide-HLA-TCR complexes, based on two independent co-crystal structure templates, reveal that effective and ineffective clonotypes bind to the terminal portions of the peptide-MHC through similar salt bridges, but their hydrophobic side-chain packings can be very different, which accounts for the major part of the differences among these clonotypes. Non-specific hydrogen bonding to viral peptide also accommodates greater epitope variants. Furthermore, free energy perturbation calculations for point mutations on the viral peptide KK10 show excellent agreement with in vivo mutagenesis assays, with new predictions confirmed by additional experiments. These findings indicate a direct structural basis for heterogeneous CTL antiviral function. C1 [Xia, Zhen; Kang, Seung-gu; Tien Huynh; Zhou, Ruhong] IBM Thomas J Watson Res Ctr, Computat Biol Ctr, Yorktown Hts, NY USA. [Chen, Huabiao; Fang, Justin W.; Lamothe, Pedro A.; Walker, Bruce D.] MIT, Massachusetts Gen Hosp, Ragon Inst, Cambridge, MA 02139 USA. [Chen, Huabiao; Fang, Justin W.; Lamothe, Pedro A.; Walker, Bruce D.] Harvard Univ, Cambridge, MA 02138 USA. [Walker, Bruce D.] Howard Hughes Med Inst, Chevy Chase, MD USA. [Zhou, Ruhong] Columbia Univ, Dept Chem, New York, NY 10027 USA. RP Walker, BD (reprint author), MIT, Massachusetts Gen Hosp, Ragon Inst, 77 Massachusetts Ave, Cambridge, MA 02139 USA. EM bwalker@partners.org; ruhongz@us.ibm.com RI Xia, Zhen/B-3391-2014 FU IBM Blue Gene Science Program; Harvard University Center for AIDS Research [5 P30 AI060354-04]; Bill and Melinda Gates Foundation; Doris Duke Charitable Foundation; NIH [AI030914]; Howard Hughes Medical Institute; Mark and Lisa Schwartz Foundation FX This work was supported by the IBM Blue Gene Science Program (R.Z.), the Harvard University Center for AIDS Research (5 P30 AI060354-04), grants from the Bill and Melinda Gates Foundation (B.D.W.), the Doris Duke Charitable Foundation (B.D.W.), the NIH (B.D.W. AI030914), the Howard Hughes Medical Institute (B.D.W.), and the Mark and Lisa Schwartz Foundation (B.D.W.). We also thank IBM Watson Blue Gene Supercomputer Center for computational resources. NR 61 TC 5 Z9 5 U1 0 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD FEB 13 PY 2014 VL 4 AR 4087 DI 10.1038/srep04087 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AA7QN UT WOS:000331292100006 PM 24522437 ER PT J AU Rosenbaum, L AF Rosenbaum, Lisa TI "Misfearing" - Culture, Identity, and Our Perceptions of Health Risks SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material C1 [Rosenbaum, Lisa] Univ Penn, Philadelphia Vet Affairs Med Ctr, Philadelphia, PA 19104 USA. [Rosenbaum, Lisa] Univ Penn, Robert Wood Johnson Fdn, Clin Scholars Program, Philadelphia, PA 19104 USA. RP Rosenbaum, L (reprint author), Univ Penn, Philadelphia Vet Affairs Med Ctr, Philadelphia, PA 19104 USA. NR 5 TC 7 Z9 7 U1 0 U2 4 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD FEB 13 PY 2014 VL 370 IS 7 BP 595 EP 597 DI 10.1056/NEJMp1314638 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA AA6CX UT WOS:000331187500005 PM 24521105 ER PT J AU Allen, RP Chen, C Garcia-Borreguero, D Polo, O DuBrava, S Miceli, J Knapp, L Winkelman, JW AF Allen, Richard P. Chen, Crystal Garcia-Borreguero, Diego Polo, Olli DuBrava, Sarah Miceli, Jeffrey Knapp, Lloyd Winkelman, John W. TI Comparison of Pregabalin with Pramipexole for Restless Legs Syndrome SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID GROUP RATING-SCALE; DOUBLE-BLIND; CONTROLLED-TRIAL; CLINICAL-TRIALS; SYNDROME RLS; AUGMENTATION; LEVODOPA; VALIDATION; ROPINIROLE; EFFICACY AB BackgroundDopaminergic medications relieve symptoms of the restless legs syndrome (RLS) but have the potential to cause iatrogenic worsening (augmentation) of RLS with long-term treatment. Pregabalin may be an effective alternative. MethodsIn this 52-week, randomized, double-blind trial, we assessed efficacy and augmentation in patients with RLS who were treated with pregabalin as compared with placebo and pramipexole. Patients were randomly assigned to receive 52 weeks of treatment with pregabalin at a dose of 300 mg per day or pramipexole at a dose of 0.25 mg or 0.5 mg per day or 12 weeks of placebo followed by 40 weeks of randomly assigned active treatment. The primary analyses involved a comparison of pregabalin and placebo over a period of 12 weeks with use of the International RLS (IRLS) Study Group Rating Scale (on which the score ranges from 0 to 40, with a higher score indicating more severe symptoms), the Clinical Global Impression of Improvement scale (which was used to assess the proportion of patients with symptoms that were very much improved or much improved), and a comparison of rates of augmentation with pregabalin and pramipexole over a period of 40 or 52 weeks of treatment. ResultsA total of 719 participants received daily treatment, 182 with 300 mg of pregabalin, 178 with 0.25 mg of pramipexole, 180 with 0.5 mg of pramipexole, and 179 with placebo. Over a period of 12 weeks, the improvement (reduction) in mean scores on the IRLS scale was greater, by 4.5 points, among participants receiving pregabalin than among those receiving placebo (P<0.001), and the proportion of patients with symptoms that were very much improved or much improved was also greater with pregabalin than with placebo (71.4% vs. 46.8%, P<0.001). The rate of augmentation over a period of 40 or 52 weeks was significantly lower with pregabalin than with pramipexole at a dose of 0.5 mg (2.1% vs. 7.7%, P=0.001) but not at a dose of 0.25 mg (2.1% vs. 5.3%, P=0.08). There were six cases of suicidal ideation in the group receiving pregabalin, three in the group receiving 0.25 mg of pramipexole, and two in the group receiving 0.5 mg of pramipexole. ConclusionsPregabalin provided significantly improved treatment outcomes as compared with placebo, and augmentation rates were significantly lower with pregabalin than with 0.5 mg of pramipexole. (Funded by Pfizer; ClinicalTrials.gov number, NCT00806026.) C1 [Allen, Richard P.] Johns Hopkins Univ, Dept Neurol, Baltimore, MD 21224 USA. [Chen, Crystal; DuBrava, Sarah; Miceli, Jeffrey; Knapp, Lloyd] Pfizer Global Res & Dev, Groton, CT USA. [Garcia-Borreguero, Diego] Sleep Res Inst, Madrid, Spain. [Polo, Olli] Tampere Univ Hosp, Dept Pulm Med, Tampere, Finland. [Winkelman, John W.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Allen, RP (reprint author), Johns Hopkins Univ, Dept Neurol, 5501 Hopkins Bayview Cir, Baltimore, MD 21224 USA. EM richardjhu@mac.com FU Pfizer FX Funded by Pfizer; ClinicalTrials.gov number, NCT00806026. NR 37 TC 51 Z9 53 U1 0 U2 11 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 FEB 13 PY 2014 VL 370 IS 7 BP 621 EP 631 DI 10.1056/NEJMoa1303646 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA AA6CX UT WOS:000331187500008 PM 24521108 ER PT J AU Baggett, MV Turbett, SE Schwartzenberg, SS Stone, JR AF Baggett, Meridale V. Turbett, Sarah E. Schwartzenberg, Shmuel S. Stone, James R. TI Case 5-2014: A 59-Year-Old Man with Fever, Confusion, Thrombocytopenia, Rash, and Renal Failure SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID MOUNTAIN SPOTTED-FEVER; INFECTIVE ENDOCARDITIS; SURGICAL PATHOLOGY; PATHOGENESIS; SPECIMENS; DIAGNOSIS; LESIONS C1 [Baggett, Meridale V.; Turbett, Sarah E.; Schwartzenberg, Shmuel S.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Stone, James R.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Baggett, Meridale V.; Turbett, Sarah E.; Schwartzenberg, Shmuel S.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Stone, James R.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Baggett, MV (reprint author), Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. FU GlaxoSmithKline; Merck FX Dr. Stone reports receiving consulting fees from GlaxoSmithKline and Merck, and providing expert testimony for GlaxoSmithKline regarding rosiglitazone. No other potential conflict of interest relevant to this article was reported. NR 20 TC 3 Z9 3 U1 0 U2 3 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD FEB 13 PY 2014 VL 370 IS 7 BP 651 EP 660 DI 10.1056/NEJMcpc1310004 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA AA6CX UT WOS:000331187500012 PM 24521112 ER PT J AU Jessen, H Allen, TM Streeck, H AF Jessen, Heiko Allen, Todd M. Streeck, Hendrik TI How a Single Patient Influenced HIV Research-15-Year Follow-up SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter ID ANTIRETROVIRAL THERAPY; INFECTION; INTERRUPTION C1 [Jessen, Heiko] J2 Private Clin Infect Dis, Berlin, Germany. [Allen, Todd M.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Streeck, Hendrik] US Mil HIV Res Program, Silver Spring, MD USA. RP Jessen, H (reprint author), J2 Private Clin Infect Dis, Berlin, Germany. EM hstreeck@hivresearch.org RI Allen, Todd/F-5473-2011 FU NIAID NIH HHS [R01 AI091450, R01 AI091450-01, R01 AI094602, R01 AI094602-01] NR 5 TC 10 Z9 10 U1 1 U2 1 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD FEB 13 PY 2014 VL 370 IS 7 BP 682 EP 683 DI 10.1056/NEJMc1308413 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA AA6CX UT WOS:000331187500033 PM 24521131 ER PT J AU Bateman, AR El-Hachem, N Beck, AH Aerts, HJWL Haibe-Kains, B AF Bateman, Alain R. El-Hachem, Nehme Beck, Andrew H. Aerts, Hugo J. W. L. Haibe-Kains, Benjamin TI Importance of collection in gene set enrichment analysis of drug response in cancer cell lines SO SCIENTIFIC REPORTS LA English DT Article ID EXPRESSION; SENSITIVITY; PATHWAY; ENCYCLOPEDIA; SIGNATURES; DISCOVERY; CISPLATIN; TOOL AB Gene set enrichment analysis (GSEA) associates gene sets and phenotypes, its use is predicated on the choice of a pre-defined collection of sets. The defacto standard implementation of GSEA provides seven collections yet there are no guidelines for the choice of collections and the impact of such choice, if any, is unknown. Here we compare each of the standard gene set collections in the context of a large dataset of drug response in human cancer cell lines. We define and test a new collection based on gene co-expression in cancer cell lines to compare the performance of the standard collections to an externally derived cell line based collection. The results show that GSEA findings vary significantly depending on the collection chosen for analysis. Henceforth, collections should be carefully selected and reported in studies that leverage GSEA. C1 [Bateman, Alain R.; El-Hachem, Nehme; Haibe-Kains, Benjamin] Univ Montreal, Inst Rech Clin Montreal, Bioinformat & Computat Genom Lab, Montreal, PQ, Canada. [Beck, Andrew H.] Beth Israel Deaconess Med Ctr, Dept Pathol, Boston, MA 02215 USA. [Beck, Andrew H.] Harvard Univ, Sch Med, Boston, MA USA. [Aerts, Hugo J. W. L.] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Aerts, Hugo J. W. L.] Dana Farber Canc Inst, Ctr Canc Computat Biol, Boston, MA 02115 USA. [Aerts, Hugo J. W. L.] Harvard Univ, Brigham & Womens Hosp, Sch Med,Dana Farber Canc Inst, Dept Radiat Oncol & Radiol, Boston, MA 02115 USA. [Aerts, Hugo J. W. L.] Maastricht Univ, Dept Radiat Oncol, Maastricht, Netherlands. [Haibe-Kains, Benjamin] Univ Hlth Network, Princess Margaret Canc Ctr, Ontario Canc Inst, Toronto, ON, Canada. RP Haibe-Kains, B (reprint author), Univ Montreal, Inst Rech Clin Montreal, Bioinformat & Computat Genom Lab, Montreal, PQ, Canada. EM bhaibeka@uhnresearch.ca RI Haibe-Kains, Benjamin/D-3702-2011; Aerts, Hugo/P-6350-2015 OI Haibe-Kains, Benjamin/0000-0002-7684-0079; Aerts, Hugo/0000-0002-2122-2003 NR 36 TC 2 Z9 2 U1 0 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD FEB 13 PY 2014 VL 4 AR 4092 DI 10.1038/srep04092 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AA7QU UT WOS:000331292800004 PM 24522610 ER PT J AU Fromer, M Pocklington, AJ Kavanagh, DH Williams, HJ Dwyer, S Gormley, P Georgieva, L Rees, E Palta, P Ruderfer, DM Carrera, N Humphreys, I Johnson, JS Roussos, P Barker, DD Banks, E Milanova, V Grant, SG Hannon, E Rose, SA Chambert, K Mahajan, M Scolnick, EM Moran, JL Kirov, G Palotie, A McCarroll, SA Holmans, P Sklar, P Owen, MJ Purcell, SM O'Donovan, MC AF Fromer, Menachem Pocklington, Andrew J. Kavanagh, David H. Williams, Hywel J. Dwyer, Sarah Gormley, Padhraig Georgieva, Lyudmila Rees, Elliott Palta, Priit Ruderfer, Douglas M. Carrera, Noa Humphreys, Isla Johnson, Jessica S. Roussos, Panos Barker, Douglas D. Banks, Eric Milanova, Vihra Grant, Seth G. Hannon, Eilis Rose, Samuel A. Chambert, Kimberly Mahajan, Milind Scolnick, Edward M. Moran, Jennifer L. Kirov, George Palotie, Aarno McCarroll, Steven A. Holmans, Peter Sklar, Pamela Owen, Michael J. Purcell, Shaun M. O'Donovan, Michael C. TI De novo mutations in schizophrenia implicate synaptic networks SO NATURE LA English DT Article ID AUTISM SPECTRUM DISORDERS; COPY-NUMBER VARIANTS; INTELLECTUAL DISABILITY; DISEASE; GENE; PLASTICITY; MECHANISMS; COMPLEXITY; PATTERNS; RATES AB Inherited alleles account for most of the genetic risk for schizophrenia. However, new (de novo) mutations, in the form of large chromosomal copy number changes, occur in a small fraction of cases and disproportionally disrupt genes encoding postsynaptic proteins. Here we show that small de novo mutations, affecting one ora few nucleotides, are overrepresented among glutamatergic postsynaptic proteins comprising activity-regulated cytoskeleton-associated protein (ARC) and N-methyl-D-aspartate receptor (NMDAR) complexes. Mutations are additionally enriched in proteins that interact with these complexes to modulate synaptic strength, namely proteins regulating actin filament dynamics and those whose messenger RNAs are targets of fragile X mental retardation protein (FMRP). Genes affected by mutations in schizophrenia overlap those mutated in autism and intellectual disability, as do mutation-enriched synaptic pathways. Aligning our findings with a parallel case-control study, we demonstrate reproducible insights into aetiological mechanisms for schizophrenia and reveal pathophysiology shared with other neurodevelopmental disorders. C1 [Fromer, Menachem; Ruderfer, Douglas M.; Johnson, Jessica S.; Roussos, Panos; Mahajan, Milind; Sklar, Pamela; Purcell, Shaun M.] Icahn Sch Med Mt Sinai, Dept Psychiat, Div Psychiat Genom, New York, NY 10029 USA. [Fromer, Menachem; Ruderfer, Douglas M.; Johnson, Jessica S.; Roussos, Panos; Mahajan, Milind; Sklar, Pamela; Purcell, Shaun M.] Icahn Sch Med Mt Sinai, Inst Genom & Multiscale Biol, New York, NY 10029 USA. [Fromer, Menachem; Barker, Douglas D.; Rose, Samuel A.; Chambert, Kimberly; Scolnick, Edward M.; Moran, Jennifer L.; McCarroll, Steven A.; Purcell, Shaun M.] Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Cambridge, MA 02142 USA. [Pocklington, Andrew J.; Kavanagh, David H.; Williams, Hywel J.; Dwyer, Sarah; Georgieva, Lyudmila; Rees, Elliott; Ruderfer, Douglas M.; Carrera, Noa; Humphreys, Isla; Hannon, Eilis; Kirov, George; Holmans, Peter; Owen, Michael J.; O'Donovan, Michael C.] Cardiff Univ, Inst Psychol Med & Clin Neurosci, Med Res Council Ctr Neuropsychiat Genet & Genom, Cardiff CF24 4HQ, S Glam, Wales. [Gormley, Padhraig; Palta, Priit; Palotie, Aarno] Wellcome Trust Sanger Inst, Hinxton CB10 1SA, England. [Gormley, Padhraig; Banks, Eric; Palotie, Aarno; McCarroll, Steven A.] Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA 02142 USA. [Palta, Priit] Univ Tartu, Inst Mol & Cell Biol, Dept Bioinformat, EE-51010 Tartu, Estonia. [Palta, Priit; Palotie, Aarno] Univ Helsinki, Inst Mol Med Finland FIMM, FIN-00290 Helsinki, Finland. [Milanova, Vihra] Med Univ, Dept Psychiat, Sofia 1431, Bulgaria. [Grant, Seth G.] Univ Edinburgh, Ctr Neuroregenerat, Edinburgh EH16 4SB, Midlothian, Scotland. [McCarroll, Steven A.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Sklar, Pamela] Icahn Sch Med Mt Sinai, Friedman Brain Inst, New York, NY 10029 USA. [Purcell, Shaun M.] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA. RP Owen, MJ (reprint author), Cardiff Univ, Inst Psychol Med & Clin Neurosci, Med Res Council Ctr Neuropsychiat Genet & Genom, Cardiff CF24 4HQ, S Glam, Wales. EM owenmj@cardiff.ac.uk RI Holmans, Peter/F-4518-2015; Ruderfer, Douglas/M-5795-2016; Roussos, Panos/J-7090-2013 OI McCarroll, Steven/0000-0002-6954-8184; Gormley, Padhraig/0000-0002-8908-6968; O'Donovan, Michael/0000-0001-7073-2379; Holmans, Peter/0000-0003-0870-9412; Moran, Jennifer/0000-0002-5664-4716; Palta, Priit/0000-0001-9320-7008; Hannon, Eilis/0000-0001-6840-072X; Ruderfer, Douglas/0000-0002-2365-386X; Roussos, Panos/0000-0002-4640-6239 FU Medical Research Council (MRC) Centre [G0800509, G0801418]; European Community [HEALTH-F2-2010-241909]; NIMH [2 P50 MH066392-05A1]; Friedman Brain Institute; Institute for Genomics and Multiscale Biology; National Institutes of Health [R01HG005827, R01MH099126, R01MH071681]; Fidelity Foundations; Sylvan Herman Foundation; Stanley Medical Research Institute; Wellcome Trust [WT089062, WT098051]; European Commission [261123] FX Work in Cardiff was supported by Medical Research Council (MRC) Centre (G0800509) and Program Grants (G0801418), the European Community's Seventh Framework Programme (HEALTH-F2-2010-241909 (Project EU-GEI)), and NIMH (2 P50 MH066392-05A1). Work at the Icahn School of Medicine at Mount Sinai was supported by the Friedman Brain Institute, the Institute for Genomics and Multiscale Biology (including computational resources and staff expertise provided by the Department of Scientific Computing), and National Institutes of Health grants R01HG005827 (S. M. P.), R01MH099126 (S. M. P.), and R01MH071681 (P. S.). Work at the Broad Institute was funded by Fidelity Foundations, the Sylvan Herman Foundation, philanthropic gifts from K. and E. Dauten, and the Stanley Medical Research Institute. Work at the Wellcome Trust Sanger Institute was supported by The Wellcome Trust (grant numbers WT089062 and WT098051) and also by the European Commission FP7 project gEUVADIS no. 261123 (P. P.). We would like to thank M. Daly, B. Neale and K. Samocha for discussions and providing unpublished autism data. We would also like to acknowledge M. DePristo, S. Gabriel, T. J. Fennel, K. Shakir, C. Tolonen and H. Shah for their help in generating and processing the various data sets. NR 43 TC 372 Z9 373 U1 17 U2 87 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 FEB 13 PY 2014 VL 506 IS 7487 BP 179 EP + DI 10.1038/nature12929 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AA5AK UT WOS:000331107700029 PM 24463507 ER PT J AU Purcell, SM Moran, JL Fromer, M Ruderfer, D Solovieff, N Roussos, P O'Dushlaine, C Chambert, K Bergen, SE Kahler, A Duncan, L Stahl, E Genovese, G Fernandez, E Collins, MO Komiyama, NH Choudhary, JS Magnusson, PKE Banks, E Shakir, K Garimella, K Fennell, T DePristo, M Grant, SGN Haggarty, SJ Gabriel, S Scolnick, EM Lander, ES Hultman, CM Sullivan, PF McCarroll, SA Sklar, P AF Purcell, Shaun M. Moran, Jennifer L. Fromer, Menachem Ruderfer, Douglas Solovieff, Nadia Roussos, Panos O'Dushlaine, Colm Chambert, Kimberly Bergen, Sarah E. Kahler, Anna Duncan, Laramie Stahl, Eli Genovese, Giulio Fernandez, Esperanza Collins, Mark O. Komiyama, Noboru H. Choudhary, Jyoti S. Magnusson, Patrik K. E. Banks, Eric Shakir, Khalid Garimella, Kiran Fennell, Tim DePristo, Mark Grant, Seth G. N. Haggarty, Stephen J. Gabriel, Stacey Scolnick, Edward M. Lander, Eric S. Hultman, Christina M. Sullivan, Patrick F. McCarroll, Steven A. Sklar, Pamela TI A polygenic burden of rare disruptive mutations in schizophrenia SO NATURE LA English DT Article ID DE-NOVO MUTATIONS; INTELLECTUAL DISABILITY; MESSENGER-RNA; POSTSYNAPTIC DENSITY-95; PSYCHIATRIC-DISORDERS; ASSOCIATION ANALYSIS; SEQUENCING DATA; NMDA RECEPTOR; RISK LOCI; AUTISM AB Schizophrenia is a common disease with a complex aetiology, probably involving multiple and heterogeneous genetic factors. Here, by analysing the exome sequences of 2,536 schizophrenia cases and 2,543 controls, we demonstrate a polygenic burden primarily arising from rare (less than 1 in 10,000), disruptive mutations distributed across many genes. Particularly enriched gene sets include the voltage-gated calcium ion channel and the signalling complex formed by the activity-regulated cytoskeleton-associated scaffold protein (ARC) of the postsynaptic density, sets previously implicated by genome-wide association and copy-number variation studies. Similar to reports in autism, targets of the fragile X mental retardation protein (FMRP, product of FMR1) are enriched for case mutations. No individual gene-based test achieves significance after correction for multiple testing and we do not detect any alleles of moderately low frequency (approximately 0.5 to 1 per cent) and moderately large effect. Taken together, these data suggest that population-based exome sequencing can discover risk alleles and complements established gene-mapping paradigms in neuropsychiatric disease. C1 [Purcell, Shaun M.; Moran, Jennifer L.; Fromer, Menachem; O'Dushlaine, Colm; Chambert, Kimberly; Bergen, Sarah E.; Duncan, Laramie; Genovese, Giulio; Haggarty, Stephen J.; Scolnick, Edward M.; McCarroll, Steven A.] Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Cambridge, MA 02142 USA. [Purcell, Shaun M.; Fromer, Menachem; Ruderfer, Douglas; Roussos, Panos; Stahl, Eli; Sklar, Pamela] Icahn Sch Med Mt Sinai, Div Psychiat Genom, Dept Psychiat, New York, NY 10029 USA. [Purcell, Shaun M.; Fromer, Menachem; Ruderfer, Douglas; Roussos, Panos; Stahl, Eli; Sklar, Pamela] Icahn Sch Med Mt Sinai, Inst Genom & Multiscale Biol, New York, NY 10029 USA. [Purcell, Shaun M.; Fromer, Menachem; Solovieff, Nadia; Duncan, Laramie; Haggarty, Stephen J.] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA. [Purcell, Shaun M.; Duncan, Laramie; Banks, Eric; Shakir, Khalid; Garimella, Kiran; Fennell, Tim; DePristo, Mark; Gabriel, Stacey; Lander, Eric S.; McCarroll, Steven A.] Broad Inst MIT & Harvard, Med & Populat Genet Program, Cambridge, MA 02142 USA. [Bergen, Sarah E.; Kahler, Anna; Magnusson, Patrik K. E.; Hultman, Christina M.] Karolinska Inst, Dept Med Epidemiol & Biostat, SE-17177 Stockholm, Sweden. [Fernandez, Esperanza] Katholieke Univ Leuven, Ctr Human Genet, B-3000 Louvain, Belgium. [Fernandez, Esperanza] VIB Ctr Biol Dis, B-3000 Louvain, Belgium. [Collins, Mark O.; Komiyama, Noboru H.; Choudhary, Jyoti S.] Wellcome Trust Sanger Inst, Prote Mass Spectrometry, Cambridge CB10 1SA, England. [Grant, Seth G. N.] Univ Edinburgh, Ctr Clin Brain Sci, Genes Cognit Programme, Edinburgh EH16 4SB, Midlothian, Scotland. [Grant, Seth G. N.] Univ Edinburgh, Ctr Neuroregenerat, Edinburgh EH16 4SB, Midlothian, Scotland. [Haggarty, Stephen J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurol, Boston, MA 02114 USA. [Sullivan, Patrick F.] Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA. [Sullivan, Patrick F.] Univ N Carolina, Dept Psychiat, Chapel Hill, NC 27599 USA. [McCarroll, Steven A.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Sklar, Pamela] Icahn Sch Med Mt Sinai, Friedman Brain Inst, New York, NY 10029 USA. RP Purcell, SM (reprint author), Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Cambridge, MA 02142 USA. EM shaun@broadinstitute.org RI Kahler, Anna/J-2874-2012; Ruderfer, Douglas/M-5795-2016; Roussos, Panos/J-7090-2013; Magnusson, Patrik/C-4458-2017; OI McCarroll, Steven/0000-0002-6954-8184; Moran, Jennifer/0000-0002-5664-4716; Haggarty, Stephen J./0000-0002-7872-168X; Ruderfer, Douglas/0000-0002-2365-386X; Roussos, Panos/0000-0002-4640-6239; Bergen, Sarah/0000-0002-5888-0034 FU National Institutes of Health (NIH)/National Institute of Mental Health (NIMH) ARRA Grand Opportunity grant [NIMH RC2 MH089905]; Sylvan Herman Foundation; Stanley Center for Psychiatric Research; Stanley Medical Research Institute; NIH/National Human Genome Research Institute (NHGRI) [U54HG003067]; NIH/NIMH [R01 MH095088, R01 MH091115, R01 MH099126, R01 MH077139, R01 MH095034, T32 MH017119]; Tau Consortium; NIH/NHGRI [R01 HG005827]; Friedman Brain Institute at Mount Sinai School of Medicine; Karolinska Institutet, Karolinska University Hospital; Swedish Research Council; ALF from Swedish County Council; Soderstrom Konigska Foundation; Netherlands Scientific Organization [NWO 645-000-003]; Wellcome Trust; Genes to Cognition Program; Medical Research Council; European Union [241995, 242498, 242167]; Institute for Genomics and Multiscale Biology FX We are grateful for the participation of all subjects contributing to this research, and to the collection team that worked to recruit them: E. Flordal-Thelander, A.-B. Holmgren, M. Hallin, M. Lundin, A.-K. Sundberg, C. Pettersson, R. Satgunanthan-Dawoud, S. Hassellund, M. Radstrom, B. Ohlander, L. Nyren and I. Kizling. We acknowledge funding support from National Institutes of Health (NIH)/National Institute of Mental Health (NIMH) ARRA Grand Opportunity grant NIMH RC2 MH089905 (S. M. P., P. S.), the Sylvan Herman Foundation, the Stanley Center for Psychiatric Research, the Stanley Medical Research Institute, NIH/National Human Genome Research Institute (NHGRI) grant U54HG003067 (E. S. L.), NIH/NIMH grant R01 MH095088 (S.J.H.), NIH/NIMH grant R01 MH091115 (S.J.H.), the Tau Consortium (S.J.H.), NIH/NIMH grant R01 MH099126 (S. M. P.), NIH/NHGRI grant R01 HG005827 (S. M. P.), NIH/NIMH grant R01 MH077139 (P. F. S.), NIH/NIMH grant R01 MH095034 (P. S.), NIH/NIMH grant T32 MH017119 (L. D.), the Friedman Brain Institute at Mount Sinai School of Medicine, the Karolinska Institutet, Karolinska University Hospital, the Swedish Research Council, an ALF grant from Swedish County Council, the Soderstrom Konigska Foundation, the Netherlands Scientific Organization (NWO 645-000-003), the Wellcome Trust, Genes to Cognition Program, The Medical Research Council and European Union projects GENCODYS no. 241995, EUROSPIN no. 242498 and SYNSYS no. 242167 (E. F., M.O.C., N.H.K., J.S.C., S.G.N.G.). Work at the Icahn School of Medicine at Mount Sinai was also supported by the Institute for Genomics and Multiscale Biology (including computational resources and staff expertise provided by the Department of Scientific Computing). The funders had no role in study design, execution, analysis or manuscript preparation. NR 49 TC 352 Z9 355 U1 17 U2 89 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 FEB 13 PY 2014 VL 506 IS 7487 BP 185 EP + DI 10.1038/nature12975 PG 17 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AA5AK UT WOS:000331107700030 PM 24463508 ER PT J AU Venditti, EM Wylie-Rosett, J Delahanty, LM Mele, L Hoskin, MA Edelstein, SL AF Venditti, Elizabeth M. Wylie-Rosett, Judith Delahanty, Linda M. Mele, Lisa Hoskin, Mary A. Edelstein, Sharon L. CA Diabetes Prevention Program Res Gr TI Short and long-term lifestyle coaching approaches used to address diverse participant barriers to weight loss and physical activity adherence SO INTERNATIONAL JOURNAL OF BEHAVIORAL NUTRITION AND PHYSICAL ACTIVITY LA English DT Article DE Lifestyle intervention; Diabetes prevention; Barriers; Behavioral approaches; Problem-solving; Toolbox strategies ID DIABETES-PREVENTION-PROGRAM; OF-THE-LITERATURE; RANDOMIZED CONTROLLED-TRIAL; COMMUNITY-BASED TRANSLATION; SELF-MANAGEMENT; PSYCHOLOGICAL PREDICTORS; CARDIOVASCULAR-DISEASE; INTERVENTION PROGRAM; PRIMARY-CARE; OBESITY AB Background: Individual barriers to weight loss and physical activity goals in the Diabetes Prevention Program, a randomized trial with 3.2 years average treatment duration, have not been previously reported. Evaluating barriers and the lifestyle coaching approaches used to improve adherence in a large, diverse participant cohort can inform dissemination efforts. Methods: Lifestyle coaches documented barriers and approaches after each session (mean session attendance = 50.3 +/- 21.8). Subjects were 1076 intensive lifestyle participants (mean age = 50.6 years; mean BMI = 33.9 kg/m(2); 68% female, 48% non-Caucasian). Barriers and approaches used to improve adherence were ranked by the percentage of the cohort for whom they applied. Barrier groupings were also analyzed in relation to baseline demographic characteristics. Results: Top weight loss barriers reported were problems with self-monitoring (58%); social cues (58%); holidays (54%); low activity (48%); and internal cues (thought/mood) (44%). Top activity barriers were holidays (51%); time management (50%); internal cues (30%); illness (29%), and motivation (26%). The percentage of the cohort having any type of barrier increased over the long-term intervention period. A majority of the weight loss barriers were significantly associated with younger age, greater obesity, and non-Caucasian race/ethnicity (p-values vary). Physical activity barriers, particularly thought and mood cues, social cues and time management, physical injury or illness and access/weather, were most significantly associated with being female and obese (p < 0.001 for all). Lifestyle coaches used problem-solving with most participants (>= 75% short-term; > 90% long term) and regularly reviewed self-monitoring skills. More costly approaches were used infrequently during the first 16 sessions (<= 10%) but increased over 3.2 years. Conclusion: Behavioral problem solving approaches have short and long term dissemination potential for many kinds of participant barriers. Given minimal resources, increased attention to training lifestyle coaches in the consistent use of these approaches appears warranted. C1 [Venditti, Elizabeth M.] Univ Pittsburgh, Sch Med, Western Psychiat Inst & Clin, Pittsburgh, PA 15213 USA. [Wylie-Rosett, Judith] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10461 USA. [Delahanty, Linda M.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Diabet Res Ctr, Boston, MA 02114 USA. [Venditti, Elizabeth M.; Mele, Lisa; Edelstein, Sharon L.] George Washington Univ, Ctr Biostat, Rockville, MD 20852 USA. [Hoskin, Mary A.] ACKCO Inc, Southwestern Amer Indian Ctr, Phoenix, AZ 85016 USA. RP Venditti, EM (reprint author), Univ Pittsburgh, Sch Med, Western Psychiat Inst & Clin, 3811 OHara St, Pittsburgh, PA 15213 USA. EM dppmail@bsc.gwu.edu RI Uwaifo, Gabriel/M-2361-2016; OI Uwaifo, Gabriel/0000-0002-6962-9304; Franks, Paul/0000-0002-0520-7604 FU National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health; NIDDK; Indian Health Service; Office of Research on Minority Health; National Institute of Child Health and Human Development; National Institute on Aging; Centers for Disease Control and Prevention; Office of Research on Women's Health; American Diabetes Association; LifeScan Inc.; Health O Meter; Hoechst Marion Roussel, Inc.; Merck-Medco Managed Care, Inc.; Merck and Co.; Nike Sports Marketing; Slim Fast Foods Co. FX The Investigators gratefully acknowledge the commitment and dedication of the participants of the DPP. The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health provided funding to the clinical centers and the Coordinating Center for the design and conduct of the study; and collection, management, analysis, and interpretation of the data (U01 DK048489). The Southwestern American Indian Centers were supported directly by the NIDDK and the Indian Health Service. The General Clinical Research Center Program, National Center for Research Resources supported data collection at many of the clinical centers. Funding for data collection and participant support was also provided by the Office of Research on Minority Health, the National Institute of Child Health and Human Development, the National Institute on Aging, the Centers for Disease Control and Prevention, the Office of Research on Women's Health, and the American Diabetes Association. Bristol-Myers Squibb and Parke-Davis provided medication. This research was also supported, in part, by the intramural research program of the NIDDK. LifeScan Inc., Health O Meter, Hoechst Marion Roussel, Inc., Merck-Medco Managed Care, Inc., Merck and Co., Nike Sports Marketing, Slim Fast Foods Co., and Quaker Oats Co. donated materials, equipment, or medicines for concomitant conditions. McKesson BioServices Corp., Matthews Media Group, Inc., and the Henry M. Jackson Foundation provided support services under subcontract with the Coordinating Center. The opinions expressed are those of the investigators and do not necessarily reflect the views of the Indian Health Service or other funding agencies. A complete list of Centers, investigators, and staff can be found in the Additional file 1: Appendix. NR 65 TC 9 Z9 10 U1 5 U2 35 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1479-5868 J9 INT J BEHAV NUTR PHY JI Int. J. Behav. Nutr. Phys. Act. PD FEB 12 PY 2014 VL 11 AR 16 DI 10.1186/1479-5868-11-16 PG 12 WC Nutrition & Dietetics; Physiology SC Nutrition & Dietetics; Physiology GA AD0OI UT WOS:000332933400001 PM 24521153 ER PT J AU Rashighi, M Agarwal, P Richmond, JM Harris, TH Dresser, K Su, MW Zhou, YW Deng, A Hunter, CA Luster, AD Harris, JE AF Rashighi, Mehdi Agarwal, Priti Richmond, Jillian M. Harris, Tajie H. Dresser, Karen Su, Ming-Wan Zhou, Youwen Deng, April Hunter, Christopher A. Luster, Andrew D. Harris, John E. TI CXCL10 Is Critical for the Progression and Maintenance of Depigmentation in a Mouse Model of Vitiligo SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID CD8(+) T-CELLS; UNFOLDED PROTEIN RESPONSE; GENERALIZED VITILIGO; IMMUNE-RESPONSE; PROINFLAMMATORY CYTOKINES; AUTOIMMUNE VITILIGO; OXIDATIVE STRESS; CROHNS-DISEASE; CXCR3 LIGANDS; LYMPH-NODES AB Vitiligo is an autoimmune disease of the skin that results in disfiguring white spots. There are no U.S. Food and Drug Administration-approved treatments for vitiligo, and most off-label treatments yield unsatisfactory results. Vitiligo patients have increased numbers of autoreactive, melanocyte-specific CD8(+) T cells in the skin and blood, which are directly responsible for melanocyte destruction. We report that gene expression in lesional skin from vitiligo patients revealed an interferon-gamma (IFN-gamma)-specific signature, including the chemokine CXCL10. CXCL10 was elevated in both vitiligo patient skin and serum, and CXCR3, its receptor, was expressed on pathogenic T cells. To address the function of CXCL10 in vitiligo, we used a mouse model of disease that also exhibited an IFN-gamma-specific gene signature, expression of CXCL10 in the skin, and up-regulation of CXCR3 on antigen-specific T cells. Mice that received Cxcr3(-/-) T cells developed minimal depigmentation, as did mice lacking Cxcl10 or treated with CXCL10-neutralizing antibody. CXCL9 promoted autoreactive T cell global recruitment to the skin but not effector function, whereas CXCL10 was required for effector function and localization within the skin. Surprisingly, CXCL10 neutralization in mice with established, widespread depigmentation induces reversal of disease, evidenced by repigmentation. These data identify a critical role for CXCL10 in both the progression and maintenance of vitiligo and thereby support inhibiting CXCL10 as a targeted treatment strategy. C1 [Rashighi, Mehdi; Agarwal, Priti; Richmond, Jillian M.; Harris, John E.] Univ Massachusetts, Sch Med, Dept Med, Div Dermatol, Worcester, MA 01605 USA. [Harris, Tajie H.; Hunter, Christopher A.] Univ Penn, Sch Vet Med, Dept Pathobiol, Philadelphia, PA 19104 USA. [Dresser, Karen; Deng, April] Univ Massachusetts, Sch Med, Dept Pathol, Worcester, MA 01605 USA. [Su, Ming-Wan; Zhou, Youwen] Univ British Columbia, Dept Dermatol & Skin Sci, Vancouver, BC V5Z 4E8, Canada. [Luster, Andrew D.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Immunol & Inflammatory Dis,Div Rheumatol Alle, Boston, MA 02114 USA. RP Harris, JE (reprint author), Univ Massachusetts, Sch Med, Dept Med, Div Dermatol, Worcester, MA 01605 USA. EM john.harris@umassmed.edu OI Harris, Tajie/0000-0002-1355-2109 FU National Institute of Arthritis and Musculoskeletal and Skin Diseases part of the NIH [AR061437]; Charles H. Hood Foundation; Vitiligo Research Foundation; Dermatology Foundation; NIH [UL1TR000161, 5-P30-AR057217-03, P30 CA010815] FX Funding: Supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases, part of the NIH, under Award Number AR061437, and research grants from the Charles H. Hood Foundation, Vitiligo Research Foundation, and Dermatology Foundation (to J.E.H.). The University of Massachusetts Center for Clinical Research was responsible for blood and serum collection and is supported by NIH Clinical and Translational Sciences Award UL1TR000161. The University of Pennsylvania Skin Disease Research Center Core was responsible for identification and processing of human tissue samples for gene expression analysis and is supported by NIH grant 5-P30-AR057217-03. The Wistar Institute Genomics Core performed Illumina gene expression analyses and is supported by NIH grant P30 CA010815. Flow cytometry equipment used for this study is maintained by the UMMS and the University of Pennsylvania Flow Cytometry Core Facility. NR 62 TC 34 Z9 36 U1 3 U2 12 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 FEB 12 PY 2014 VL 6 IS 223 AR 223ra23 DI 10.1126/scitranslmed.3007811 PG 10 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA AB0IV UT WOS:000331476100006 PM 24523323 ER PT J AU Brashear, A Ozelius, LJ Sweadner, KJ AF Brashear, Allison Ozelius, Laurie J. Sweadner, Kathleen J. TI ATP1A3 mutations What is the phenotype? SO NEUROLOGY LA English DT Editorial Material ID ONSET DYSTONIA-PARKINSONISM; DE-NOVO MUTATIONS; ALTERNATING HEMIPLEGIA; CHILDHOOD; GENE AB Rapid-onset dystonia-parkinsonism (RDP) occurs in children over 18 months of age, teens, and adults, and alternating hemiplegia of childhood (AHC) occurs in children less than 18 months. They appear to be different diseases, but both are caused by mutations in ATP1A3.(1-4)ATP1A3 encodes the subunit of the Na+/K+-ATPase that is partially responsible for maintaining the electrical gradient in neurons. Motor symptoms, particularly dystonia, are obvious in both RDP and AHC, but RDP is predominantly fixed and AHC is known for its episodic and fluctuating course. There is now a broader phenotypic spectrum of RDP than originally described in 1993,(5,6) including psychosis,(7) new phenotypes in children,(8) and late onset.(9) The nonmotor phenotypes of both RDP (cognitive and psychiatric) and AHC (developmental delay, cognitive, and behavioral)(10,11) suggest that ATP1A3 mutations may play a role in other neurologic and psychiatric disorders. Mutations causing RDP or AHC cause symptoms such as dystonia, parkinsonism, epilepsy (including status epilepticus), hemiplegic episodes, abnormal ocular movements, developmental delay, psychosis, depression, anxiety, and gait disorders in ages ranging from newborns to age 87 years. It is likely that there will be a broad continuum of patients found, and even a role for the gene in polygenic disorders. C1 [Brashear, Allison] Wake Forest Baptist Hlth, Wake Forest Sch Med, Dept Neurol, Winston Salem, NC 27103 USA. [Ozelius, Laurie J.] Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY USA. [Sweadner, Kathleen J.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Brashear, A (reprint author), Wake Forest Baptist Hlth, Wake Forest Sch Med, Dept Neurol, Winston Salem, NC 27103 USA. EM abrashea@wakehealth.edu RI Brashear, Allison/G-3853-2015 FU NINDS NIH HHS [R01 NS058949] NR 12 TC 7 Z9 7 U1 0 U2 2 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 FEB 11 PY 2014 VL 82 IS 6 BP 468 EP 469 DI 10.1212/WNL.0000000000000113 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA AH9VW UT WOS:000336493900005 PM 24431297 ER PT J AU Woolley, JD Khan, BK Natesan, A Karydas, A Dallman, M Havel, P Miller, BL Rankin, KP AF Woolley, Josh D. Khan, Baber K. Natesan, Alamelu Karydas, Anna Dallman, Mary Havel, Peter Miller, Bruce L. Rankin, Katherine P. TI Satiety-related hormonal dysregulation in behavioral variant frontotemporal dementia SO NEUROLOGY LA English DT Article ID BINGE-EATING DISORDER; PLASMA GHRELIN; ALZHEIMERS-DISEASE; INSULIN-SECRETION; FOOD REWARD; BRAIN; LEPTIN; STRESS; HUMANS; WOMEN AB Objective:To investigate whether patients with behavioral variant frontotemporal dementia (bvFTD) have dysregulation in satiety-related hormonal signaling using a laboratory-based case-control study.Methods:Fifty-four participants (19 patients with bvFTD, 17 patients with Alzheimer disease dementia, and 18 healthy normal controls [NCs]) were recruited from a tertiary-care dementia clinic. During a standardized breakfast, blood was drawn before, during, and after the breakfast protocol to quantify levels of peripheral satiety-related hormones (ghrelin, cortisol, insulin, leptin, and peptide YY) and glucose. To further explore the role of patients' feeding abnormalities on hormone levels, patients were classified into overeating and nonovereating subgroups based on feeding behavior during separate laboratory-based standardized lunch feeding sessions.Results:Irrespective of their feeding behavior in the laboratory, patients with bvFTD, but not patients with Alzheimer disease dementia, have significantly lower levels of ghrelin and cortisol and higher levels of insulin compared with NCs. Furthermore, while laboratory feeding behavior did not predict alterations in levels of ghrelin, cortisol, and insulin, only patients with bvFTD who significantly overate in the laboratory demonstrated significantly higher levels of leptin compared with NCs, suggesting that leptin may be sensitive to particularly severe feeding abnormalities in bvFTD.Conclusions:Despite a tendency to overeat, patients with bvFTD have a hormonal profile that should decrease food intake. Aberrant hormone levels may represent a compensatory response to the behavioral or neuroanatomical abnormalities of bvFTD. C1 [Woolley, Josh D.] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94143 USA. [Dallman, Mary] Univ Calif San Francisco, Dept Physiol, San Francisco, CA USA. [Dallman, Mary] Univ Calif San Francisco, Dept Neurosci, San Francisco, CA USA. [Khan, Baber K.; Natesan, Alamelu; Karydas, Anna; Miller, Bruce L.; Rankin, Katherine P.] Univ Calif San Francisco, Dept Neurol, Memory & Aging Ctr, San Francisco, CA USA. [Woolley, Josh D.] San Francisco VA Med Ctr, Dept Psychiat, San Francisco, CA USA. [Havel, Peter] Univ Calif Davis, Sch Vet Med, Dept Mol Biosci, Davis, CA 95616 USA. [Havel, Peter] Univ Calif Davis, Sch Vet Med, Dept Nutr, Davis, CA 95616 USA. RP Woolley, JD (reprint author), Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94143 USA. EM josh.woolley@ucsf.edu FU National Institute on Aging (NIA) [5-P01 AG19724, P50 AG023501]; state of California, Alzheimer's Disease Research Center of California [03-7527]; NIH [R01AG038791, R01AG031278]; National Center for Research Resources; National Center for Advancing Translational Sciences, NIH, through UCSF-CTSI [UL1 RR024131] FX National Institute on Aging (NIA) grants 5-P01 AG19724 and P50 AG023501; state of California, Alzheimer's Disease Research Center of California grant 03-7527; NIH grants R01AG038791 and R01AG031278; 2004 UCSF REAC grant (Rankin). This publication was supported by the National Center for Research Resources and the National Center for Advancing Translational Sciences, NIH, through UCSF-CTSI grant UL1 RR024131. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. NR 39 TC 8 Z9 8 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 FEB 11 PY 2014 VL 82 IS 6 BP 512 EP 520 DI 10.1212/WNL.0000000000000106 PG 9 WC Clinical Neurology SC Neurosciences & Neurology GA AH9VW UT WOS:000336493900012 PM 24415571 ER PT J AU Hannah-Shmouni, F Matiello, M Russell, DS Hasbani, MJ AF Hannah-Shmouni, Fady Matiello, Marcelo Russell, David S. Hasbani, Mayer J. TI Teaching Video NeuroImages: Spasmodic dysphonia preceding idiopathic parkinsonism SO NEUROLOGY LA English DT Editorial Material AB An 83-year-old woman presented initially with a 20-year history of phonatory breaks (video e-1 on the Neurology (R) Web site at www.neurology.org), exacerbated by stress, and then recently a left hand rest tremor. After the onset of rest tremor, DaTscan SPECT of the brain, obtained in the Parkinson Progression Marker Initiative clinical research trial,(1) revealed near symmetrical loss of dopaminergic terminals in the striata (figure), supporting a diagnosis of idiopathic Parkinson disease (PD). Most patients with PD will demonstrate vocal difficulties during their disease course,(2) including some with spasmodic dysphonia (focal dystonia of the intrinsic laryngeal muscles arising from a dysfunction of the basal ganglia/extrapyramidal tract), which may precede PD by many years. C1 [Hannah-Shmouni, Fady] Yale New Haven Med Ctr, Dept Med, New Haven, CT 06504 USA. [Russell, David S.; Hasbani, Mayer J.] Yale Univ, Sch Med, New Haven, CT USA. [Russell, David S.] Inst Neurodegenerat Disorders, New Haven, CT USA. [Matiello, Marcelo] Harvard Univ, Brigham & Womens Hosp, Sch Med, Harvard Neurol Residency Program, Boston, MA 02115 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. RP Hannah-Shmouni, F (reprint author), Yale New Haven Med Ctr, Dept Med, New Haven, CT 06504 USA. EM fady.hannah-shmouni@yale.edu NR 2 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 FEB 11 PY 2014 VL 82 IS 6 BP E55 EP E55 DI 10.1212/WNL.0000000000000110 PG 1 WC Clinical Neurology SC Neurosciences & Neurology GA AH9VW UT WOS:000336493900003 PM 24514016 ER PT J AU Roman, AKS Jayewickreme, CD Murtaugh, LC Shivdasani, RA AF Roman, Adrianna K. San Jayewickreme, Chenura D. Murtaugh, L. Charles Shivdasani, Ramesh A. TI Wnt Secretion from Epithelial Cells and Subepithelial Myofibroblasts Is Not Required in the Mouse Intestinal Stem Cell Niche In Vivo SO STEM CELL REPORTS LA English DT Article ID FOCAL DERMAL HYPOPLASIA; PANETH CELLS; WNT/BETA-CATENIN; BETA-CATENIN; LGR5; DIFFERENTIATION; CANCER; PORCN; COLON; MICE AB Wnt signaling is a crucial aspect of the intestinal stem cell niche required for crypt cell proliferation and differentiation. Paneth cells or subepithelial myofibroblasts are leading candidate sources of the required Wnt ligands, but this has not been tested in vivo. To abolish Wnt-ligand secretion, we used Porcupine (Porcn) conditional-null mice crossed to strains expressing inducible Cre recombinase in the epithelium, including Paneth cells (Villin-Cre(ERT2)); in smooth muscle, including subepithelial myofibroblasts (Myh11-Cre(ERT2)); and simultaneously in both compartments. Elimination of Wnt secretion from any of these compartments did not disrupt tissue morphology, cell proliferation, differentiation, or Wnt pathway activity. Thus, Wnt-ligand secretion from these cell populations is dispensable for intestinal homeostasis, revealing that a minor cell type or significant and unexpected redundancy is responsible for physiologic Wnt signaling in vivo. C1 [Roman, Adrianna K. San; Jayewickreme, Chenura D.; Shivdasani, Ramesh A.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Roman, Adrianna K. San] Harvard Univ, Sch Med, Program Biol & Biomed Sci, Boston, MA 02215 USA. [Murtaugh, L. Charles] Univ Utah, Dept Human Genet, Salt Lake City, UT 84112 USA. [Shivdasani, Ramesh A.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Shivdasani, Ramesh A.] Harvard Univ, Sch Med, Boston, MA 02215 USA. RP Shivdasani, RA (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. EM ramesh_shivdasani@dfci.harvard.edu FU National Institute of Health [R01DK081113, R01DK082889]; National Science Foundation Graduate Research Fellowship FX We thank Sylvie Robine for VillinCre-ERT2 mice. This work was supported by National Institute of Health grants R01DK081113 and R01DK082889 to R.A.S. and a National Science Foundation Graduate Research Fellowship to A.K.S.R. NR 48 TC 3 Z9 3 U1 0 U2 9 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2213-6711 J9 STEM CELL REP JI Stem Cell Rep. PD FEB 11 PY 2014 VL 2 IS 2 BP 127 EP 134 DI 10.1016/j.stemcr.2013.12.012 PG 8 WC Cell & Tissue Engineering; Cell Biology SC Cell Biology GA AI1XD UT WOS:000336647600002 ER PT J AU Leyton-Mange, JS Mills, RW Macri, VS Jang, MY Butte, FN Ellinor, PT Milan, DJ AF Leyton-Mange, Jordan S. Mills, Robert W. Macri, Vincenzo S. Jang, Min Young Butte, Faraz N. Ellinor, Patrick T. Milan, David J. TI Rapid Cellular Phenotyping of Human Pluripotent Stem Cell-Derived Cardiomyocytes using a Genetically Encoded Fluorescent Voltage Sensor SO STEM CELL REPORTS LA English DT Article ID ACTION-POTENTIALS; GENE DELIVERY; DIFFERENTIATION; PROLONGATION; MECHANISM; CALCIUM; NEURONS AB In addition to their promise in regenerative medicine, pluripotent stem cells have proved to be faithful models of many human diseases. In particular, patient-specific stem cell-derived cardiomyocytes recapitulate key features of several life-threatening cardiac arrhythmia syndromes. For both modeling and regenerative approaches, phenotyping of stem cell-derived tissues is critical. Cellular phenotyping has largely relied upon expression of lineage markers rather than physiologic attributes. This is especially true for cardiomyocytes, in part because electrophysiological recordings are labor intensive. Likewise, most optical voltage indicators suffer from phototoxicity, which damages cells and degrades signal quality. Here we present the use of a genetically encoded fluorescent voltage indicator, ArcLight, which we demonstrate can faithfully report transmembrane potentials in human stem cell-derived cardiomyocytes. We demonstrate the application of this fluorescent sensor in high-throughput, serial phenotyping of differentiating cardiomyocyte populations and in screening for drug-induced cardiotoxicity. C1 [Leyton-Mange, Jordan S.; Mills, Robert W.; Macri, Vincenzo S.; Jang, Min Young; Butte, Faraz N.; Ellinor, Patrick T.; Milan, David J.] Massachusetts Gen Hosp East, Cardiovasc Res Ctr, Charlestown, MA 02129 USA. RP Milan, DJ (reprint author), Massachusetts Gen Hosp East, Cardiovasc Res Ctr, Charlestown, MA 02129 USA. EM dmilan@partners.org FU Corrigan Minehan Foundation; Harvard Stem Cell Institute; NIH [R01HL109004, R01HL092577, R01HL104156, 1K24HL105780, T32HL007208]; American Heart Association [13EIA14220013]; Heart Rhythm Society FX This work was supported by the Corrigan Minehan Foundation (D.J.M.), the Harvard Stem Cell Institute (D.J.M.), the NIH (grants R01HL109004 to D.J.M.; R01HL092577, R01HL104156, and 1K24HL105780 to P.T.E.; and T32HL007208 to J.L.M. and R.W.M.), the American Heart Association (grant 13EIA14220013 to P.T.E.), and the Heart Rhythm Society (V.S.M.). NR 25 TC 29 Z9 29 U1 1 U2 8 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2213-6711 J9 STEM CELL REP JI Stem Cell Rep. PD FEB 11 PY 2014 VL 2 IS 2 BP 163 EP 170 DI 10.1016/j.stemcr.2014.01.003 PG 8 WC Cell & Tissue Engineering; Cell Biology SC Cell Biology GA AI1XD UT WOS:000336647600006 PM 24527390 ER PT J AU Tsuang, D Esterberg, M Braff, D Calkins, M Cadenhead, K Dobie, D Freedman, R Green, MF Greenwood, T Gur, R Gur, R Horan, W Lazzeroni, LC Light, GA Millard, SP Olincy, A Nuechterlein, K Seidman, L Siever, L Silverman, J Stone, W Sprock, J Sugar, C Swerdlow, N Tsuang, M Turetsky, B Radant, A AF Tsuang, Debby Esterberg, Michelle Braff, David Calkins, Monica Cadenhead, Kristin Dobie, Dorcas Freedman, Robert Green, Michael F. Greenwood, Tiffany Gur, Raquel Gur, Ruben Horan, William Lazzeroni, Laura C. Light, Gregory A. Millard, Steven P. Olincy, Ann Nuechterlein, Keith Seidman, Larry Siever, Larry Silverman, Jeremy Stone, William Sprock, Joyce Sugar, Catherine Swerdlow, Neal Tsuang, Ming Turetsky, Bruce Radant, Allen TI Is There an Association between Advanced Paternal Age and Endophenotype Deficit Levels in Schizophrenia? SO PLOS ONE LA English DT Article ID PARENTAL AGE; NEUROCOGNITIVE ENDOPHENOTYPES; ANTISACCADE PERFORMANCE; RISK; CONSORTIUM; GENETICS; DISORDER; AUTISM; MULTISITE; RELATIVES AB The children of older fathers have increased risks of developing schizophrenia spectrum disorders, and among those who develop these disorders, those with older fathers present with more severe clinical symptoms. However, the influence of advanced paternal age on other important domains related to schizophrenia, such as quantitative endophenotype deficit levels, remains unknown. This study investigated the associations between paternal age and level of endophenotypic impairment in a well-characterized family-based sample from the Consortium on the Genetics of Schizophrenia (COGS). All families included at least one affected subject and one unaffected sibling. Subjects met criteria for schizophrenia (probands; n = 293) or were unaffected first-degree siblings of those probands (n = 382). Paternal age at the time of subjects' birth was documented. Subjects completed a comprehensive clinical assessment and a battery of tests that measured 16 endophenotypes. After controlling for covariates, potential paternal age-endophenotype associations were analyzed using one model that included probands alone and a second model that included both probands and unaffected siblings. Endophenotype deficits in the Identical Pairs version of the 4-digit Continuous Performance Test and in the Penn Computerized Neurocognitive Battery verbal memory test showed significant associations with paternal age. However, after correcting for multiple comparisons, no endophenotype was significantly associated with paternal age. These findings suggest that factors other than advanced paternal age at birth may account for endophenotypic deficit levels in schizophrenia. C1 [Tsuang, Debby] VA Puget Sound Hlth Care Syst, VISN Geriatr Res Educ & Clin Ctr 20, Seattle, WA 98108 USA. [Tsuang, Debby; Esterberg, Michelle; Dobie, Dorcas; Radant, Allen] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. [Braff, David; Light, Gregory A.] VA San Diego Healthcare Syst, VISN Mental Illness Res Educ & Clin Ctr 22, San Diego, CA USA. [Braff, David; Cadenhead, Kristin; Greenwood, Tiffany; Light, Gregory A.; Sprock, Joyce; Swerdlow, Neal; Tsuang, Ming] Univ Calif San Diego, Dept Psychiat, San Diego, CA 92103 USA. [Calkins, Monica; Gur, Raquel; Gur, Ruben; Turetsky, Bruce] Univ Penn, Dept Psychiat, Philadelphia, PA 19104 USA. [Dobie, Dorcas; Millard, Steven P.] VA Puget Sound Hlth Care Syst, VISN Mental Illness Res Educ & Clin Ctr 20, Seattle, WA USA. [Freedman, Robert; Olincy, Ann] Univ Colorado, Hlth Sci Ctr, Dept Psychiat, Denver, CO 80262 USA. [Green, Michael F.; Horan, William; Nuechterlein, Keith; Sugar, Catherine] Univ Calif Los Angeles, Dept Psychiat & Biobehav Sci, Geffen Sch Med, Los Angeles, CA 90024 USA. [Green, Michael F.; Horan, William; Sugar, Catherine] VA Greater Los Angeles Hlth Care Syst, Los Angeles, CA USA. [Lazzeroni, Laura C.] Stanford Univ, Dept Psychiat & Behav Sci, Palo Alto, CA 94304 USA. [Seidman, Larry; Stone, William] Harvard Univ, Beth Israel Deaconess Med Ctr, Massachusetts Mental Hlth Ctr Publ, Psychiat Div,Med Sch,Dept Psychiat, Boston, MA 02215 USA. [Siever, Larry; Silverman, Jeremy] Mt Sinai Sch Med, Dept Psychiat, New York, NY USA. [Siever, Larry; Silverman, Jeremy] James J Peters VA Med Ctr, VISN Mental Illness Res Educ & Clin Ctr 3, New York, NY USA. RP Tsuang, D (reprint author), VA Puget Sound Hlth Care Syst, VISN Geriatr Res Educ & Clin Ctr 20, Seattle, WA 98108 USA. EM dwt1@uw.edu RI Tsuang, Debby/L-7234-2016; OI Tsuang, Debby/0000-0002-4716-1894; Lazzeroni, Laura/0000-0002-1846-6920; Greenwood, Tiffany/0000-0002-6080-6503 FU Office of Research and Development Medical Research Service, Department of Veterans Affairs; NIMH [R01 MH65571, R01 MH042228, R01 MH65588, R01 MH65562, R01 MH65707, R01 MH65554, R01 MH65578, R01 MH086135, R01 MH65558] FX This material is based upon work supported (or supported in part) by the Office of Research and Development Medical Research Service, Department of Veterans Affairs. This study was supported by NIMH grants R01 MH65571, R01 MH042228, R01 MH65588, R01 MH65562, R01 MH65707, R01 MH65554, R01 MH65578, R01 MH086135, and R01 MH65558. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 46 TC 3 Z9 3 U1 0 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 FEB 11 PY 2014 VL 9 IS 2 AR e88379 DI 10.1371/journal.pone.0088379 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AA7DT UT WOS:000331258100037 PM 24523888 ER PT J AU Desai, NR Giugliano, RP Zhou, J Kohli, P Somaratne, R Hoffman, E Liu, T Scott, R Wasserman, SM Sabatine, MS AF Desai, Nihar R. Giugliano, Robert P. Zhou, Jing Kohli, Payal Somaratne, Ransi Hoffman, Elaine Liu, Thomas Scott, Robert Wasserman, Scott M. Sabatine, Marc S. TI AMG 145, a Monoclonal Antibody Against PCSK9, Facilitates Achievement of National Cholesterol Education Program-Adult Treatment Panel III Low-Density Lipoprotein Cholesterol Goals Among High-Risk Patients SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE cholesterol; LDL; PCSK9; statins ID SUBTILISIN/KEXIN TYPE 9; EFFICACY; SAFETY; THERAPY; STATIN AB Objectives This study sought to define the ability of AMG 145, a monoclonal antibody directed against proprotein convertase subtilisin kexin type 9 (PCSK9), to enable subjects at high risk for major adverse cardiovascular events to achieve National Cholesterol Education Program-Adult Treatment Panel III (NCEP-ATP III) parameters for low-density lipoprotein cholesterol (LDL-C) and other lipid goals. Background Many patients at high risk for adverse cardiovascular events are unable to achieve the NCEP-ATP III LDL-C goal of <70 mg/dl, even with high-potency statin therapy. Methods In 282 subjects from the LAPLACE-TIMI 57 (LDL-C Assessment with PCSK9 monoclonaL Antibody Inhibition Combined With Statin thErapy-Thrombolysis In Myocardial Infarction 57) trial at high risk according to NCEP-ATP III criteria, we compared the proportion of subjects achieving the NCEP-ATP III recommended LDL-C goal of <70 mg/dl across treatment arms. Other outcomes included the triple goals of LDL-C <70 mg/dl, non-high-density lipoprotein cholesterol (HDL-C) <100 mg/dl, and apolipoprotein B (ApoB) <80 mg/dl. Results During the dosing interval, more than 90% of subjects in both of the top dose groups every 2 weeks and every 4 weeks attained this lipid target over the dosing interval, with similar success rates for the triple lipid goal. Conclusions PCSK9 inhibition with AMG 145 enables high-risk patients to achieve established lipid goals. If this therapy demonstrates efficacy for reducing cardiovascular events with a favorable safety profile in ongoing phase 3 trials, we believe it will have major public health implications. (C) 2014 by the American College of Cardiology Foundation C1 [Desai, Nihar R.; Giugliano, Robert P.; Zhou, Jing; Hoffman, Elaine; Sabatine, Marc S.] Harvard Univ, Brigham & Womens Hosp, Sch Med, TIMI Study Grp,Div Cardiovasc Med, Boston, MA 02115 USA. [Kohli, Payal] Univ Calif San Francisco, Div Cardiovasc Med, San Francisco, CA 94143 USA. [Somaratne, Ransi; Liu, Thomas; Scott, Robert; Wasserman, Scott M.] Amgen Inc, Thousand Oaks, CA 91320 USA. RP Sabatine, MS (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med, TIMI Study Grp,Div Cardiovasc Med, 350 Longwood Ave, Boston, MA 02115 USA. EM msabatine@partners.org FU Amgen, Inc.; Brigham and Women's Hospital; Abbott Laboratories; Accumetrics; Amgen; AstraZeneca; AstraZeneca/Bristol-Myers Squibb Alliance; Bristol-Myers Squibb/Sanofi-Aventis joint venture; Critical Diagnostics; Daiichi Sankyo; Eisai; Genzyme; GlaxoSmithKline; Intarcia; Merck; Nanosphere; Roche Diagnostics; Sanofi-Aventis; Takeda FX From the *TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; yDivision of Cardiovascular Medicine, University of California at San Francisco, San Francisco, California; and zAmgen, Inc., Thousand Oaks, California. The LAPLACE-TIMI 57 trial was supported by a research grant from Amgen, Inc., to the TIMI Study Group, Brigham and Women's Hospital, Boston, Massachusetts. Dr. Giugliano has received research grant support through Brigham and Women's Hospital from Daiichi Sankyo and Merck; and honoraria for consulting from Amgen, Daiichi Sankyo, and Merck. Drs. Somaratne, Liu, Scott, and Wasserman are employees of Amgen and own Amgen stock. Dr. Sabatine has received research grant support through Brigham and Women's Hospital from Abbott Laboratories, Accumetrics, Amgen, AstraZeneca, AstraZeneca/Bristol-Myers Squibb Alliance, Bristol-Myers Squibb/Sanofi-Aventis joint venture, Critical Diagnostics, Daiichi Sankyo, Eisai, Genzyme, GlaxoSmithKline, Intarcia, Merck, Nanosphere, Roche Diagnostics, Sanofi-Aventis, and Takeda; and honoraria for consulting from Aegerion, Amgen, AstraZeneca/ Bristol-Myers Squibb Alliance, GlaxoSmithKline, Merck, Pfizer, Sanofi- Aventis, and Vertex. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. NR 6 TC 24 Z9 25 U1 1 U2 10 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 FEB 11 PY 2014 VL 63 IS 5 BP 430 EP 433 DI 10.1016/j.jacc.2013.09.048 PG 4 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 304BX UT WOS:000330721800005 PM 24161333 ER PT J AU Hill-Burns, EM Wissemann, WT Hamza, TH Factor, SA Zabetian, CP Payami, H AF Hill-Burns, Erin M. Wissemann, William T. Hamza, Taye H. Factor, Stewart A. Zabetian, Cyrus P. Payami, Haydeh TI Identification of a novel Parkinson's disease locus via stratified genome-wide association study SO BMC GENOMICS LA English DT Article DE GWAS; Parkinson's disease; SNCA; MAPT; HLA; Genetic heterogeneity; Secondary GWAS; Stratified GWAS; Chromosome 1p ID HUMAN PREFRONTAL CORTEX; GENE-EXPRESSION; HLA REGION; MUTATIONS; ZINC; VISUALIZATION; DIAGNOSIS; VARIANTS; RISK; IRON AB Background: Parkinson's disease (PD) is complex and heterogeneous. The numerous susceptibility loci that have been identified reaffirm the complexity of PD but do not fully explain it; e. g., it is not known if any given PD susceptibility gene is associated with all PD or a disease subtype. We also suspect that important disease genes may have escaped detection because of this heterogeneity. We used presence/ absence of family history to subdivide the cases and performed genome-wide association studies (GWAS) in Sporadic-PD and Familial-PD separately. The aim was to uncover new genes and gain insight into the genetic architecture of PD. Results: Employing GWAS on the NeuroGenetics Research Consortium (NGRC) dataset stratified by family history (1565 Sporadic-PD, 435 Familial-PD, 1986 controls), we identified a novel locus on chromosome 1p21 in Sporadic-PD (PNGRC= 4x10(-8)) and replicated the finding (PReplication = 6x10(-3); PPooled= 4x10(-10)) in 1528 Sporadic-PD and 796 controls from the National Institutes of Neurologic Disease and Stroke (NINDS) Repository. This is the fifth PD locus to be mapped to the short arm of chromosome 1. It is flanked by S1PR1 and OLFM3 genes, and is 200 kb from a multiple sclerosis susceptibility gene. The second aim of the study was to extend the stratified GWAS to the well-established PD genes. SNCA_ rs356220 was associated with both Sporadic-PD (OR = 1.37, P = 1x10(-9)) and Familial-PD (OR = 1.40, P = 2x10(-5)). HLA_ rs3129882 was more strongly associated with Sporadic-PD (OR = 1.38, P = 5x10(-10)) than Familial-PD (OR = 1.12, P = 0.15). In the MAPT region, virtually every single nucleotide polymorphism (SNP) had a stronger effect-size and lower P-value in Familial-PD (peak P = 8x10(-7)) than in Sporadic-PD (peak P = 2x10(-5)). Conclusions: We discovered and replicated a new locus for Sporadic-PD which had escaped detection in un-stratified GWAS. This demonstrates that by stratifying on a key variable the power gained due to diminished heterogeneity can sometimes outweigh the power lost to reduced sample size. We also detected distinct patterns of disease associations for previously established PD susceptibility genes, which gives an insight to the genetic architecture of the disease and could aid in the selection of appropriate study population for future studies. C1 [Hill-Burns, Erin M.; Wissemann, William T.; Hamza, Taye H.; Payami, Haydeh] New York State Dept Hlth, Wadsworth Ctr, Div Genet, Albany, NY USA. [Factor, Stewart A.] Emory Univ, Sch Med, Dept Neurol, Atlanta, GA 30322 USA. [Zabetian, Cyrus P.] Univ Washington, VA Puget Sound Hlth Care Syst, Seattle, WA 98195 USA. [Zabetian, Cyrus P.] Univ Washington, Dept Neurol, Seattle, WA 98195 USA. [Payami, Haydeh] SUNY Albany, Sch Publ Hlth, Dept Biomed Sci, Albany, NY USA. RP Payami, H (reprint author), New York State Dept Hlth, Wadsworth Ctr, Div Genet, Albany, NY USA. EM hpayami@wadsworth.org OI Zabetian, Cyrus/0000-0002-7739-4306 FU National Institute of Neurological Disorders And Stroke [R01NS36960]; Global Genetic Consortium Grant from the Michael J Fox Foundation for Parkinson's Disease Research; Department of Veterans Affairs [1I01BX000531]; National Institutes of Aging [P30AG08017]; Office of Research & Development, Clinical Sciences Research & Development Service, Department of Veteran Affairs; NIH at National Library of Medicine; Close to the Cure Foundation. Genotyping services; Center for Inherited Disease Research (CIDR),; National Institutes of Health to The Johns Hopkins University [HHSN268200782096C]; NINDS Human Genetics Resource Center DNA and Cell Line Repository FX We would like to acknowledge the persons with PD, their families and healthy volunteers who participated in this study. The project was supported by Award Number R01NS36960 from the National Institute of Neurological Disorders And Stroke. Additional support was provided by a Global Genetic Consortium Grant from the Michael J Fox Foundation for Parkinson's Disease Research, Merit Review Award from the Department of Veterans Affairs (1I01BX000531), National Institutes of Aging (P30AG08017), Office of Research & Development, Clinical Sciences Research & Development Service, Department of Veteran Affairs, The Intramural Research Program of the NIH at National Library of Medicine, and the Close to the Cure Foundation. Genotyping services were provided by the Center for Inherited Disease Research (CIDR), which is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, contract number HHSN268200782096C. This study used samples from the NINDS Human Genetics Resource Center DNA and Cell Line Repository (http:// ccr. coriell. org/ ninds), as well as clinical data. Funding for NINDS- Genome-Wide Genotyping in Parkinson's Disease which generated the GWAS used for replication was provided by NINDS, and the GWAS data were obtained from the NINDS database at (http:// www. ncbi. nlm. nih. gov/ gap) accession number phs000089. v3. p2. The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding agencies. NR 49 TC 18 Z9 19 U1 1 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 FEB 10 PY 2014 VL 15 AR 15:118 DI 10.1186/1471-2164-15-118 PG 9 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA AC5ZD UT WOS:000332598600003 PM 24511991 ER PT J AU Ba, D Temereanca, S Brown, EN AF Ba, Demba Temereanca, Simona Brown, Emery N. TI Algorithms for the analysis of ensemble neural spiking activity using simultaneous-event multivariate point-process models SO FRONTIERS IN COMPUTATIONAL NEUROSCIENCE LA English DT Article DE multivariate point-process; simultaneous events; multinomial GLM; thalamic synchrony ID TRAIN DATA-ANALYSIS; SYNCHRONY; IDENTIFICATION; SPIKES; CODE AB Understanding how ensembles of neurons represent and transmit information in the patterns of their joint spiking activity is a fundamental question in computational neuroscience. At present, analyses of spiking activity from neuronal ensembles are limited because multivariate point process (MPP) models cannot represent simultaneous occurrences of spike events at an arbitrarily small time resolution. Solo recently reported a simultaneous-event multivariate point process (SEMPP) model to correct this key limitation. In this paper, we show how Solo's discrete-time formulation of the SEMPP model can be efficiently fit to ensemble neural spiking activity using a multinomial generalized linear model (mGLM). Unlike existing approximate procedures for fitting the discrete-time SEMPP model, the mGLM is an exact algorithm. The MPP time-rescaling theorem can be used to assess model goodness-of-fit. We also derive a new marked point-process (MkPP) representation of the SEMPP model that leads to new thinning and time-rescaling algorithms for simulating an SEMPP stochastic process. These algorithms are much simpler than multivariate extensions of algorithms for simulating a univariate point process, and could not be arrived at without the MkPP representation. We illustrate the versatility of the SEMPP model by analyzing neural spiking activity from pairs of simultaneously-recorded rat thalamic neurons stimulated by periodic whisker deflections, and by simulating SEMPP data. In the data analysis example, the SEMPP model demonstrates that whisker motion significantly modulates simultaneous spiking activity at the 1 ms time scale and that the stimulus effect is more than one order of magnitude greater for simultaneous activity compared with non-simultaneous activity. Together, the mGLM, the MPP time-rescaling theorem and the MkPP representation of the SEMPP model offer a theoretically sound, practical tool for measuring joint spiking propensity in a neuronal ensemble. C1 [Ba, Demba; Brown, Emery N.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Charlestown, MA USA. [Ba, Demba; Brown, Emery N.] MIT, Dept Brain & Cognit Sci, Cambridge, MA 02139 USA. [Temereanca, Simona] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Brown, Emery N.] MIT, Inst Med Engn & Sci, Cambridge, MA 02139 USA. RP Ba, D (reprint author), MIT, Dept Brain & Cognit Sci, Neurosci Stat Res Lab, 43 Vassar St,Room 6057, Cambridge, MA 02139 USA. EM demba@mit.edu FU National Science Foundation [0836720]; National Institutes of Health [DA-015644, DP10D003646] FX Support was provided by National Science Foundation Grant 0836720 and National Institutes of Health Grants DA-015644 and DP10D003646 to E. N. Brown. NR 40 TC 4 Z9 4 U1 0 U2 2 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1662-5188 J9 FRONT COMPUT NEUROSC JI Front. Comput. Neurosci. PD FEB 10 PY 2014 VL 8 AR 6 DI 10.3389/fncom.2014.00006 PG 13 WC Mathematical & Computational Biology; Neurosciences SC Mathematical & Computational Biology; Neurosciences & Neurology GA AC4RZ UT WOS:000332509800001 PM 24575001 ER PT J AU Tozburun, S Siddiqui, M Vakoc, BJ AF Tozburun, Serhat Siddiqui, Meena Vakoc, Benjamin J. TI A rapid, dispersion-based wavelength-stepped and wavelength-swept laser for optical coherence tomography SO OPTICS EXPRESS LA English DT Article ID DOMAIN MODE-LOCKING; LOCKED FIBER LASER; MEGAHERTZ OCT; WIDE AB Optical-domain subsampling enables Fourier-domain OCT imaging at high-speeds and extended depth ranges while limiting the required acquisition bandwidth. To perform optical-domain subsampling, a wavelength-stepped rather than a wavelength-swept source is required. This preliminary study introduces a novel design for a rapid wavelength-stepped laser source that uses dispersive fibers in combination with a fast lithium-niobate modulator to achieve wavelength selection. A laser with 200 GHz wavelength-stepping and a sweep rate of 9 MHz over a 94 nm range at a center wavelength of 1550 nm is demonstrated. A reconfiguration of this source design to a continuous wavelength-swept light for conventional Fourier-domain OCT is also demonstrated. (C) 2014 Optical Society of America C1 [Tozburun, Serhat; Vakoc, Benjamin J.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Tozburun, Serhat; Vakoc, Benjamin J.] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. [Siddiqui, Meena; Vakoc, Benjamin J.] Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. RP Tozburun, S (reprint author), Harvard Univ, Sch Med, Boston, MA 02115 USA. EM tozburun.serhat@mgh.harvard.edu FU Center for Biomedical OCT Research and Translation [P41EB015903]; National Center for Research Resources; National Institute of Biomedical Imaging and Bioengineering of the National Institutes of Health; NIH [R01CA163528]; DOD [FA9550-11-1-0331]; NSF [11-031]; Martinos scholars program FX This project was supported by the Center for Biomedical OCT Research and Translation through Grant Number P41EB015903, awarded by the National Center for Research Resources and the National Institute of Biomedical Imaging and Bioengineering of the National Institutes of Health. This work was also supported by NIH grant R01CA163528 and DOD FA9550-11-1-0331. Meena Siddiqui was partially supported by an NSF fellowship 11-031 and a Martinos scholars program. NR 19 TC 8 Z9 8 U1 1 U2 21 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 FEB 10 PY 2014 VL 22 IS 3 BP 3414 EP 3424 DI 10.1364/OE.22.003414 PG 11 WC Optics SC Optics GA AC4VB UT WOS:000332518100124 PM 24663631 ER PT J AU Mamon, HJ Tepper, JE AF Mamon, Harvey J. Tepper, Joel E. TI Combination Chemoradiation Therapy: The Whole Is More Than the Sum of the Parts SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Editorial Material ID PHASE-III TRIAL; RANDOMIZED-TRIAL; BREAST-CANCER; CONCURRENT CHEMORADIATION; LOCAL RECURRENCE; TOTAL MASTECTOMY; RECTAL-CANCER; FOLLOW-UP; RADIOTHERAPY; CHEMORADIOTHERAPY C1 [Mamon, Harvey J.] Brigham & Womens Hosp, Dana Farber Canc Inst, Boston, MA 02115 USA. [Tepper, Joel E.] Univ N Carolina, Chapel Hill, NC USA. RP Mamon, HJ (reprint author), Brigham & Womens Hosp, Dana Farber Canc Inst, 75 Francis St, Boston, MA 02115 USA. NR 22 TC 8 Z9 8 U1 0 U2 4 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 10 PY 2014 VL 32 IS 5 BP 367 EP 369 DI 10.1200/JCO.2013.54.3108 PG 3 WC Oncology SC Oncology GA AA7AS UT WOS:000331250100003 PM 24419110 ER PT J AU Steensma, DP Kantarjian, HM AF Steensma, David P. Kantarjian, Hagop M. TI Impact of Cancer Research Bureaucracy on Innovation, Costs, and Patient Care SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Editorial Material ID COOPERATIVE-ONCOLOGY-GROUP; III CLINICAL-TRIALS C1 [Steensma, David P.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Kantarjian, Hagop M.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. RP Steensma, DP (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. OI Steensma, David/0000-0001-5130-9284 FU NCI NIH HHS [P30 CA016672] NR 25 TC 14 Z9 14 U1 0 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 FEB 10 PY 2014 VL 32 IS 5 BP 376 EP 378 DI 10.1200/JCO.2013.54.2548 PG 3 WC Oncology SC Oncology GA AA7AS UT WOS:000331250100006 PM 24395852 ER PT J AU Billmire, DF Cullen, JW Rescorla, FJ Davis, M Schlatter, MG Olson, TA Malogolowkin, MH Pashankar, F Villaluna, D Krailo, M Egler, RA Rodriguez-Galindo, C Frazier, AL AF Billmire, Deborah F. Cullen, John W. Rescorla, Frederick J. Davis, Mary Schlatter, Marc G. Olson, Thomas A. Malogolowkin, Marcio H. Pashankar, Farzana Villaluna, Doojduen Krailo, Mark Egler, Rachel A. Rodriguez-Galindo, Carlos Frazier, A. Lindsay TI Surveillance After Initial Surgery for Pediatric and Adolescent Girls With Stage I Ovarian Germ Cell Tumors: Report From the Children's Oncology Group SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID TESTICULAR CANCER; INTERGROUP; CHEMOTHERAPY; BLEOMYCIN; ETOPOSIDE; POLICY AB Purpose To determine whether overall survival (OS) can be preserved for patients with stage I pediatric malignant ovarian germ cell tumor (MOGCT) with an initial strategy of surveillance after surgical resection. Patients and Methods Between November 2003 and July 2011, girls age 0 to 16 years with stage I MOGCT were enrolled onto Children's Oncology Group study AGCT0132. Required histology included yolk sac, embryonal carcinoma, or choriocarcinoma. Surveillance included measurement of serum tumor markers and radiologic imaging at defined intervals. In those with residual or recurrent disease, chemotherapy with compressed PEB (cisplatin, etoposide, and bleomycin) was initiated every 3 weeks for three cycles (cisplatin 33 mg/m(2) on days 1 to 3, etoposide 167 mg/m(2) on days 1 to 3, bleomycin 15 U/m(2) on day 1). Survivor functions for event-free survival (EFS) and OS were estimated using the Kaplan-Meier method. Results Twenty-five girls (median age, 12 years) with stage I MOGCT were enrolled onto AGCT0132. Twenty-three patients had elevated alpha-fetoprotein (AFP) at diagnosis. Predominant histology was yolk sac. After a median follow-up of 42 months, 12 patients had evidence of persistent or recurrent disease (4-year EFS, 52%; 95% CI, 31% to 69%). Median time to recurrence was 2 months. All patients had elevated AFP at recurrence; six had localized disease, two had metastatic disease, and four had tumor marker elevation only. Eleven of 12 patients experiencing relapse received successful salvage chemotherapy (4-year OS, 96%; 95% CI, 74% to 99%). Conclusion Fifty percent of patients with stage I pediatric MOGCT can be spared chemotherapy; treatment for those who experience recurrence preserves OS. Further study is needed to identify the factors that predict recurrence and whether this strategy can be extended successfully to older adolescents and young adults. (C) 2014 by American Society of Clinical Oncology C1 [Billmire, Deborah F.; Rescorla, Frederick J.] Riley Hosp Children, Indianapolis, IN USA. [Cullen, John W.] Rocky Mt Hosp Children, Presbyterian St Lukes Med, Denver, CO USA. [Davis, Mary; Schlatter, Marc G.] Spectrum Hlth, Helen DeVos Childrens Hosp, Grand Rapids, MI USA. [Olson, Thomas A.] Emory Univ, Childrens Healthcare Atlanta, Atlanta, GA 30322 USA. [Malogolowkin, Marcio H.] Med Coll Wisconsin, Childrens Hosp Wisconsin, Milwaukee, WI 53226 USA. [Pashankar, Farzana] Yale Univ, New Haven, CT USA. [Villaluna, Doojduen] Childrens Oncol Grp, Monrovia, CA USA. [Krailo, Mark] Univ So Calif, Keck Sch Med, Los Angeles, CA 90033 USA. [Egler, Rachel A.] Rainbow Babies & Childrens Hosp, Cleveland, OH 44106 USA. [Rodriguez-Galindo, Carlos; Frazier, A. Lindsay] Dana Farber Canc Inst, Boston, MA 02115 USA. [Rodriguez-Galindo, Carlos; Frazier, A. Lindsay] Boston Childrens Hosp, Boston, MA USA. RP Billmire, DF (reprint author), Indiana Univ, Riley Hosp Children, 705 Riley Hosp Dr,Ste 2500, Indianapolis, IN 46202 USA. EM dbillmir@iupui.edu FU NCI NIH HHS [U10 CA098543] NR 20 TC 31 Z9 31 U1 0 U2 4 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 10 PY 2014 VL 32 IS 5 BP 465 EP 470 DI 10.1200/JCO.2013.51.1006 PG 6 WC Oncology SC Oncology GA AA7AS UT WOS:000331250100019 PM 24395845 ER PT J AU Munshi, NC Anderson, KC AF Munshi, Nikhil C. Anderson, Kenneth C. TI Minimal Residual Disease: What Are the Minimum Requirements? Reply SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Letter C1 [Munshi, Nikhil C.] VA Boston Healthcare Syst, Boston, MA 02130 USA. [Munshi, Nikhil C.; Anderson, Kenneth C.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Jerome Lipper Multiple Myeloma Ctr, Boston, MA 02115 USA. RP Munshi, NC (reprint author), VA Boston Healthcare Syst, Boston, MA 02130 USA. NR 1 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 FEB 10 PY 2014 VL 32 IS 5 BP 478 EP 478 DI 10.1200/JCO.2013.53.0998 PG 1 WC Oncology SC Oncology GA AA7AS UT WOS:000331250100023 PM 24419117 ER PT J AU Okada, Y Diogo, D Greenberg, JD Mouassess, F Achkar, WAL Fulton, RS Denny, JC Gupta, N Mirel, D Gabriel, S Li, G Kremer, JM Pappas, DA Carroll, RJ Eyler, AE Trynka, G Stahl, EA Cui, J Saxena, R Coenen, MJH Guchelaar, HJ Huizinga, TWJ Dieude, P Mariette, X Barton, A Canhao, H Fonseca, JE de Vries, N Tak, PP Moreland, LW Bridges, SL Miceli-Richard, C Choi, HK Kamatani, Y Galan, P Lathrop, M Raj, T De Jager, PL Raychaudhuri, S Worthington, J Padyukov, L Klareskog, L Siminovitch, KA Gregersen, PK Mardis, ER Arayssi, T Kazkaz, LA Plenge, RM AF Okada, Yukinori Diogo, Dorothee Greenberg, Jeffrey D. Mouassess, Faten Achkar, Walid A. L. Fulton, Robert S. Denny, Joshua C. Gupta, Namrata Mirel, Daniel Gabriel, Stacy Li, Gang Kremer, Joel M. Pappas, Dimitrios A. Carroll, Robert J. Eyler, Anne E. Trynka, Gosia Stahl, Eli A. Cui, Jing Saxena, Richa Coenen, Marieke J. H. Guchelaar, Henk-Jan Huizinga, Tom W. J. Dieude, Philippe Mariette, Xavier Barton, Anne Canhao, Helena Fonseca, Joao E. de Vries, Niek Tak, Paul P. Moreland, Larry W. Bridges, S. Louis, Jr. Miceli-Richard, Corinne Choi, Hyon K. Kamatani, Yoichiro Galan, Pilar Lathrop, Mark Raj, Towfique De Jager, Philip L. Raychaudhuri, Soumya Worthington, Jane Padyukov, Leonid Klareskog, Lars Siminovitch, Katherine A. Gregersen, Peter K. Mardis, Elaine R. Arayssi, Thurayya Kazkaz, Layla A. Plenge, Robert M. TI Integration of Sequence Data from a Consanguineous Family with Genetic Data from an Outbred Population Identifies PLB1 as a Candidate Rheumatoid Arthritis Risk Gene SO PLOS ONE LA English DT Article ID GENOME-WIDE ASSOCIATION; SYSTEMIC-LUPUS-ERYTHEMATOSUS; SUSCEPTIBILITY LOCI; AMERICAN-COLLEGE; COMMON VARIANTS; RARE; DISEASE; CRITERIA; TRAITS; DNA AB Integrating genetic data from families with highly penetrant forms of disease together with genetic data from outbred populations represents a promising strategy to uncover the complete frequency spectrum of risk alleles for complex traits such as rheumatoid arthritis (RA). Here, we demonstrate that rare, low-frequency and common alleles at one gene locus, phospholipase B1 (PLB1), might contribute to risk of RA in a 4-generation consanguineous pedigree (Middle Eastern ancestry) and also in unrelated individuals from the general population (European ancestry). Through identity-by-descent (IBD) mapping and whole-exome sequencing, we identified a non-synonymous c.2263G. C (p.G755R) mutation at the PLB1 gene on 2q23, which significantly co-segregated with RA in family members with a dominant mode of inheritance (P = 0.009). We further evaluated PLB1 variants and risk of RA using a GWAS meta-analysis of 8,875 RA cases and 29,367 controls of European ancestry. We identified significant contributions of two independent non-coding variants near PLB1 with risk of RA (rs116018341 [MAF = 0.042] and rs116541814 [MAF = 0.021], combined P = 3.26 x 10(-6)). Finally, we performed deep exon sequencing of PLB1 in 1,088 RA cases and 1,088 controls (European ancestry), and identified suggestive dispersion of rare protein-coding variant frequencies between cases and controls (P = 0.049 for C-alpha test and P = 0.055 for SKAT). Together, these data suggest that PLB1 is a candidate risk gene for RA. Future studies to characterize the full spectrum of genetic risk in the PLB1 genetic locus are warranted. C1 [Okada, Yukinori; Diogo, Dorothee; Li, Gang; Trynka, Gosia; Cui, Jing; Raychaudhuri, Soumya; Plenge, Robert M.] Harvard Univ, Brigham & Womens Hosp, Div Rheumatol Immunol & Allergy, Sch Med, Boston, MA 02115 USA. [Okada, Yukinori; Diogo, Dorothee; Trynka, Gosia; Raj, Towfique; De Jager, Philip L.; Raychaudhuri, Soumya; Plenge, Robert M.] Harvard Univ, Brigham & Womens Hosp, Div Genet, Sch Med, Boston, MA 02115 USA. [Okada, Yukinori; Diogo, Dorothee; Gupta, Namrata; Mirel, Daniel; Gabriel, Stacy; Trynka, Gosia; Raj, Towfique; De Jager, Philip L.; Raychaudhuri, Soumya; Plenge, Robert M.] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. [Okada, Yukinori] Tokyo Med & Dent Univ, Dept Human Genet & Dis Divers, Grad Sch Med & Dent Sci, Tokyo, Japan. [Okada, Yukinori; Kamatani, Yoichiro] RIKEN, Lab Stat Anal, Ctr Integrat Med Sci, Yokohama, Kanagawa, Japan. [Greenberg, Jeffrey D.] NYU, Hosp Joint Dis, New York, NY USA. [Mouassess, Faten; Achkar, Walid A. L.] Mol Biol & Biotechnol Dept, Div Human Genet, Damascus, Syria. [Fulton, Robert S.; Mardis, Elaine R.] Washington Univ, Sch Med, Genome Inst, St Louis, MO USA. [Denny, Joshua C.; Carroll, Robert J.] Vanderbilt Univ, Sch Med, Dept Biomed Informat, Nashville, TN 37212 USA. [Kremer, Joel M.] Albany Med Ctr, Dept Med, Albany, NY USA. [Kremer, Joel M.] Ctr Rheumatol, Albany, NY USA. [Pappas, Dimitrios A.] Columbia Univ, Coll Phys & Surg, Dept Med, Div Rheumatol,Presbyterian Hosp, New York, NY USA. [Eyler, Anne E.] Vanderbilt Univ, Sch Med, Dept Med, Nashville, TN 37212 USA. [Stahl, Eli A.] Mt Sinai Sch Med, Dept Psychiat, New York, NY USA. [Saxena, Richa] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Human Genet Res, Boston, MA USA. [Coenen, Marieke J. H.] Radboud Univ Nijmegen Med Ctr, Dept Human Genet, Nijmegen, Netherlands. [Guchelaar, Henk-Jan] Leiden Univ, Dept Clin Pharm & Toxicol, Med Ctr, Leiden, Netherlands. [Huizinga, Tom W. J.] Leiden Univ, Dept Rheumatol, Med Ctr, Leiden, Netherlands. [Dieude, Philippe] Hop Bichat Claude Bernard, AP HP, Serv Rhumatol, F-75877 Paris 18, France. [Dieude, Philippe] Hop Bichat Claude Bernard, AP HP, INSERM, U699, F-75877 Paris 18, France. [Dieude, Philippe] Univ Paris 07, Paris, France. [Mariette, Xavier; Miceli-Richard, Corinne] Univ Paris 11, Hop Univ Paris Sud, AP HP, INSERM,U1012, Le Kremlin Bicetre, France. [Barton, Anne; Worthington, Jane] Univ Manchester, Manchester Acad Hlth Sci Ctr, Ctr Musculoskeletal Res, Arthrit Res UK Epidemiol Unit, Manchester, Lancs, England. [Canhao, Helena; Fonseca, Joao E.] Univ Lisbon, Rheumatol Res Unit, Inst Med Mol, Fac Med, P-1699 Lisbon, Portugal. [Canhao, Helena; Fonseca, Joao E.] Santa Maria Hosp CHLN, Dept Rheumatol, Lisbon, Portugal. [de Vries, Niek; Tak, Paul P.] Univ Amsterdam, Acad Med Ctr, Dept Clin Immunol & Rheumatol, NL-1105 AZ Amsterdam, Netherlands. [de Vries, Niek] Univ Amsterdam, Acad Med Ctr, Dept Genome Anal, NL-1105 AZ Amsterdam, Netherlands. [Tak, Paul P.] GlaxoSmithKline, Stevenage, Herts, England. [Moreland, Larry W.] Univ Pittsburgh, Div Rheumatol & Clin Immunol, Pittsburgh, PA USA. [Bridges, S. Louis, Jr.] Univ Alabama Birmingham, Dept Med, Div Clin Immunol & Rheumatol, Birmingham, AL 35294 USA. [Choi, Hyon K.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Channing Lab,Dept Med, Boston, MA 02115 USA. [Choi, Hyon K.] Boston Univ, Sch Med, Rheumatol Sect, Boston, MA 02118 USA. [Choi, Hyon K.] Boston Univ, Sch Med, Clin Epidemiol Res & Training Unit, Boston, MA 02118 USA. [Kamatani, Yoichiro] CEPH, Paris, France. [Galan, Pilar] Univ Paris 13, Sorbonne Paris Cite, UREN, Inserm,Inra,Cnam,U557,U1125, Bobigny, France. [Lathrop, Mark] McGill Univ, Montreal, PQ, Canada. [Lathrop, Mark] Genome Quebec Innovat Ctr, Montreal, PQ, Canada. [Raj, Towfique; De Jager, Philip L.] Brigham & Womens Hosp, Program Translat NeuroPsychiat Genom, Inst Neurosci, Dept Neurol, Boston, MA 02115 USA. [Raychaudhuri, Soumya] Manchester Acad Hlth Sci Ctr, NIHR Manchester Musculoskeletal Biomed, Res Unit, Cent Manchester NHS Fdn Trust, Manchester, Lancs, England. [Worthington, Jane] Manchester Acad Hlth Sci Ctr, Natl Inst Hlth Res, Manchester Musculoskeletal Biomed Res Unit, Cent Manchester Univ Hosp Natl Hlth Serv Fdn Trus, Manchester, Lancs, England. [Padyukov, Leonid; Klareskog, Lars] Karolinska Inst, Rheumatol Unit, Dept Med Solna, Stockholm, Sweden. [Siminovitch, Katherine A.] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON M5G 1X5, Canada. [Siminovitch, Katherine A.] Toronto Gen Res Inst, Toronto, ON, Canada. [Siminovitch, Katherine A.] Univ Toronto, Dept Med, Toronto, ON, Canada. [Gregersen, Peter K.] North Shore Long Isl Jewish Hlth Syst, Feinstein Inst Med Res, Manhasset, NY USA. [Arayssi, Thurayya] Weill Cornell Med Coll Qatar, Doha, Qatar. [Kazkaz, Layla A.] Tishreen Hosp, Damascus, Syria. [Kazkaz, Layla A.] Syrian Assoc Rheumatol, Damascus, Syria. RP Plenge, RM (reprint author), Harvard Univ, Brigham & Womens Hosp, Div Rheumatol Immunol & Allergy, Sch Med, Boston, MA 02115 USA. EM robert.plenge@merck.com RI Siminovitch, Katherine/K-1475-2013; Worthington, Jane/M-9770-2014; Coenen, Marieke/A-2159-2010; Kamatani, Yoichiro/N-5513-2015; OI Padyukov, Leonid/0000-0003-2950-5670; Worthington, Jane/0000-0003-0544-042X; Arayssi, Thurayya/0000-0003-2469-0272; Klareskog, Lars/0000-0001-9601-6186; Canhao, Helena/0000-0003-1894-4870; Dieude, Philippe/0000-0002-4814-0307 FU National Institutes of Health (NIH) [R01-AR057108, R01-AR056768, U01-GM092691, R01-AR059648]; Burroughs Wellcome Fund; Japan Society of the Promotion of Science (JSPS); Japan Science and Technology Agency (JST); Netherlands Organization for Scientific Research (NOW); NIH (NIAMS) [R01-AR056291, R01-AR065944, P60 AR047785, R21 AR056042]; NIH [R01AR063759-01A1, K08-KAR055688A]; European Research Council (ERC); Canada Research Chair; Sherman Family Chair in Genomic Medicine; Ontario Research Fund [RE01-061]; Canadian Institutes of Health Research [MOP79321]; Qatar National Research Fund (QNRF) [4-344-3-105] FX R.M.P. is supported by National Institutes of Health (NIH) grants R01-AR057108, R01-AR056768, U01-GM092691, and R01-AR059648 and holds a Career Award for Medical Scientists from the Burroughs Wellcome Fund. Y.O. is supported by grants from the Japan Society of the Promotion of Science (JSPS) and the Japan Science and Technology Agency (JST). G.T. is supported by the Rubicon grant from the Netherlands Organization for Scientific Research (NOW). H. K. C. is supported by NIH (NIAMS) grants R01-AR056291, R01-AR065944, P60 AR047785, and R21 AR056042. S. R. is supported by NIH grants R01AR063759-01A1 and K08-KAR055688A. L.P. and L.K. are supported by a senior investigator grant from the European Research Council (ERC). K.A.S is supported by a Canada Research Chair, the Sherman Family Chair in Genomic Medicine and by grants from the Ontario Research Fund (RE01-061) and the Canadian Institutes of Health Research (MOP79321). This research was generously supported by the Qatar National Research Fund (QNRF), NPRP # 4-344-3-105. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 63 TC 6 Z9 8 U1 3 U2 13 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD FEB 10 PY 2014 VL 9 IS 2 AR e87645 DI 10.1371/journal.pone.0087645 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AA7CL UT WOS:000331254600026 PM 24520335 ER PT J AU Pava, MJ den Hartog, CR Blanco-Centurion, C Shiromani, PJ Woodward, JJ AF Pava, Matthew J. den Hartog, Carolina R. Blanco-Centurion, Carlos Shiromani, Priyattam J. Woodward, John J. TI Endocannabinoid Modulation of Cortical Up-States and NREM Sleep SO PLOS ONE LA English DT Article ID CB1 CANNABINOID RECEPTOR; VENTRAL TEGMENTAL AREA; LONG-TERM DEPRESSION; PREFRONTAL CORTEX; PYRAMIDAL NEURONS; ENDOGENOUS CANNABINOIDS; IN-VIVO; NEOCORTICAL INTERNEURONS; GLUTAMATERGIC NEURONS; VANILLOID RECEPTORS AB Up-/down-state transitions are a form of network activity observed when sensory input into the cortex is diminished such as during non-REM sleep. Up-states emerge from coordinated signaling between glutamatergic and GABAergic synapses and are modulated by systems that affect the balance between inhibition and excitation. We hypothesized that the endocannabinoid (EC) system, a neuromodulatory system intrinsic to the cortical microcircuitry, is an important regulator of up-states and sleep. To test this hypothesis, up-states were recorded from layer V/VI pyramidal neurons in organotypic cultures of wild-type or CB1R knockout (KO) mouse prefrontal cortex. Activation of the cannabinoid 1 receptor (CB1) with exogenous agonists or by blocking metabolism of endocannabinoids, anandamide or 2-arachidonoyl glycerol, increased up-state amplitude and facilitated action potential discharge during up-states. The CB1 agonist also produced a layer II/IIIselective reduction in synaptic GABAergic signaling that may underlie its effects on up-state amplitude and spiking. Application of CB1 antagonists revealed that an endogenous EC tone regulates up-state duration. Paradoxically, the duration of up-states in CB1 KO cultures was increased suggesting that chronic absence of EC signaling alters cortical activity. Consistent with increased cortical excitability, CB1 KO mice exhibited increased wakefulness as a result of reduced NREM sleep and NREM bout duration. Under baseline conditions, NREM delta (0.5-4 Hz) power was not different in CB1 KO mice, but during recovery from forced sleep deprivation, KO mice had reduced NREM delta power and increased sleep fragmentation. Overall, these findings demonstrate that the EC system actively regulates cortical up-states and important features of NREM sleep such as its duration and low frequency cortical oscillations. C1 [Pava, Matthew J.; den Hartog, Carolina R.; Woodward, John J.] Med Univ S Carolina, Dept Neurosci, Charleston, SC 29425 USA. [Pava, Matthew J.; den Hartog, Carolina R.; Woodward, John J.] Med Univ S Carolina, Ctr Drug & Alcohol Programs, Charleston, SC 29425 USA. [Blanco-Centurion, Carlos; Shiromani, Priyattam J.; Woodward, John J.] Med Univ S Carolina, Dept Psychiat & Behav Sci, Charleston, SC 29425 USA. [Blanco-Centurion, Carlos; Shiromani, Priyattam J.] Ralph H Johnson VA Med Ctr, Charleston, SC USA. RP Woodward, JJ (reprint author), Med Univ S Carolina, Dept Neurosci, Charleston, SC 29425 USA. EM woodward@musc.edu OI Pava, Matthew/0000-0002-9867-4577 FU National Institutes of Health [P50 AA010761, F31 AA018908, MH055772, NS052287, NS079940]; Medical Research Service of the Department of Veterans Affairs FX This work was supported by National Institutes of Health grants P50 AA010761 (RC3; Charleston Alcohol Research Center; JJW), F31 AA018908 (MJP), MH055772 (PJM), NS052287 (PJM), NS079940 (PJM), and Medical Research Service of the Department of Veterans Affairs (PJM). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 70 TC 6 Z9 6 U1 1 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 FEB 10 PY 2014 VL 9 IS 2 AR e88672 DI 10.1371/journal.pone.0088672 PG 17 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AA7CL UT WOS:000331254600102 PM 24520411 ER PT J AU Puissant, A Fenouille, N Alexe, G Pikman, Y Bassi, CF Mehta, S Du, JY Kazi, JU Luciano, F Ronnstrand, L Kung, AL Aster, JC Galinsky, I Stone, RM DeAngelo, DJ Hemann, MT Stegmaier, K AF Puissant, Alexandre Fenouille, Nina Alexe, Gabriela Pikman, Yana Bassi, Christopher F. Mehta, Swapnil Du, Jinyan Kazi, Julhash U. Luciano, Frederic Ronnstrand, Lars Kung, Andrew L. Aster, Jon C. Galinsky, Ilene Stone, Richard M. DeAngelo, Daniel J. Hemann, Michael T. Stegmaier, Kimberly TI SYK Is a Critical Regulator of FLT3 in Acute Myeloid Leukemia SO CANCER CELL LA English DT Article ID RISK MYELODYSPLASTIC SYNDROME; CHRONIC LYMPHOCYTIC-LEUKEMIA; MLL-REARRANGED LEUKEMIA; TYROSINE KINASE 3; IN-VIVO; MYELOGENOUS LEUKEMIA; THERAPEUTIC TARGET; MOUSE MODELS; BCR-ABL; INHIBITOR AB Cooperative dependencies between mutant oncoproteins and wild-type proteins are critical in cancer pathogenesis and therapy resistance. Although spleen tyrosine kinase (SYK) has been implicated in hematologic malignancies, it is rarely mutated. We used kinase activity profiling to identify collaborators of SYK in acute myeloid leukemia (AML) and determined that FMS-like tyrosine kinase 3 (FLT3) is transactivated by SYK via direct binding. Highly activated SYK is predominantly found in FLT3-ITD positive AML and cooperates with FLT3-ITD to activate MYC transcriptional programs. FLT3-ITD AML cells are more vulnerable to SYK suppression than FLT3 wild-type counterparts. In a FLT3-ITD in vivo model, SYK is indispensable for myeloproliferative disease (MPD) development, and SYK overexpression promotes overt transformation to AML and resistance to FLT3-ITD-targeted therapy. C1 [Puissant, Alexandre; Alexe, Gabriela; Pikman, Yana; Bassi, Christopher F.; Mehta, Swapnil; Stegmaier, Kimberly] Harvard Univ, Sch Med, Dept Pediat Oncol, Dana Farber Canc Inst, Boston, MA 02215 USA. [Puissant, Alexandre; Alexe, Gabriela; Pikman, Yana; Bassi, Christopher F.; Mehta, Swapnil; Stegmaier, Kimberly] Harvard Univ, Sch Med, Boston Childrens Hosp, Boston, MA 02215 USA. [Fenouille, Nina; Hemann, Michael T.] MIT, Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA. [Alexe, Gabriela; Du, Jinyan; Stegmaier, Kimberly] Broad Inst Harvard Univ & Massachusetts Inst Tech, Cambridge, MA 02139 USA. [Alexe, Gabriela] Boston Univ, Bioinformat Grad Program, Boston, MA 02215 USA. [Kazi, Julhash U.; Ronnstrand, Lars] Lund Univ, Dept Lab Med, S-22100 Lund, Sweden. [Luciano, Frederic] C3M INSERM U1065 Team Cell Death Differentiat Inf, F-06204 Nice, France. [Kung, Andrew L.] Columbia Univ, Pediat Dept, Med Ctr, New York, NY 10032 USA. [Aster, Jon C.] Harvard Univ, Sch Med, Dept Pathol, Brigham & Womens Hosp, Boston, MA 02215 USA. [Galinsky, Ilene; Stone, Richard M.; DeAngelo, Daniel J.] Harvard Univ, Sch Med, Dept Med Oncol, Dana Farber Canc Inst, Boston, MA 02215 USA. RP Stegmaier, K (reprint author), Harvard Univ, Sch Med, Dept Pediat Oncol, Dana Farber Canc Inst, Boston, MA 02215 USA. EM kimberly_stegmaier@dfci.harvard.edu RI PUISSANT, ALEXANDRE/O-9575-2016; OI PUISSANT, ALEXANDRE/0000-0002-3997-9282; Kazi, Julhash/0000-0002-0719-5336; Kung, Andrew/0000-0002-9091-488X; Pikman, Yana/0000-0002-5336-0216 FU National Cancer Institute [R01 CA140292]; American Cancer Society; Starr Cancer Consortium; Project Cupid and One Mission; Swedish Research Council; Swedish Cancer Society FX We thank Merck for providing their small-molecule inhibitor of SYK. This research was supported by grants from the National Cancer Institute (R01 CA140292), the American Cancer Society, the Starr Cancer Consortium, Project Cupid and One Mission (to K.S.), and the Swedish Research Council and Swedish Cancer Society (to L.R. and J.U.K.). A.P. is a Leukemia and Lymphoma Society (LLS) Fellow, and K.S. is an LLS Scholar. NR 30 TC 38 Z9 39 U1 1 U2 16 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 FEB 10 PY 2014 VL 25 IS 2 BP 226 EP 242 DI 10.1016/j.ccr.2014.01.022 PG 17 WC Oncology; Cell Biology SC Oncology; Cell Biology GA AB0QU UT WOS:000331498000010 PM 24525236 ER PT J AU Tanaka, N Stufflebeam, SM AF Tanaka, Naoaki Stufflebeam, Steven M. TI Clinical application of spatiotemporal distributed source analysis in presurgical evaluation of epilepsy SO FRONTIERS IN HUMAN NEUROSCIENCE LA English DT Article DE magnetoencephalography; epilepsy; distributed source analysis; spike propagation; minimum norm estimate; epilepsy surgery ID SIGNAL-SPACE SEPARATION; TEMPORAL-LOBE EPILEPSY; SURFACE-BASED ANALYSIS; TO-NOISE-RATIOS; SOURCE LOCALIZATION; EPILEPTIFORM ACTIVITY; INTERICTAL DISCHARGES; SOURCE RECONSTRUCTION; CORTICAL ACTIVITY; MAGNETOENCEPHALOGRAPHY AB Magnetoencephalography (MEG), which acquires neuromagnetic fields in the brain, is a useful diagnostic tool in presurgical evaluation of epilepsy. Previous studies have shown that MEG affects the planning intracranial electroencephalography placement and correlates with surgical outcomes by using a single dipole model. Spatiotemporal source analysis using distributed source models is an advanced method for analyzing MEG, and has been recently introduced for analyzing epileptic spikes. It has advantages over the conventional single dipole analysis for obtaining accurate sources and understanding the propagation of epileptic spikes. In this article, we review the source analysis methods, describe the techniques of the distributed source analysis, interpretation of source distribution maps, and discuss the benefits and feasibility of this method in evaluation of epilepsy. C1 [Tanaka, Naoaki; Stufflebeam, Steven M.] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. RP Tanaka, N (reprint author), Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, 149 Thirteenth St,Suite 2301, Charlestown, MA 02129 USA. EM naoro@nmr.mgh.harvard.edu FU National Institutes of Health [S10RR014978, 1R01NS069696-01A1]; NIBIB [P41EB015896] FX This work was supported by National Institutes of Health (S10RR014978, 1R01NS069696-01A1) and NIBIB (P41EB015896). NR 69 TC 7 Z9 7 U1 0 U2 4 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1662-5161 J9 FRONT HUM NEUROSCI JI Front. Hum. Neurosci. PD FEB 10 PY 2014 VL 8 AR 62 DI 10.3389/fnhum.2014.00062 PG 8 WC Neurosciences; Psychology SC Neurosciences & Neurology; Psychology GA AB7BI UT WOS:000331943900001 PM 24574999 ER PT J AU Seliger, SL Fried, LF AF Seliger, Stephen L. Fried, Linda F. TI Serum Potassium in Dual Renin-Angiotensin-Aldosterone System Blockade SO CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Editorial Material ID DIABETIC-NEPHROPATHY; HEART-FAILURE; HYPERKALEMIA; RISK; OUTCOMES; TRIAL; TELMISARTAN; INHIBITION; ALISKIREN; LOSARTAN C1 [Seliger, Stephen L.] Vet Affairs Maryland Healthcare Syst, Baltimore, MD USA. [Seliger, Stephen L.] Univ Maryland, Sch Med, Baltimore, MD 21201 USA. [Fried, Linda F.] Vet Affairs Pittsburgh Healthcare Syst, Pittsburgh, PA 15240 USA. [Fried, Linda F.] Univ Pittsburgh, Sch Med, Pittsburgh, PA USA. RP Fried, LF (reprint author), Vet Affairs Pittsburgh Healthcare Syst, Univ Dr C,Mailstop 111F-U, Pittsburgh, PA 15240 USA. EM Linda.Fried@va.gov NR 23 TC 1 Z9 1 U1 0 U2 2 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1555-9041 EI 1555-905X J9 CLIN J AM SOC NEPHRO JI Clin. J. Am. Soc. Nephrol. PD FEB 7 PY 2014 VL 9 IS 2 BP 219 EP 221 DI 10.2215/CJN.12411213 PG 3 WC Urology & Nephrology SC Urology & Nephrology GA AI9FY UT WOS:000337238400001 PM 24408119 ER PT J AU Faubel, S AF Faubel, Sarah TI Renal Relevant Radiology: Introduction SO CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Editorial Material C1 [Faubel, Sarah] Univ Colorado, Div Internal Med, Denver, CO 80202 USA. [Faubel, Sarah] Denver Vet Affairs Med Ctr, Denver, CO USA. RP Faubel, S (reprint author), Univ Colorado Denver, Div Nephrol, 12700 East 19th Ave,Box C281, Aurora, CO 80045 USA. EM sarah.faubel@ucdenver.edu NR 5 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1555-9041 EI 1555-905X J9 CLIN J AM SOC NEPHRO JI Clin. J. Am. Soc. Nephrol. PD FEB 7 PY 2014 VL 9 IS 2 BP 371 EP 372 DI 10.2215/CJN.10211013 PG 2 WC Urology & Nephrology SC Urology & Nephrology GA AI9FY UT WOS:000337238400022 PM 24510108 ER PT J AU Faubel, S Patel, NU Lockhart, ME Cadnapaphornchai, MA AF Faubel, Sarah Patel, Nayana U. Lockhart, Mark E. Cadnapaphornchai, Melissa A. TI Renal Relevant Radiology: Use of Ultrasonography in Patients with AKI SO CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID ACUTE TUBULAR-NECROSIS; ACUTE KIDNEY INJURY; HEMOLYTIC-UREMIC SYNDROME; RESISTIVE INDEX; HEALTHY-CHILDREN; SONOGRAPHIC MEASUREMENTS; ADULT VOLUNTEERS; DUPLEX-DOPPLER; FOLLOW-UP; ULTRASOUND AB As judged by the American College of Radiology Appropriateness Criteria, renal Doppler ultrasonography is the most appropriate imaging test in the evaluation of AKI and has the highest level of recommendation. Unfortunately, nephrologists are rarely specifically trained in ultrasonography technique and interpretation, and important clinical information obtained from renal ultrasonography may not be appreciated. In this review, the strengths and limitations of grayscale ultrasonography in the evaluation of patients with AKI will be discussed with attention to its use for (1) assessment of intrinsic causes of AKI, (2) distinguishing acute from chronic kidney diseases, and (3) detection of obstruction. The use of Doppler imaging and the resistive index in patients with AKI will be reviewed with attention to its use for (1) predicting the development of AKI, (2) predicting the prognosis of AKI, and (3) distinguishing prerenal azotemia from intrinsic AKI. Finally, pediatric considerations in the use of ultrasonography in AKI will be reviewed. C1 [Faubel, Sarah] Univ Colorado, Div Internal Med, Denver, CO 80202 USA. [Faubel, Sarah] Denver Vet Affairs Med Ctr, Denver, CO USA. [Patel, Nayana U.] Univ Colorado Denver, Dept Radiol, Denver, CO USA. [Cadnapaphornchai, Melissa A.] Univ Colorado Denver, Dept Internal Med, Denver, CO USA. [Lockhart, Mark E.] Univ Alabama Birmingham, Dept Radiol, Birmingham, AL USA. RP Faubel, S (reprint author), Univ Colorado Denver, Denver Vet Adm Med Ctr, Div Nephrol, 12700 East 19th Ave,Box C281, Aurora, CO 80045 USA. EM sarah.faubel@ucdenver.edu NR 62 TC 9 Z9 10 U1 1 U2 1 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1555-9041 EI 1555-905X J9 CLIN J AM SOC NEPHRO JI Clin. J. Am. Soc. Nephrol. PD FEB 7 PY 2014 VL 9 IS 2 BP 382 EP 394 DI 10.2215/CJN.04840513 PG 13 WC Urology & Nephrology SC Urology & Nephrology GA AI9FY UT WOS:000337238400024 PM 24235286 ER PT J AU Ahn, BJ Le, H Shin, MW Bae, SJ Lee, EJ Wee, HJ Cha, JH Lee, HJ Lee, HS Kim, JH Kim, CY Seo, JH Lo, EH Jeon, S Lee, MN Oh, GT Yin, GN Ryu, JK Suh, JK Kim, KW AF Ahn, Bum Ju Le, Hoang Shin, Min Wook Bae, Sung-Jin Lee, Eun Ji Wee, Hee-Jun Cha, Jong-Ho Lee, Hyo-Jong Lee, Hye Shin Kim, Jeong Hun Kim, Chang-Yeon Seo, Ji Hae Lo, Eng H. Jeon, Sejin Lee, Mi-Ni Oh, Goo Taeg Yin, Guo Nan Ryu, Ji-Kan Suh, Jun-Kyu Kim, Kyu-Won TI Ninjurin1 Deficiency Attenuates Susceptibility of Experimental Autoimmune Encephalomyelitis in Mice SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article DE Autoimmune Diseases; Autoimmunity; Inflammation; Leukocyte; Multiple Sclerosis; EAE; Ninjurin1; Leukocyte Trafficking; Transendothelial Migration ID CENTRAL-NERVOUS-SYSTEM; TRANSENDOTHELIAL MIGRATION; LEUKOCYTE ADHESION; MYELOID CELLS; RESPONSES; DISEASE; TRANSMIGRATION; INFLAMMATION; DIAPEDESIS; CHEMOKINES AB Background: Effect of Ninjurin1 deletion in the experimental autoimmune encephalomyelitis (EAE) mice has not been examined. Results: Ninjurin1 knock-out (KO) mice are resistance to EAE due to a defect of leukocyte recruitment into lesion sites. Conclusion: Ninjurin1 is a potent target molecule for treating inflammatory diseases such as multiple sclerosis. Significance: Our study proved contribution of Ninjurin1 in EAE pathogenesis in vivo and supports the importance of its targeting strategies. Ninjurin1 is a homotypic adhesion molecule that contributes to leukocyte trafficking in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. However, in vivo gene deficiency animal studies have not yet been done. Here, we constructed Ninjurin1 knock-out (KO) mice and investigated the role of Ninjurin1 on leukocyte trafficking under inflammation conditions such as EAE and endotoxin-induced uveitis. Ninjurin1 KO mice attenuated EAE susceptibility by reducing leukocyte recruitment into the injury regions of the spinal cord and showed less adhesion of leukocytes on inflamed retinal vessels in endotoxin-induced uveitis mice. Moreover, the administration of a custom-made antibody (Ab(26-37)) targeting the Ninjurin1 binding domain ameliorated the EAE symptoms, showing the contribution of its adhesion activity to leukocyte trafficking. In addition, we addressed the transendothelial migration (TEM) activity of bone marrow-derived macrophages and Raw264.7 cells according to the expression level of Ninjurin1. TEM activity was decreased in Ninjurin1 KO bone marrow-derived macrophages and siNinj1 Raw264.7 cells. Consistent with this, GFP-tagged mNinj1-overexpressing Raw264.7 cells increased their TEM activity. Taken together, we have clarified the contribution of Ninjurin1 to leukocyte trafficking in vivo and delineated its direct functions to TEM, emphasizing Ninjurin1 as a beneficial therapeutic target against inflammatory diseases such as multiple sclerosis. C1 [Ahn, Bum Ju; Le, Hoang; Shin, Min Wook; Bae, Sung-Jin; Lee, Eun Ji; Wee, Hee-Jun; Cha, Jong-Ho; Seo, Ji Hae; Kim, Kyu-Won] Seoul Natl Univ, Coll Pharm, SNU Harvard NeuroVasc Protect Res Ctr, Seoul 151742, South Korea. [Ahn, Bum Ju; Le, Hoang; Shin, Min Wook; Bae, Sung-Jin; Lee, Eun Ji; Wee, Hee-Jun; Cha, Jong-Ho; Seo, Ji Hae; Kim, Kyu-Won] Seoul Natl Univ, Pharmaceut Sci Res Inst, Seoul 151742, South Korea. [Kim, Kyu-Won] Seoul Natl Univ, Dept Mol Med & Biopharmaceut Sci, Seoul 151742, South Korea. [Lee, Hyo-Jong] Inje Univ, Coll Pharm, Gimhae 621749, South Korea. [Lee, Hye Shin] Univ Texas MD Anderson Canc Ctr, Dept Canc Biol, Houston, TX 77030 USA. [Kim, Jeong Hun] Seoul Natl Univ Hosp, Clin Res Inst, Fight Angiogenesis Related Blindness Lab, Seoul 110744, South Korea. [Kim, Jeong Hun] Seoul Natl Univ, Coll Med, Dept Ophthalmol, Seoul 110744, South Korea. [Kim, Chang-Yeon] Yale Univ, Sch Med, New Haven, CT 06510 USA. [Seo, Ji Hae; Lo, Eng H.] Massachusettes Gen Hosp, Neuroprotect Res Lab, Dept Radiol, Boston, MA 02114 USA. [Seo, Ji Hae; Lo, Eng H.] Massachusettes Gen Hosp, Neuroprotect Res Lab, Dept Neurol, Boston, MA 02114 USA. [Seo, Ji Hae; Lo, Eng H.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Jeon, Sejin; Lee, Mi-Ni; Oh, Goo Taeg] Ewha Womans Univ, Dept Life Sci, Seoul 120750, South Korea. [Jeon, Sejin; Lee, Mi-Ni; Oh, Goo Taeg] Ewha Womans Univ, Program GT5, Seoul 120750, South Korea. [Yin, Guo Nan; Ryu, Ji-Kan; Suh, Jun-Kyu] Inha Univ, Sch Med, Natl Res Ctr Sexual Med, Inchon 402751, South Korea. [Yin, Guo Nan; Ryu, Ji-Kan; Suh, Jun-Kyu] Inha Univ, Sch Med, Dept Urol, Inchon 402751, South Korea. RP Kim, KW (reprint author), Seoul Natl Univ, Coll Pharm, SNU Harvard NeuroVasc Protect Res Ctr, Seoul 151742, South Korea. EM qwonkim@snu.ac.kr FU National Research Foundation of Korea; Ministry of Education, Science, and Technology through the Global Research Laboratory Program [2011-0021874]; Brain Korea 21 Program [2013-036038]; Global Core Research Center Program [2012-0001187]; National Institutes of Health [R37-NS37074, R01-76694, P01-NS55104]; Korea government (Ministry of Education, Science, and Technology) [2013003407]; Ministry for Health, Welfare, and Family Affairs [A110076] FX This work was supported by a grant from a National Research Foundation of Korea funded by the Ministry of Education, Science, and Technology through the Global Research Laboratory Program (2011-0021874), Brain Korea 21 Program (2013-036038), and the Global Core Research Center Program (2012-0001187). This work was also supported by National Institutes of Health Grants R37-NS37074, R01-76694, and P01-NS55104.; Supported by the National Research Foundation of Korea grant funded by the Korea government (Ministry of Education, Science, and Technology) 2013003407.; Supported by Korea Healthcare technology R&D Project, Ministry for Health, Welfare, and Family Affairs Grant A110076. NR 36 TC 4 Z9 4 U1 0 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 7 PY 2014 VL 289 IS 6 BP 3328 EP 3338 DI 10.1074/jbc.M113.498212 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AA8TU UT WOS:000331368700020 PM 24347169 ER PT J AU Saleh, ZH Apte, AP Sharp, GC Shusharina, NP Wang, Y Veeraraghavan, H Thor, M Muren, LP Rao, SS Lee, NY Deasy, JO AF Saleh, Ziad H. Apte, Aditya P. Sharp, Gregory C. Shusharina, Nadezhda P. Wang, Ya Veeraraghavan, Harini Thor, Maria Muren, Ludvig P. Rao, Shyam S. Lee, Nancy Y. Deasy, Joseph O. TI The distance discordance metric-a novel approach to quantifying spatial uncertainties in intra- and inter-patient deformable image registration SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article DE deformable image registration; distance discordance; uncertainty; inaccuracy ID MORBIDITY FOLLOWING RADIOTHERAPY; PROSTATE-CANCER; HEAD; ACCURACY; CONSISTENCY; STRATEGIES; PREDICTION; ALGORITHM; DEMONS; TRIAL AB Previous methods to estimate the inherent accuracy of deformable image registration (DIR) have typically been performed relative to a known ground truth, such as tracking of anatomic landmarks or known deformations in a physical or virtual phantom. In this study, we propose a new approach to estimate the spatial geometric uncertainty of DIR using statistical sampling techniques that can be applied to the resulting deformation vector fields (DVFs) for a given registration. The proposed DIR performance metric, the distance discordance metric (DDM), is based on the variability in the distance between corresponding voxels from different images, which are co-registered to the same voxel at location (X) in an arbitrarily chosen 'reference' image. The DDM value, at location (X) in the reference image, represents the mean dispersion between voxels, when these images are registered to other images in the image set. The method requires at least four registered images to estimate the uncertainty of the DIRs, both for inter- and intra-patient DIR. To validate the proposed method, we generated an image set by deforming a software phantom with known DVFs. The registration error was computed at each voxel in the 'reference' phantom and then compared to DDM, inverse consistency error (ICE), and transitivity error (TE) over the entire phantom. The DDM showed a higher Pearson correlation (R-p) with the actual error (Rp ranged from 0.6 to 0.9) in comparison with ICE and TE (Rp ranged from 0.2 to 0.8). In the resulting spatial DDM map, regions with distinct intensity gradients had a lower discordance and therefore, less variability relative to regions with uniform intensity. Subsequently, we applied DDM for intra-patient DIR in an image set of ten longitudinal computed tomography (CT) scans of one prostate cancer patient and for inter-patient DIR in an image set of ten planning CT scans of different head and neck cancer patients. For both intra-and inter-patient DIR, the spatial DDM map showed large variation over the volume of interest (the pelvis for the prostate patient and the head for the head and neck patients). The highest discordance was observed in the soft tissues, such as the brain, bladder, and rectum, due to higher variability in the registration. The smallest DDM values were observed in the bony structures in the pelvis and the base of the skull. The proposed metric, DDM, provides a quantitative tool to evaluate the performance of DIR when a set of images is available. Therefore, DDM can be used to estimate and visualize the uncertainty of intra- and/or inter-patient DIR based on the variability of the registration rather than the absolute registration error. C1 [Saleh, Ziad H.; Apte, Aditya P.; Wang, Ya; Veeraraghavan, Harini; Thor, Maria; Deasy, Joseph O.] Mem Sloan Kettering Canc Ctr, Dept Med Phys, New York, NY 10021 USA. [Sharp, Gregory C.; Shusharina, Nadezhda P.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Thor, Maria; Muren, Ludvig P.] Aarhus Univ, Aarhus Univ Hosp, Dept Med Phys, Aarhus, Denmark. [Muren, Ludvig P.] Univ Bergen, Dept Phys & Technol, Bergen, Norway. [Rao, Shyam S.; Lee, Nancy Y.] Mem Sloan Kettering Canc Ctr, Dept Radiat Oncol, New York, NY 10021 USA. RP Deasy, JO (reprint author), Mem Sloan Kettering Canc Ctr, Dept Med Phys, New York, NY 10021 USA. EM deasyj@mskcc.org OI Sharp, Gregory/0000-0001-8575-9611; Deasy, Joseph/0000-0002-9437-266X FU NIH [R01 CA85181] FX The authors would like to thank Per Munck af Rosenschold from the Department of Radiation Oncology at Rigshospitalet for valuable comments on the initial manuscript during his visit to MSKCC. This research was partially supported by NIH Grant R01 CA85181. NR 35 TC 5 Z9 5 U1 0 U2 7 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 FEB 7 PY 2014 VL 59 IS 3 BP 733 EP 746 DI 10.1088/0031-9155/59/3/733 PG 14 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA AB6YU UT WOS:000331937000015 PM 24440838 ER PT J AU Unkelbach, J Menze, BH Konukoglu, E Dittmann, F Le, M Ayache, N Shih, HA AF Unkelbach, Jan Menze, Bjoern H. Konukoglu, Ender Dittmann, Florian Le, Matthieu Ayache, Nicholas Shih, Helen A. TI Radiotherapy planning for glioblastoma based on a tumor growth model: improving target volume delineation SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article DE glioblastoma; tumor growth modeling; radiotherapy; target delineation ID BRAIN-TUMORS; MATHEMATICAL-MODEL; GRADE GLIOMAS; MR-IMAGES; DIFFUSION; SURVIVAL; ASTROCYTOMAS; CHEMOTHERAPY; IRRADIATION; SIMULATION AB Glioblastoma differ from many other tumors in the sense that they grow infiltratively into the brain tissue instead of forming a solid tumor mass with a defined boundary. Only the part of the tumor with high tumor cell density can be localized through imaging directly. In contrast, brain tissue infiltrated by tumor cells at low density appears normal on current imaging modalities. In current clinical practice, a uniform margin, typically two centimeters, is applied to account for microscopic spread of disease that is not directly assessable through imaging. The current treatment planning procedure can potentially be improved by accounting for the anisotropy of tumor growth, which arises from different factors: anatomical barriers such as the falx cerebri represent boundaries for migrating tumor cells. In addition, tumor cells primarily spread in white matter and infiltrate gray matter at lower rate. We investigate the use of a phenomenological tumor growth model for treatment planning. The model is based on the Fisher-Kolmogorov equation, which formalizes these growth characteristics and estimates the spatial distribution of tumor cells in normal appearing regions of the brain. The target volume for radiotherapy planning can be defined as an isoline of the simulated tumor cell density. This paper analyzes the model with respect to implications for target volume definition and identifies its most critical components. A retrospective study involving ten glioblastoma patients treated at our institution has been performed. To illustrate the main findings of the study, a detailed case study is presented for a glioblastoma located close to the falx. In this situation, the falx represents a boundary for migrating tumor cells, whereas the corpus callosum provides a route for the tumor to spread to the contralateral hemisphere. We further discuss the sensitivity of the model with respect to the input parameters. Correct segmentation of the brain appears to be the most crucial model input. We conclude that the tumor growth model provides a method to account for anisotropic growth patterns of glioma, and may therefore provide a tool to make target delineation more objective and automated. C1 [Unkelbach, Jan; Dittmann, Florian; Le, Matthieu; Shih, Helen A.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Unkelbach, Jan; Konukoglu, Ender; Dittmann, Florian; Le, Matthieu; Shih, Helen A.] Harvard Univ, Sch Med, Boston, MA USA. [Menze, Bjoern H.; Le, Matthieu; Ayache, Nicholas] INRIA Sophia Antipolis, Asclepios Project, Sophia Antipolis, France. [Menze, Bjoern H.] Swiss Fed Inst Technol, Comp Vis Lab, Zurich, Switzerland. [Konukoglu, Ender] Massachusetts Gen Hosp, Martinos Ctr Biomed Imaging, Boston, MA 02114 USA. RP Unkelbach, J (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. EM junkelbach@partners.org FU Federal Share of program [C06 CA059267]; ERC Advanced Grant MedYMA FX The project was supported by the Federal Share of program income earned by Massachusetts General Hospital on C06 CA059267, Proton Research and Treatment Center. Additional support was provided by the ERC Advanced Grant MedYMA. NR 36 TC 12 Z9 12 U1 1 U2 11 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 FEB 7 PY 2014 VL 59 IS 3 BP 747 EP 770 DI 10.1088/0031-9155/59/3/747 PG 24 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA AB6YU UT WOS:000331937000016 PM 24440875 ER PT J AU Unkelbach, J Menze, BH Konukoglu, E Dittmann, F Ayache, N Shih, HA AF Unkelbach, Jan Menze, Bjoern H. Konukoglu, Ender Dittmann, Florian Ayache, Nicholas Shih, Helen A. TI Radiotherapy planning for glioblastoma based on a tumor growth model: implications for spatial dose redistribution SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article DE glioblastoma; tumor growth modeling; radiotherapy; prescribed dose distribution ID HIGH-GRADE GLIOMAS; RADIATION-THERAPY; CONFORMAL RADIOTHERAPY; IMPROVED DELINEATION; MULTIFORME; SURVIVAL; FAILURE; BRAIN; TRIAL; IRRADIATION AB Gliomas differ from many other tumors as they grow infiltratively into the brain parenchyma rather than forming a solid tumor mass with a well-defined boundary. Tumor cells can be found several centimeters away from the central tumor mass that is visible using current imaging techniques. The infiltrative growth characteristics of gliomas question the concept of a radiotherapy target volume that is irradiated to a homogeneous dose-the standard in current clinical practice. We discuss the use of the Fisher-Kolmogorov glioma growth model in radiotherapy treatment planning. The phenomenological tumor growth model assumes that tumor cells proliferate locally and migrate into neighboring brain tissue, which is mathematically described via a partial differential equation for the spatio-temporal evolution of the tumor cell density. In this model, the tumor cell density drops approximately exponentially with distance from the visible gross tumor volume, which is quantified by the infiltration length, a parameter describing the distance at which the tumor cell density drops by a factor of e. This paper discusses the implications for the prescribed dose distribution in the periphery of the tumor. In the context of the exponential cell kill model, an exponential fall-off of the cell density suggests a linear fall-off of the prescription dose with distance. We introduce the dose fall-off rate, which quantifies the steepness of the prescription dose fall-off in units of Gy mm(-1). It is shown that the dose fall-off rate is given by the inverse of the product of radiosensitivity and infiltration length. For an infiltration length of 3 mm and a surviving fraction of 50% at 2 Gy, this suggests a dose fall-off of approximately 1 Gy mm(-1). The concept is illustrated for two glioblastoma patients by optimizing intensity-modulated radiotherapy plans. The dose fall-off rate concept reflects the idea that infiltrating gliomas lack a defined boundary and are characterized by a continuous fall-off of the density of infiltrating tumor cells. The approach can potentially be used to individualize the prescribed dose distribution if better methods to estimate radiosensitivity and infiltration length on a patient by patient basis become available. C1 [Unkelbach, Jan; Dittmann, Florian; Shih, Helen A.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Unkelbach, Jan; Konukoglu, Ender; Dittmann, Florian; Shih, Helen A.] Harvard Univ, Sch Med, Boston, MA USA. [Menze, Bjoern H.; Ayache, Nicholas] INRIA Sophia Antipolis, Asclepios Project, Sophia Antipolis, France. [Menze, Bjoern H.] Swiss Fed Inst Technol, Comp Vis Lab, Zurich, Switzerland. [Konukoglu, Ender] Massachusetts Gen Hosp, Martinos Ctr Biomed Imaging, Boston, MA 02114 USA. RP Unkelbach, J (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. EM junkelbach@partners.org FU Federal Share of program [C06 CA059267] FX The project was supported by the Federal Share of program income earned by Massachusetts General Hospital on C06 CA059267, Proton Therapy Research and Treatment Center. NR 36 TC 7 Z9 7 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 FEB 7 PY 2014 VL 59 IS 3 BP 771 EP 789 DI 10.1088/0031-9155/59/3/771 PG 19 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA AB6YU UT WOS:000331937000017 PM 24440905 ER PT J AU Katolik, A Johnsson, R Montemayor, E Lackey, JG Hart, PJ Damha, MJ AF Katolik, Adam Johnsson, Richard Montemayor, Eric Lackey, Jeremy G. Hart, P. John Damha, Masad J. TI Regiospecific Solid-Phase Synthesis of Branched Oligoribonucleotides That Mimic Intronic Lariat RNA Intermediates SO JOURNAL OF ORGANIC CHEMISTRY LA English DT Article ID YEAST DEBRANCHING ENZYME; SINGLE-STRANDED-DNA; IN-VITRO; MYXOCOCCUS-XANTHUS; SELF-CLEAVAGE; INHIBITION; FRAGMENTS; OLIGODEOXYNUCLEOTIDES; OLIGONUCLEOTIDES; CEREVISIAE AB We have developed new solid phase methods for the synthesis of branched RNAs that mimic intronic lariat RNA intermediates. These methods produce branched oligoribonucleotide sequences of arbitrary length, base composition, and regiochemistry at the branchpoint junction. The methods utilize branching monomers that allow for the growth of each branch regioselectively from any of the hydroxyl positions (5', 3', or 2') at the branch-point junction. The integrity and branchpoint connectivity of the synthetic products have been confirmed by HPLC and MS analysis, and cleavage of the 2',5' linkage by recombinant debranching enzyme. Nonhydrolyzable branched RNA analogues containing arabinose instead of ribose at the branchpoint junction were shown to inhibit debranching activity and, hence, represent "decoys" for sequestering RNA binding proteins thought to drive amyotrophic lateral sclerosis (ALS). C1 [Katolik, Adam; Johnsson, Richard; Lackey, Jeremy G.; Damha, Masad J.] McGill Univ, Montreal, PQ H3A 0B8, Canada. [Montemayor, Eric; Hart, P. John] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Hart, P. John] South Texas Vet Hlth Care Syst, Dept Vet Affairs, San Antonio, TX 78229 USA. RP Damha, MJ (reprint author), McGill Univ, 801 Sherbrooke St W, Montreal, PQ H3A 0B8, Canada. EM masad.damha@mcgill.ca RI Johnsson, Richard/B-8954-2011 FU National Science and Engineering Council of Canada; Robert A. Welch Foundation [AQ-1399]; National Science Foundation [DBI-0905865]; Swedish Research Council FX This work was supported by grants from the National Science and Engineering Council of Canada (Discovery Grant to AID.), the Robert A. Welch Foundation (AQ-1399) (P.J.H.), the National Science Foundation (DBI-0905865) (E.M.), and the Swedish Research Council (R.J.). NR 45 TC 12 Z9 12 U1 0 U2 7 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-3263 J9 J ORG CHEM JI J. Org. Chem. PD FEB 7 PY 2014 VL 79 IS 3 BP 963 EP 975 DI 10.1021/jo4024182 PG 13 WC Chemistry, Organic SC Chemistry GA AA5TZ UT WOS:000331163800014 PM 24401015 ER PT J AU Van Vleet, T DeGutis, J Dabit, S Chiu, C AF Van Vleet, Thomas DeGutis, Joseph Dabit, Sawsan Chiu, Christopher TI Randomized control trial of computer-based rehabilitation of spatial neglect syndrome: the RESPONSE trial protocol SO BMC NEUROLOGY LA English DT Article DE Hemispatial neglect; Rehabilitation; Non-spatial attention; Stroke; Computer-based cognitive training ID UNILATERAL NEGLECT; VISUAL-ATTENTION; HEMISPATIAL NEGLECT; SUSTAINED ATTENTION; PARIETAL; SCALE; AWARENESS; DEFICITS; LOBE; TASK AB Background: Spatial neglect is a frequent and debilitating consequence of acquired brain injury and currently has no widely accepted standard of care. While previous interventions for spatial neglect have targeted patients' overt spatial deficits (e.g., reduced contralesional visual scanning), far fewer have directly targeted patients' non-spatial deficits (e.g., sustained attention deficits). Considering that non-spatial deficits have shown to be highly predictive of long-term disability, we developed a novel computer based training program that targets both sustained (tonic) and moment-to-moment (phasic) aspects of non-spatial attention (Tonic and Phasic Alertness Training, TAPAT). Preliminary studies demonstrate that TAPAT is safe and effective in improving both spatial and non-spatial attention deficits in the post-acute recovery phase in neglect patients. The purpose of the current trial (referred to as the REmediation of SPatial Neglect or RESPONSE trial) is to compare TAPAT to an active control training condition, include a larger sample of patients, and assess both cognitive and functional outcomes. Methods/Design: We will employ a multi-site, longitudinal, blinded randomized controlled trial (RCT) design with a target sample of 114 patients with spatial neglect. Patients will either perform, at their home, the experimental TAPAT training program or an active control computer games condition for thirty minutes/day, five days a week, over three months. Patients will be assessed on a battery of cognitive and functional outcomes on three occasions: a) immediately before training, b) within forty-eight hours post completion of total training, and c) after a three-month no-contact period post completion of total training, to assess the longevity of potential training effects. Discussion: The strengths of this protocol are that it tests an innovative, in-home administered treatment that targets a fundamental deficit in neglect, employs highly sensitive computer-based assessments of cognition as well as functional outcomes, and incorporates a large sample size (relative to other neglect treatment studies) in an RCT design. C1 [Van Vleet, Thomas; Dabit, Sawsan] Brain Plast Inst, San Francisco, CA 94108 USA. [DeGutis, Joseph; Chiu, Christopher] Harvard Univ, Sch Med, Dept Med, Boston Attent & Learning Lab,VA Boston Healthcare, Boston, MA 02130 USA. RP Van Vleet, T (reprint author), Brain Plast Inst, 77 Geary St, San Francisco, CA 94108 USA. EM tom.vanvleet@positscience.com FU Phase II SBIR Grant from the National Institute of Neurological Disorders and Stroke [R44 NS071780-03A1] FX This project is funded by a Phase II SBIR Grant (R44 NS071780-03A1) from the National Institute of Neurological Disorders and Stroke. NR 49 TC 0 Z9 0 U1 5 U2 17 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2377 J9 BMC NEUROL JI BMC Neurol. PD FEB 7 PY 2014 VL 14 AR 25 DI 10.1186/1471-2377-14-25 PG 11 WC Clinical Neurology SC Neurosciences & Neurology GA AA6ML UT WOS:000331212300001 ER PT J AU Cassidy, BS Hedden, T Yoon, C Gutchess, AH AF Cassidy, Brittany S. Hedden, Trey Yoon, Carolyn Gutchess, Angela H. TI Age differences in medial prefrontal activity for subsequent memory of truth value SO FRONTIERS IN PSYCHOLOGY LA English DT Article DE medial prefrontal cortex; truth value; aging; encoding; insula ID ADULT LIFE-SPAN; OLDER-ADULTS; SOCIAL COGNITION; EMOTIONAL EXPERIENCE; ANTERIOR INSULA; SOCIOEMOTIONAL SELECTIVITY; FUNCTIONAL NEUROANATOMY; WORKING-MEMORY; FMRI; METAANALYSIS AB Much research has demonstrated that aging is marked by decreased source memory relative to young adults, yet a smaller body of work has demonstrated that increasing the socioemotional content of source information may be one way to reduce age-related performance differences. Although dorsomedial prefrontal cortex (dmPFC) activity may support source memory among young and older adults, the extent to which one activates dorsal vs. ventral mPFC may reflect one's personal connection with incoming information. Because truth value may be one salient marker that impacts one's connection with information and allocation of attention toward incoming material, we investigated whether the perceived truth value of information differently impacts differences in mPFC activity associated with encoding source information, particularly with age. Twelve young (18-23 years) and 12 older adults (63-80 years) encoded true and false statements. Behavioral results showed similar memory performance between the age groups. With respect to neural activity associated with subsequent memory, young adults, relative to older adults, exhibited greater activity in dmPFC while older adults displayed enhanced ventromedial prefrontal cortex (vmPFC) and insula engagement relative to young. These results may potentially indicate that young adults focus on a general knowledge acquisition goal, while older adults focus on emotionally relevant aspects of the material. The findings demonstrate that age-related differences in recruitment of mPFC associated with encoding source information may in some circumstances underlie age-equivalent behavioral performance. C1 [Cassidy, Brittany S.; Gutchess, Angela H.] Brandeis Univ, Dept Psychol, Waltham, MA 02454 USA. [Hedden, Trey] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Boston, MA 02114 USA. [Yoon, Carolyn] Univ Michigan, Ann Arbor, MI 48109 USA. RP Cassidy, BS (reprint author), Brandeis Univ, Dept Psychol, 415 South St,MS 062, Waltham, MA 02454 USA. EM bcassidy@brandeis.edu FU NIA NIH HHS [K01 AG040197]; NIGMS NIH HHS [T32 GM084907] NR 65 TC 4 Z9 4 U1 1 U2 7 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1664-1078 J9 FRONT PSYCHOL JI Front. Psychol. PD FEB 7 PY 2014 VL 5 AR 87 DI 10.3389/fpsyg.2014.00087 PG 10 WC Psychology, Multidisciplinary SC Psychology GA AA7ON UT WOS:000331286900001 PM 24570672 ER PT J AU Lee, IA Kamba, A Low, D Mizoguchi, E AF Lee, In-Ah Kamba, Alan Low, Daren Mizoguchi, Emiko TI Novel methylxanthine derivative-mediated anti-inflammatory effects in inflammatory bowel disease SO WORLD JOURNAL OF GASTROENTEROLOGY LA English DT Article DE Adherent-invasive Escherichia coli; Chitinase 3-like 1; Chitinase inhibitors; Intestinal epithelial cells; Host-microbial interactions; Inflammatory bowel disease ID COLONIC EPITHELIAL-CELLS; ACIDIC MAMMALIAN CHITINASE; HUMAN CARTILAGE GLYCOPROTEIN-39; ADENOSINE RECEPTOR ANTAGONIST; INVASIVE ESCHERICHIA-COLI; BETA-CATENIN ACTIVATION; TNF-ALPHA PRODUCTION; CROHNS-DISEASE; ULCERATIVE-COLITIS; SIGNALING PATHWAY AB Family 18 chitinases have a binding capacity with chitin, a polymer of N-acetylglucosamine. Recent studies strongly suggested that chitinase 3-like 1 (CHI3L1, also known as YKL-40) and acidic mammalian chitinase, the two major members of family 18 chitinases, play a pivotal role in the pathogenesis of inflammatory bowel disease (IBD), bronchial asthma and several other inflammatory disorders. Based on the data from high-throughput screening, it has been found that three methylxanthine derivatives, caffeine, theophylline, and pentoxifylline, have competitive inhibitory effects against a fungal family 18 chitinase by specifically interacting with conserved tryptophans in the active site of this protein. Methylxanthine derivatives are also known as adenosine receptor antagonists, phosphodiesterase inhibitors and histone deacetylase inducers. Anti-inflammatory effects of methylxanthine derivatives have been well-documented in the literature. For example, a beneficial link between coffee or caffeine consumption and type 2 diabetes as well as liver cirrhosis has been reported. Furthermore, theophylline has a long history of being used as a bronchodilator in asthma therapy, and pentoxifylline has an immuno-modulating effect for peripheral vascular disease. However, it is still largely unknown whether these methylxanthine derivative-mediated anti-inflammatory effects are associated with the inhibition of CHI3L1-induced cytoplasmic signaling cascades in epithelial cells. In this review article we will examine the above possibility and summarize the biological significance of methylxanthine derivatives in intestinal epithelial cells. We hope that this study will provide a rationale for the development of methylxanthine derivatives, in particular caffeine, -based anti-inflammatory therapeutics in the field of IBD and IBD-associated carcinogenesis. (C) 2014 Baishideng Publishing Group Co., Limited. All rights reserved. C1 [Lee, In-Ah; Kamba, Alan; Low, Daren; Mizoguchi, Emiko] Harvard Univ, Sch Med, Dept Med, Gastrointestinal Unit, Boston, MA 02114 USA. [Mizoguchi, Emiko] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Study Inflammatory Bowel Dis, Boston, MA 02114 USA. RP Mizoguchi, E (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Study Inflammatory Bowel Dis, GRJ 825D,55 Fruit St, Boston, MA 02114 USA. EM emizoguchi@mgh.harvard.edu FU National Institutes of Health [DK80070]; Broad Medical Foundation; National Research Foundation of Korea; Singapore A*STAR Graduate Academy FX Supported by National Institutes of Health DK80070; and grants from the Broad Medical Foundation to Mizoguchi E; the National Research Foundation of Korea to Lee IA; and the fellowship grant supported by the Singapore A*STAR Graduate Academy to Low D NR 87 TC 9 Z9 9 U1 1 U2 6 PU BAISHIDENG PUBL GRP CO LTD PI WANCHAI PA ROOM 1701, 17-F, HENAN BUILDING, NO. 90, JAFFE RD, WANCHAI, HONG KONG 100025, PEOPLES R CHINA SN 1007-9327 EI 2219-2840 J9 WORLD J GASTROENTERO JI World J. Gastroenterol. PD FEB 7 PY 2014 VL 20 IS 5 BP 1127 EP 1138 DI 10.3748/wjg.v20.i5.1127 PG 12 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AA1LI UT WOS:000330857300001 PM 24574789 ER PT J AU Glykys, J Dzhala, V Egawa, K Balena, T Saponjian, Y Kuchibhotla, KV Bacskai, BJ Kahle, KT Zeuthen, T Staley, KJ AF Glykys, J. Dzhala, V. Egawa, K. Balena, T. Saponjian, Y. Kuchibhotla, K. V. Bacskai, B. J. Kahle, K. T. Zeuthen, T. Staley, K. J. TI Local Impermeant Anions Establish the Neuronal Chloride Concentration SO SCIENCE LA English DT Article ID INTRACELLULAR CHLORIDE; HIPPOCAMPAL-NEURONS; NEONATAL SEIZURES; PYRAMIDAL NEURONS; RAT HIPPOCAMPUS; IN-VITRO; BRAIN; GABA; COTRANSPORTER; INHIBITION AB Neuronal intracellular chloride concentration [Cl-](i) is an important determinant of gamma-aminobutyric acid type A (GABA(A)) receptor (GABA(A)R)-mediated inhibition and cytoplasmic volume regulation. Equilibrative cation-chloride cotransporters (CCCs) move Cl- across the membrane, but accumulating evidence suggests factors other than the bulk concentrations of transported ions determine [Cl-](i). Measurement of [Cl-](i) in murine brain slice preparations expressing the transgenic fluorophore Clomeleon demonstrated that cytoplasmic impermeant anions ([A](i)) and polyanionic extracellular matrix glycoproteins ([A](o)) constrain the local [Cl-]. CCC inhibition had modest effects on [Cl-] i and neuronal volume, but substantial changes were produced by alterations of the balance between [A](i) and [A](o). Therefore, CCCs are important elements of Cl- homeostasis, but local impermeant anions determine the homeostatic set point for [Cl-], and hence, neuronal volume and the polarity of local GABA(A)R signaling. C1 [Glykys, J.; Dzhala, V.; Egawa, K.; Balena, T.; Saponjian, Y.; Bacskai, B. J.; Staley, K. J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurol, Boston, MA 02115 USA. [Kuchibhotla, K. V.] NYU, Sch Med, Skirball Inst Biomol Med, New York, NY 10016 USA. [Kahle, K. T.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02115 USA. [Zeuthen, T.] Univ Copenhagen, Dept Cellular & Mol Med, DK-2200 Copenhagen, Denmark. RP Staley, KJ (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurol, Boston, MA 02115 USA. EM staley.kevin@mgh.harvard.edu FU National Institute of Neurological Disorders and Stroke, NIH [NS 40109-06]; American Epilepsy Society postdoctoral fellowship; NIH [R25]; Japan Foundation for Pediatric Research; Manton Center for Orphan Disease Research FX This work was supported by National Institute of Neurological Disorders and Stroke, NIH, grant NS 40109-06 the Kennedy Endowment for Child Neurology and Mental Retardation. J.G. was supported by the American Epilepsy Society postdoctoral fellowship and NIH R25. K. E. was supported by The Japan Foundation for Pediatric Research. K. T. K. was supported by the Manton Center for Orphan Disease Research and NIH R25. NR 41 TC 54 Z9 54 U1 1 U2 26 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 FEB 7 PY 2014 VL 343 IS 6171 BP 670 EP 675 DI 10.1126/science.1245423 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 304CP UT WOS:000330724000045 PM 24503855 ER PT J AU Sun, J Kudahl, UJ Simon, C Cao, ZW Reinherz, EL Brusic, V AF Sun, Jing Kudahl, Ulrich J. Simon, Christian Cao, Zhiwei Reinherz, Ellis L. Brusic, Vladimir TI Large-scale analysis of B-cell epitopes on influenza virus hemagglutinin - implications for cross-reactivity of neutralizing antibodies SO FRONTIERS IN IMMUNOLOGY LA English DT Article DE influenza virus; neutralizing antibodies; B-cell epitope; cross-reactivity; discontinuous peptide ID RECEPTOR-BINDING SITE; MONOCLONAL-ANTIBODIES; A VIRUSES; MEMBRANE GLYCOPROTEIN; RECOGNITION; IDENTIFICATION; LINEAGES; COMPLEX; MICE; H5N1 AB Influenza viruses continue to cause substantial morbidity and mortality worldwide. Fast gene mutation on surface proteins of influenza virus result in increasing resistance to current vaccines and available antiviral drugs. Broadly neutralizing antibodies (bnAbs) represent targets for prophylactic and therapeutic treatments of influenza. We performed a systematic bioinformatics study of cross-reactivity of neutralizing antibodies (nAbs) against influenza virus surface glycoprotein hemagglutinin (HA). This study utilized the available crystal structures of HA complexed with the antibodies for the analysis of tens of thousands of HA sequences. The detailed description of B-cell epitopes, measurement of epitope area similarity among different strains, and estimation of antibody neutralizing coverage provide insights into cross-reactivity status of existing nAbs against influenza virus. We have developed a method to assess the likely cross-reactivity potential of bnAbs for influenza strains, either newly emerged or existing. Our method catalogs influenza strains by a new concept named discontinuous peptide, and then provide assessment of cross-reactivity. Potentially cross-reactive strains are those that share 100% identity with experimentally verified neutralized strains. By cataloging influenza strains and their B-cell epitopes for known bnAbs, our method provides guidance for selection of representative strains for further experimental design. The knowledge of sequences, their B-cell epitopes, and differences between historical influenza strains, we enhance our preparedness and the ability to respond to the emerging pandemic threats. C1 [Sun, Jing; Kudahl, Ulrich J.; Simon, Christian; Reinherz, Ellis L.; Brusic, Vladimir] Harvard Univ, Sch Med, Dana Farber Canc Inst, Canc Vaccine Ctr, Boston, MA 02115 USA. [Sun, Jing; Reinherz, Ellis L.; Brusic, Vladimir] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Kudahl, Ulrich J.; Simon, Christian] Tech Univ Denmark, Ctr Biol Sequence Anal, DK-2800 Lyngby, Denmark. [Cao, Zhiwei] Tongji Univ, Sch Life Sci & Technol, Shanghai 200092, Peoples R China. [Reinherz, Ellis L.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Lab Immunobiol,Dept Med Oncol, Boston, MA 02115 USA. RP Brusic, V (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Canc Vaccine Ctr, 77 Ave Louis Pasteur,HIM 401, Boston, MA 02115 USA. EM vladimir_brusic@dfci.harvard.edu OI Simon, Christian/0000-0002-5866-5967 FU NIH [U01 AI 90043]; Oticon Foundation; Otto Monsted Foundation; Julie Dam's Stipend; Henry Shaws Stipend; Reinholdt Jorcks Stipend; Novo Scholarship Programme; Direktor Ib Henriksens Fond; Augustinus Fonden FX Jing Sun, Vladimir Brusic, and Ellis L. Reinherz acknowledge funding from NIH grant U01 AI 90043. Ulrich J. Kudahl was funded by Oticon Foundation, Otto Monsted Foundation, Julie Dam's Stipend, Henry Shaws Stipend, and Reinholdt Jorcks Stipend. Christian Simon was funded by the Novo Scholarship Programme, Direktor Ib Henriksens Fond, and Augustinus Fonden. NR 49 TC 6 Z9 6 U1 0 U2 2 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1664-3224 J9 FRONT IMMUNOL JI Front. Immunol. PD FEB 7 PY 2014 VL 5 AR 38 DI 10.3389/fimmu.2014.00038 PG 12 WC Immunology SC Immunology GA CI0XD UT WOS:000354462000001 PM 24570677 ER PT J AU Sekeres, MA Cutler, C AF Sekeres, Mikkael A. Cutler, Corey TI How we treat higher-risk myelodysplastic syndromes SO BLOOD LA English DT Review ID ACUTE MYELOID-LEUKEMIA; STEM-CELL TRANSPLANTATION; PROGNOSTIC SCORING SYSTEM; HISTONE DEACETYLASE INHIBITION; CRYPTIC CHROMOSOMAL LESIONS; ACUTE MYELOGENOUS LEUKEMIA; COPY NUMBER ALTERATIONS; INTERNET-BASED SURVEY; SYNDROMES MDS; DNA METHYLATION AB Higher-risk myelodysplastic syndromes (MDS) are defined by patients who fall into higher-risk group categories in the original or revised International Prognostic Scoring System. Survival for these patients is dismal, and treatment should be initiated rapidly. Standard therapies include the hypomethylating agents azacitidine and decitabine, which should be administered for a minimum of 6 cycles, and continued for as long as a patient is responding. Once a drug fails in one of these patients, further treatment options are limited, median survival is <6 months, and consideration should be given to clinical trials. Higher-risk eligible patients should be offered consultation to discuss hematopoietic stem cell transplantation close to the time of diagnosis, depending on patient goals of therapy, with consideration given to proceeding to transplantation soon after an optimal donor is located. In the interim period before transplantation, hypomethylating agent therapy, induction chemotherapy, or enrollment in a clinical trial should be considered to prevent disease progression, although the optimal pretransplantation therapy is unknown. C1 [Sekeres, Mikkael A.] Cleveland Clin, Taussig Canc Inst, Leukemia Program, Cleveland, OH 44195 USA. [Cutler, Corey] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Sekeres, MA (reprint author), Cleveland Clin, Taussig Canc Inst, Leukemia Program, Desk R35,9500 Euclid Ave, Cleveland, OH 44195 USA. EM sekerem@ccf.org NR 106 TC 29 Z9 31 U1 0 U2 2 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 FEB 6 PY 2014 VL 123 IS 6 BP 829 EP 836 DI 10.1182/blood-2013-08-496935 PG 8 WC Hematology SC Hematology GA AH0TY UT WOS:000335834600008 PM 24363399 ER PT J AU Zhou, Z Sehn, LH Rademaker, AW Gordon, LI LaCasce, AS Crosby-Thompson, A Vanderplas, A Zelenetz, AD Abel, GA Rodriguez, MA Nademanee, A Kaminski, MS Czuczman, MS Millenson, M Niland, J Gascoyne, RD Connors, JM Friedberg, JW Winter, JN AF Zhou, Zheng Sehn, Laurie H. Rademaker, Alfred W. Gordon, Leo I. LaCasce, Ann S. Crosby-Thompson, Allison Vanderplas, Ann Zelenetz, Andrew D. Abel, Gregory A. Rodriguez, Maria A. Nademanee, Auayporn Kaminski, Mark S. Czuczman, Myron S. Millenson, Michael Niland, Joyce Gascoyne, Randy D. Connors, Joseph M. Friedberg, Jonathan W. Winter, Jane N. TI An enhanced International Prognostic Index (NCCN-IPI) for patients with diffuse large B-cell lymphoma treated in the rituximab era SO BLOOD LA English DT Article ID NON-HODGKINS-LYMPHOMA; OUTCOME PREDICTION; ELDERLY-PATIENTS; R-CHOP; EXPRESSION; SURVIVAL; CHEMOTHERAPY; INTERGROUP; BIOMARKERS; SIGNATURES AB The International Prognostic Index (IPI) has been the basis for determining prognosis in patients with aggressive non-Hodgkin lymphoma (NHL) for the past 20 years. Using raw clinical data from the National Comprehensive Cancer Network (NCCN) database collected during the rituximab era, we built an enhanced IPI with the goal of improving risk stratification. Clinical features from 1650 adults with de novo diffuse large B-cell lymphoma (DLBCL) diagnosed from 2000-2010 at 7 NCCN cancer centers were assessed for their prognostic significance, with statistical efforts to further refine the categorization of age and normalized LDH. Five predictors (age, lactate dehydrogenase (LDH), sites of involvement, Ann Arbor stage, ECOG performance status) were identified and a maximum of 8 points assigned. Four risk groups were formed: low (0-1), low-intermediate (2-3), high-intermediate (4-5), and high (6-8). Compared with the IPI, the NCCN-IPI better discriminated low-and high-risk subgroups (5-year overall survival [OS]: 96% vs 33%) than the IPI (5 year OS: 90% vs 54%), respectively. When validated using an independent cohort from the British Columbia Cancer Agency (n = 1138), it also demonstrated enhanced discrimination for both low-and high-risk patients. The NCCN-IPI is easy to apply and more powerful than the IPI for predicting survival in the rituximab era. C1 [Zhou, Zheng; Rademaker, Alfred W.; Gordon, Leo I.; Winter, Jane N.] Northwestern Univ, Feinberg Sch Med, Robert H Lurie Comprehens Canc Ctr, Chicago, IL 60611 USA. [Sehn, Laurie H.; Gascoyne, Randy D.; Connors, Joseph M.] British Columbia Canc Agcy, Ctr Lymphoid Canc, Vancouver, BC V5Z 4E6, Canada. [LaCasce, Ann S.; Crosby-Thompson, Allison; Abel, Gregory A.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Vanderplas, Ann; Niland, Joyce] City Hope Natl Med Ctr, Biostat & Data Coordinating Ctr, Duarte, CA 91010 USA. [Zelenetz, Andrew D.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Rodriguez, Maria A.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Nademanee, Auayporn] City Hope Natl Med Ctr, Duarte, CA 91010 USA. [Kaminski, Mark S.] Univ Michigan, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA. [Czuczman, Myron S.] Roswell Pk Canc Inst, Dept Med, Buffalo, NY 14263 USA. [Czuczman, Myron S.] Roswell Pk Canc Inst, Dept Immunol, Buffalo, NY 14263 USA. [Millenson, Michael] Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. [Friedberg, Jonathan W.] Univ Rochester, James P Wilmot Canc Ctr, Rochester, NY USA. RP Winter, JN (reprint author), Northwestern Univ, Feinberg Sch Med, Dept Med, Div Hematol Oncol, 676 N St Clair St,Suite 850, Chicago, IL 60611 USA. EM j-winter@northwestern.edu OI Winter, Jane/0000-0001-7542-3305; Gordon, Leo/0000-0003-1666-7064 NR 28 TC 159 Z9 170 U1 1 U2 10 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 FEB 6 PY 2014 VL 123 IS 6 BP 837 EP 842 DI 10.1182/blood-2013-09-524108 PG 6 WC Hematology SC Hematology GA AH0TY UT WOS:000335834600009 PM 24264230 ER PT J AU Katz, SG LaBelle, JL Meng, HL Valeriano, RP Fisher, JK Sun, H Rodig, SJ Kleinstein, SH Walensky, LD AF Katz, Samuel G. LaBelle, James L. Meng, Hailong Valeriano, Regina P. Fisher, Jill K. Sun, Heather Rodig, Scott J. Kleinstein, Steven H. Walensky, Loren D. TI Mantle cell lymphoma in cyclin D1 transgenic mice with Bim-deficient B cells SO BLOOD LA English DT Article ID RETINOBLASTOMA PROTEIN; KAPPA-B; HOMOZYGOUS DELETIONS; INDUCED APOPTOSIS; GENE-EXPRESSION; MURINE MODEL; ACTIVATION; BCL-2; BAX; INDUCTION AB Mantle cell lymphoma (MCL) is a highly aggressive B-cell lymphoma resistant to conventional chemotherapy. Although defined by the characteristic t(11;14) translocation, MCL has not been recapitulated in transgenic mouse models of cyclin D1 overexpression alone. Indeed, several genetic aberrations have been identified in MCL that may contribute to its pathogenesis and chemoresistance. Of particular interest is the frequent biallelic deletion of the proapoptotic BCL-2 family protein BIM. BIM exerts its pro-death function via its alpha-helical BH3 death domain that has the dual capacity to inhibit antiapoptotic proteins such as BCL-2 and MCL-1 and directly trigger proapoptotic proteins such as the mitochondrial executioner protein BAX. To evaluate a functional role for Bim deletion in the pathogenesis of MCL, we generated cyclin D1-transgenic mice harboring Bim-deficient B cells. In response to immunization, E mu(CycD1)CD19(CRE)Bim(fl/fl) mice manifested selective expansion of their splenic mantle zone compartment. Three distinct immune stimulation regimens induced lymphomas with histopathologic and molecular features of human MCL in a subset of mice. Thus, deletion of Bim in B cells, in the context of cyclin D1 overexpression, disrupts a critical control point in lymphoid maturation and predisposes to the development of MCL. This genetic proof of concept for MCL pathogenesis suggests an opportunity to reactivate the death pathway by pharmacologic mimicry of proapoptotic BIM. C1 [Katz, Samuel G.; LaBelle, James L.; Valeriano, Regina P.; Fisher, Jill K.; Walensky, Loren D.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02215 USA. [Katz, Samuel G.; LaBelle, James L.; Valeriano, Regina P.; Fisher, Jill K.; Walensky, Loren D.] Dana Farber Canc Inst, Linde Program Canc Chem Biol, Boston, MA 02215 USA. [Katz, Samuel G.; Sun, Heather; Rodig, Scott J.] Harvard Univ, Sch Med, Dept Pathol, Brigham & Womens Hosp, Boston, MA 02115 USA. [Katz, Samuel G.; Meng, Hailong; Kleinstein, Steven H.] Yale Univ, Sch Med, Dept Pathol, New Haven, CT 06510 USA. [Kleinstein, Steven H.] Yale Univ, Interdept Program Computat Biol & Bioinformat, New Haven, CT USA. RP Walensky, LD (reprint author), Dana Farber Canc Inst, 450 Brookline Ave,Mayer 664, Boston, MA 02215 USA. EM loren_walensky@dfci.harvard.edu FU National Cancer Institute Cancer Center Support Grant (National Institutes of Health) [5 P30CA06516]; Leukemia and Lymphoma Society (LLS); Lymphoma Research Foundation Mantle Cell Lymphoma grant; LLS/Marshall A. Lichtman Specialized Center of Research project grant FX The Specialized Histopathology Core of the Dana-Farber/Harvard Cancer Center is funded in part by a National Cancer Institute Cancer Center Support Grant (National Institutes of Health 5 P30CA06516). This work was supported by a Leukemia and Lymphoma Society (LLS) Fellow Award and a Lymphoma Research Foundation Mantle Cell Lymphoma grant to S.G.K. and an LLS/Marshall A. Lichtman Specialized Center of Research project grant to L.D.W. NR 59 TC 5 Z9 6 U1 0 U2 3 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD FEB 6 PY 2014 VL 123 IS 6 BP 884 EP 893 DI 10.1182/blood-2013-04-499079 PG 10 WC Hematology SC Hematology GA AH0TY UT WOS:000335834600014 PM 24352880 ER PT J AU Keeton, EK McEachern, K Dillman, KS Palakurthi, S Cao, YC Grondine, MR Kaur, S Wang, SP Chen, YC Wu, A Shen, MH Gibbons, FD Lamb, ML Zheng, XL Stone, RM DeAngelo, DJ Platanias, LC Dakin, LA Chen, HW Lyne, PD Huszar, D AF Keeton, Erika K. McEachern, Kristen Dillman, Keith S. Palakurthi, Sangeetha Cao, Yichen Grondine, Michael R. Kaur, Surinder Wang, Suping Chen, Yuching Wu, Allan Shen, Minhui Gibbons, Francis D. Lamb, Michelle L. Zheng, Xiaolan Stone, Richard M. DeAngelo, Daniel J. Platanias, Leonidas C. Dakin, Les A. Chen, Huawei Lyne, Paul D. Huszar, Dennis TI AZD1208, a potent and selective pan-Pim kinase inhibitor, demonstrates efficacy in preclinical models of acute myeloid leukemia SO BLOOD LA English DT Article ID THERAPEUTIC TARGET; CELL-GROWTH; PHOSPHORYLATION; PROTEIN; SIZE; BAD; TRANSLATION; EXPRESSION; SURVIVAL; FLT3 AB Upregulation of Pim kinases is observed in several types of leukemias and lymphomas. Pim-1, -2, and -3 promote cell proliferation and survival downstream of cytokine and growth factor signaling pathways. AZD1208 is a potent, highly selective, and orally available Pim kinase inhibitor that effectively inhibits all three isoforms at <5 nM or <150 nM in enzyme and cell assays, respectively. AZD1208 inhibited the growth of 5 of 14 acute myeloid leukemia (AML) cell lines tested, and sensitivity correlates with Pim-1 expression and STAT5 activation. AZD1208 causes cell cycle arrest and apoptosis in MOLM-16 cells, accompanied by a dose-dependent reduction in phosphorylation of Bcl-2 antagonist of cell death, 4EBP1, p70S6K, and S6, as well as increases in cleaved caspase 3 and p27. Inhibition of p4EBP1 and p-p70S6K and suppression of translation are the most representative effects of Pim inhibition in sensitive AML cell lines. AZD1208 inhibits the growth of MOLM-16 and KG-1a xenograft tumors in vivo with a clear pharmacodynamic-pharmacokinetic relationship. AZD1208 also potently inhibits colony growth and Pim signaling substrates in primary AML cells from bone marrow that are Flt3 wild-type or Flt3 internal tandem duplication mutant. These results underscore the therapeutic potential of Pim kinase inhibition for the treatment of AML. C1 [Keeton, Erika K.; McEachern, Kristen; Dillman, Keith S.; Palakurthi, Sangeetha; Cao, Yichen; Grondine, Michael R.; Wang, Suping; Chen, Yuching; Wu, Allan; Shen, Minhui; Gibbons, Francis D.; Lamb, Michelle L.; Zheng, Xiaolan; Dakin, Les A.; Chen, Huawei; Lyne, Paul D.; Huszar, Dennis] AstraZeneca, Oncol iMed, Waltham, MA USA. [Kaur, Surinder; Platanias, Leonidas C.] Northwestern Univ, Sch Med, Robert H Lurie Comprehens Canc Ctr, Chicago, IL USA. [Kaur, Surinder; Platanias, Leonidas C.] Northwestern Univ, Sch Med, Div Hematol Oncol, Chicago, IL USA. [Kaur, Surinder; Platanias, Leonidas C.] Jesse Brown Vet Adm Med Ctr, Dept Med, Chicago, IL USA. [Stone, Richard M.; DeAngelo, Daniel J.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. RP Huszar, D (reprint author), 35 Gatehouse Dr, Waltham, MA 02451 USA. EM dennis.huszar@astrazeneca.com FU National Institutes of Health, National Cancer Institute [CA77816]; Department of Veterans Affairs FX This work was supported in part by National Institutes of Health, National Cancer Institute grant CA77816 and a Merit Review grant from the Department of Veterans Affairs (L.C.P.). NR 37 TC 62 Z9 62 U1 2 U2 14 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 FEB 6 PY 2014 VL 123 IS 6 BP 905 EP 913 DI 10.1182/blood-2013-04-495366 PG 9 WC Hematology SC Hematology GA AH0TY UT WOS:000335834600016 PM 24363397 ER PT J AU Zhou, PH Shaffer, DR Arias, DAA Nakazaki, Y Pos, W Torres, AJ Cremasco, V Dougan, SK Cowley, GS Elpek, K Brogdon, J Lamb, J Turley, SJ Ploegh, HL Root, DE Love, JC Dranoff, G Hacohen, N Cantor, H Wucherpfennig, KW AF Zhou, Penghui Shaffer, Donald R. Arias, Diana A. Alvarez Nakazaki, Yukoh Pos, Wouter Torres, Alexis J. Cremasco, Viviana Dougan, Stephanie K. Cowley, Glenn S. Elpek, Kutlu Brogdon, Jennifer Lamb, John Turley, Shannon J. Ploegh, Hidde L. Root, David E. Love, J. Christopher Dranoff, Glenn Hacohen, Nir Cantor, Harvey Wucherpfennig, Kai W. TI In vivo discovery of immunotherapy targets in the tumour microenvironment SO NATURE LA English DT Article ID CD8+ T-CELLS; PROGNOSTIC-FACTORS; IMMUNE CELLS; CANCER; MELANOMA; PHOSPHATASE; SUPPRESSORS; LYMPHOCYTES; PROTEINS; SURVIVAL AB Recent clinical trials showed that targeting of inhibitory receptors on T cells induces durable responses in a subset of cancer patients, despite advanced disease. However, the regulatory switches controlling T-cell function in immunosuppressive tumours are not well understood. Here we show that such inhibitory mechanisms can be systematically discovered in the tumour microenvironment. We devised an in vivo pooled short hairpin RNA (shRNA) screen in which shRNAs targeting negative regulators became highly enriched in murine tumours by releasing a block on T-cell proliferation upon tumour antigen recognition. Such shRNAs were identified by deep sequencing of the shRNA cassette from T cells infiltrating tumour or control tissues. One of the target genes was Ppp2r2d, a regulatory subunit of the PP2A phosphatase family. In tumours, Ppp2r2d knockdown inhibited T-cell apoptosis and enhanced T-cell proliferation as well as cytokine production. Key regulators of immune function can therefore be discovered in relevant tissue microenvironments. C1 [Zhou, Penghui; Shaffer, Donald R.; Arias, Diana A. Alvarez; Nakazaki, Yukoh; Pos, Wouter; Cremasco, Viviana; Elpek, Kutlu; Turley, Shannon J.; Dranoff, Glenn; Cantor, Harvey; Wucherpfennig, Kai W.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Torres, Alexis J.; Love, J. Christopher] MIT, David H Koch Inst Integrat Canc Res, Cambridge, MA 02142 USA. [Dougan, Stephanie K.; Ploegh, Hidde L.] MIT, Whitehead Inst, Cambridge, MA 02142 USA. [Cowley, Glenn S.; Root, David E.; Hacohen, Nir] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. [Brogdon, Jennifer] Novartis Inst Biomed Res, Cambridge, MA 02139 USA. [Lamb, John] Novartis Res Fdn, Genom Inst, San Diego, CA 92121 USA. RP Wucherpfennig, KW (reprint author), Dana Farber Canc Inst, Boston, MA 02115 USA. EM kai_wucherpfennig@dfci.harvard.edu FU National Institutes of Health [1R01CA173750]; Melanoma Research Alliance; DF/HCC-MIT Bridge Project; Lustgarten Foundation; Novartis Institutes of Biomedical Research; Koch Institute from the National Cancer Institute [P30-CA14051]; American Cancer Society; Terri Brodeur Breast Cancer Foundation; NIH [AI07386] FX This work was supported by the National Institutes of Health (Transformative Research Award 1R01CA173750 to K.W.W.), the Melanoma Research Alliance (to K.W.W.), the DF/HCC-MIT Bridge Project and the Lustgarten Foundation (to K.W.W., J.C.L. and H.L.P.), Novartis Institutes of Biomedical Research (to K.W.W.), the Koch Institute Support Grant P30-CA14051 from the National Cancer Institute, the American Cancer Society John W. Thatcher, Jr Postdoctoral Fellowship in Melanoma Research (to D.R.S.), the Terri Brodeur Breast Cancer Foundation Postdoctoral Fellowship (to P.Z.) and a NIH T32 grant (AI07386 to D.A.A.A.). NR 48 TC 54 Z9 55 U1 4 U2 102 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 FEB 6 PY 2014 VL 506 IS 7486 BP 52 EP + DI 10.1038/nature12988 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 303BA UT WOS:000330648100029 PM 24476824 ER PT J AU Williams, AL Jacobs, SBR Moreno-Macias, H Huerta-Chagoya, A Churchhouse, C Marquez-Luna, C Garcia-Ortiz, H Gomez-Vazquez, MJ Burtt, NP Aguilar-Salinas, CA Gonzalez-Villalpando, C Florez, JC Orozco, L Haiman, CA Tusie-Luna, T Altshuler, D Williams, AL Marquez-Luna, C Huerta-Chagoya, A Ripke, S Gomez-Vazquez, MJ Manning, AK Moreno-Macias, H Garcia-Ortiz, H Neale, B Burtt, NP Aguilar-Salinas, CA Reich, D Stram, DO Fernandez-Lopez, JC Romero-Hidalgo, S Altshuler, D Florez, JC Tusie-Luna, T Patterson, N Haiman, CA Aguilar-Delfin, I Martinez-Hernandez, A Centeno-Cruz, F Mendoza-Caamal, E Revilla-Monsalve, C Islas-Andrade, S Cordova, E Rodriguez-Arellano, E Soberon, X Orozco, L Florez, JC Gonzalez-Villalpando, C Gonzalez-Villalpando, ME Haiman, CA Henderson, BE Monroe, K Wilkens, L Kolonel, LN Le Marchand, L Riba, L Ordonez-Sanchez, ML Rodriguez-Guillen, R Cruz-Bautista, I Rodriguez-Torres, M Munoz-Hernandez, LL Saenz, T Gomez, D Alvirde, U Burtt, NP Onofrio, RC Brodeur, WM Gage, D Murphy, J Franklin, J Mahan, S Ardlie, K Crenshaw, AT Winckler, W Prufer, K Shunkov, MV Sawyer, S Stenzel, U Kelso, J Lek, M Sankararaman, S Williams, AL Patterson, N MacArthur, DG Reich, D Derevianko, AP Paabo, S Jacobs, SBR Churchhouse, C Gopal, S Grammatikos, JA Smith, IC Bullock, KH Deik, AA Souza, AL Pierce, KA Clish, CB Altshuler, D Fennell, T Farjoun, Y Gabriel, S Stram, DO Gross, MD Pereira, MA Seielstad, M Koh, WP Tai, ES Flannick, J Fontanillas, P Morris, A Teslovich, TM Burtt, NP Atzmon, G Blangero, J Bowden, DW Chambers, J Cho, YS Duggirala, R Glaser, B Hanis, C Kooner, J Laakso, M Lee, JY Tai, ES Teo, YY Wilson, JG Haiman, CA Henderson, BE Monroe, K Wilkens, L Kolonel, LN Le Marchand, L Puppala, S Farook, VS Thameem, F Abboud, HE DeFronzo, RA Jenkinson, CP Lehman, DM Curran, JE Blangero, J Duggirala, R Burtt, NP Cortes, ML Altshuler, D Florez, JC Haiman, CA Henderson, BE Aguilar-Salinas, CA Gonzalez-Villalpando, C Orozco, L Tusie-Luna, T AF Williams, Amy L. Jacobs, Suzanne B. R. Moreno-Macias, Hortensia Huerta-Chagoya, Alicia Churchhouse, Claire Marquez-Luna, Carla Garcia-Ortiz, Humberto Jose Gomez-Vazquez, Maria Burtt, Noel P. Aguilar-Salinas, Carlos A. Gonzalez-Villalpando, Clicerio Florez, Jose C. Orozco, Lorena Haiman, Christopher A. Tusie-Luna, Teresa Altshuler, David Williams, Amy L. Marquez-Luna, Carla Huerta-Chagoya, Alicia Ripke, Stephan Jose Gomez-Vazquez, Maria Manning, Alisa K. Moreno-Macias, Hortensia Garcia-Ortiz, Humberto Neale, Benjamin Burtt, Noel P. Aguilar-Salinas, Carlos A. Reich, David Stram, Daniel O. Carlos Fernandez-Lopez, Juan Romero-Hidalgo, Sandra Altshuler, David Florez, Jose C. Tusie-Luna, Teresa Patterson, Nick Haiman, Christopher A. Aguilar-Delfin, Irma Martinez-Hernandez, Angelica Centeno-Cruz, Federico Mendoza-Caamal, Elvia Revilla-Monsalve, Cristina Islas-Andrade, Sergio Cordova, Emilio Rodriguez-Arellano, Eunice Soberon, Xavier Orozco, Lorena Florez, Jose C. Gonzalez-Villalpando, Clicerio Elena Gonzalez-Villalpando, Maria Haiman, Christopher A. Henderson, Brian E. Monroe, Kristine Wilkens, Lynne Kolonel, Laurence N. Le Marchand, Loic Riba, Laura Luisa Ordonez-Sanchez, Maria Rodriguez-Guillen, Rosario Cruz-Bautista, Ivette Rodriguez-Torres, Maribel Liliana Munoz-Hernandez, Linda Saenz, Tamara Gomez, Donaji Alvirde, Ulices Burtt, Noel P. Onofrio, Robert C. Brodeur, Wendy M. Gage, Diane Murphy, Jacquelyn Franklin, Jennifer Mahan, Scott Ardlie, Kristin Crenshaw, Andrew T. Winckler, Wendy Prufer, Kay Shunkov, Michael V. Sawyer, Susanna Stenzel, Udo Kelso, Janet Lek, Monkol Sankararaman, Sriram Williams, Amy L. Patterson, Nick MacArthur, Daniel G. Reich, David Derevianko, Anatoli P. Paabo, Svante Jacobs, Suzanne B. R. Churchhouse, Claire Gopal, Shuba Grammatikos, James A. Smith, Ian C. Bullock, Kevin H. Deik, Amy A. Souza, Amanda L. Pierce, Kerry A. Clish, Clary B. Altshuler, David Fennell, Timothy Farjoun, Yossi Gabriel, Stacey Stram, Daniel O. Gross, Myron D. Pereira, Mark A. Seielstad, Mark Koh, Woon-Puay Tai, E-Shyong Flannick, Jason Fontanillas, Pierre Morris, Andrew Teslovich, Tanya M. Burtt, Noel P. Atzmon, Gil Blangero, John Bowden, Donald W. Chambers, John Cho, Yoon Shin Duggirala, Ravindranath Glaser, Benjamin Hanis, Craig Kooner, Jaspal Laakso, Markku Lee, Jong-Young Tai, E-Shyong Teo, Yik Ying Wilson, James G. Haiman, Christopher A. Henderson, Brian E. Monroe, Kristine Wilkens, Lynne Kolonel, Laurence N. Le Marchand, Loic Puppala, Sobha Farook, Vidya S. Thameem, Farook Abboud, Hanna E. DeFronzo, Ralph A. Jenkinson, Christopher P. Lehman, Donna M. Curran, Joanne E. Blangero, John Duggirala, Ravindranath Burtt, Noel P. Cortes, Maria L. Altshuler, David Florez, Jose C. Haiman, Christopher A. Henderson, Brian E. Aguilar-Salinas, Carlos A. Gonzalez-Villalpando, Clicerio Orozco, Lorena Tusie-Luna, Teresa CA SIGMA Type 2 Diabet Consortium Broad Genomics Platform T2D-GENES Consortium TI Sequence variants in SLC16A11 are a common risk factor for type 2 diabetes in Mexico SO NATURE LA English DT Article ID INSULIN-RESISTANCE; ASSOCIATION; GENOME; SUSCEPTIBILITY; TRANSPORTER; POPULATIONS; ANCESTRY; MELLITUS; LINKS; KCNQ1 AB Performing genetic studies in multiple human populations can identify disease risk alleles that are common in one population but rare in others(1), with the potential to illuminate pathophysiology, health disparities, and the population genetic origins of disease alleles. Here we analysed 9.2 million single nucleotide polymorphisms (SNPs) in each of 8,214 Mexicans and other Latin Americans: 3,848 with type 2 diabetes and 4,366 non-diabetic controls. In addition to replicating previous findings(2-4), we identified a novel locus associated with type 2 diabetes at genome-wide significance spanning the solute carriers SLC16A11 and SLC16A13 (P=3.9x10(-13); odds ratio (OR) = 1.29). The association was stronger in younger, leaner people with type 2 diabetes, and replicated in independent samples (P=1.1x10(-4); OR = 1.20). The risk haplotype carries four amino acid substitutions, all in SLC16A11; it is present at similar to 50% frequency in Native American samples and similar to 10% in east Asian, but is rare in European and African samples. Analysis of an archaic genome sequence indicated that the risk haplotype introgressed into modern humans via admixture with Neanderthals. The SLC16A11 messenger RNA is expressed in liver, and V5-tagged SLC16A11 protein localizes to the endoplasmic reticulum. Expression of SLC16A11 in heterologous cells alters lipid metabolism, most notably causing an increase in intracellular triacylglycerol levels. Despite type 2 diabetes having been well studied by genome-wide association studies in other populations, analysis in Mexican and Latin American individuals identified SLC16A11 as a novel candidate gene for type 2 diabetes with a possible role in triacylglycerol metabolism. C1 [Williams, Amy L.; Jacobs, Suzanne B. R.; Churchhouse, Claire; Florez, Jose C.; Altshuler, David; Ripke, Stephan; Manning, Alisa K.; Neale, Benjamin; Burtt, Noel P.; Murphy, Jacquelyn; Sankararaman, Sriram; Patterson, Nick; MacArthur, Daniel G.; Reich, David; Flannick, Jason; Fontanillas, Pierre] Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA 02142 USA. [Reich, David; Altshuler, David; Sankararaman, Sriram] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Moreno-Macias, Hortensia; Moreno-Macias, Hortensia] Univ Autonoma Metropolitana, Mexico City 14387, DF, Mexico. [Jose Gomez-Vazquez, Maria; Tusie-Luna, Teresa; Jose Gomez-Vazquez, Maria; Luisa Ordonez-Sanchez, Maria; Rodriguez-Guillen, Rosario; Cruz-Bautista, Ivette; Rodriguez-Torres, Maribel; Liliana Munoz-Hernandez, Linda; Saenz, Tamara; Gomez, Donaji; Alvirde, Ulices] Inst Nacl Nutr Salvador Zubiran, Mexico City 14000, DF, Mexico. [Riba, Laura; Reich, David] Univ Nacl Autonoma Mexico, Unidad Biol Mol & Med Genom, UNAM INCMNSZ, Inst Invest Biomed, Mexico City 04510, DF, Mexico. [Marquez-Luna, Carla; Orozco, Lorena; Marquez-Luna, Carla; Carlos Fernandez-Lopez, Juan; Romero-Hidalgo, Sandra; Aguilar-Delfin, Irma; Martinez-Hernandez, Angelica; Centeno-Cruz, Federico; Mendoza-Caamal, Elvia; Cordova, Emilio; Soberon, Xavier] Inst Nacl Med Genom, Mexico City 14610, DF, Mexico. [Jose Gomez-Vazquez, Maria; Jose Gomez-Vazquez, Maria] Univ Autonoma Nuevo Leon, San Nicolas De Los Garza 66451, Nuevo Leon, Mexico. [Gonzalez-Villalpando, Clicerio; Elena Gonzalez-Villalpando, Maria] Inst Nacl Salud Publ, Ctr Invest Salud Poblac, Unidad Invest Diabet & Riesgo Cardiovasc, Ctr Estudios Diabet, Mexico City 01120, DF, Mexico. [Flannick, Jason] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Flannick, Jason] Massachusetts Gen Hosp, Diabet Res Ctr, Diabet Unit, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Haiman, Christopher A.; Stram, Daniel O.; Henderson, Brian E.; Monroe, Kristine] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90089 USA. Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Mol Biol, Boston, MA 02114 USA. MIT, Dept Biol, Cambridge, MA 02139 USA. [Ripke, Stephan; Neale, Benjamin; Lek, Monkol; MacArthur, Daniel G.] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA. [Revilla-Monsalve, Cristina; Islas-Andrade, Sergio] Inst Seguro Social SXXI, Unidad Invest Med Enfermedades Metab, Mexico City 06720, DF, Mexico. [Rodriguez-Arellano, Eunice] Inst Seguridad & Serv Sociales Trabajadores Estad, Mexico City 01030, DF, Mexico. [Wilkens, Lynne; Kolonel, Laurence N.; Le Marchand, Loic] Univ Hawaii, Ctr Canc, Program Epidemiol, Honolulu, HI 96813 USA. [Onofrio, Robert C.; Brodeur, Wendy M.; Gage, Diane; Franklin, Jennifer; Mahan, Scott; Ardlie, Kristin; Crenshaw, Andrew T.; Winckler, Wendy; Fennell, Timothy; Farjoun, Yossi; Gabriel, Stacey] Broad Inst Harvard & MIT, Genom Platform, Cambridge, MA 02142 USA. [Prufer, Kay; Sawyer, Susanna; Stenzel, Udo; Kelso, Janet; Paabo, Svante] Max Planck Inst Evolutionary Anthropol, Dept Evolutionary Genet, D-04103 Leipzig, Germany. [Shunkov, Michael V.; Derevianko, Anatoli P.] Russian Acad Sci, Siberian Branch, Inst Archaeol & Ethnog, Palaeolith Dept, Novosibirsk 630090, Russia. [Gopal, Shuba; Grammatikos, James A.; Bullock, Kevin H.; Deik, Amy A.; Souza, Amanda L.; Pierce, Kerry A.; Clish, Clary B.] Broad Inst Harvard & MIT, Metabolite Profiling Platform, Cambridge, MA 02142 USA. [Smith, Ian C.] Broad Inst Harvard & MIT, Canc Biol Program, Cambridge, MA 02142 USA. [Gross, Myron D.; Pereira, Mark A.] Univ Minnesota, Minneapolis, MN 55455 USA. [Seielstad, Mark] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Koh, Woon-Puay; Tai, E-Shyong] Duke Natl Univ Singapore, Grad Med Sch, Singapore SINGAPORE16, Singapore. [Koh, Woon-Puay] Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore 117597, Singapore. Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Med, Singapore 117597, Singapore. [Morris, Andrew] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England. [Teslovich, Tanya M.] Univ Michigan, Ctr Stat Genet, Dept Biostat, Ann Arbor, MI 48109 USA. [Atzmon, Gil] Albert Einstein Coll Med, Dept Genet, Dept Med, Bronx, NY 10461 USA. [Blangero, John; Duggirala, Ravindranath; Le Marchand, Loic; Puppala, Sobha; Farook, Vidya S.; Curran, Joanne E.] Texas Biomed Res Inst, Dept Med, San Antonio, TX 78227 USA. [Bowden, Donald W.] Wake Forest Sch Med, Dept Internal Med, Dept Biochem, Ctr Genom & Personalized Med Res,Ctr Diabet Res, Winston Salem, NC 27157 USA. [Chambers, John] Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Biostat, London SW7 2AZ, England. [Kooner, Jaspal] Imperial Coll Healthcare NHS Trust, London W2 1NY, England. [Kooner, Jaspal] Ealing Hosp Natl Hlth Serv NHS Trust, Southall UB1 3HW, Middx, England. [Cho, Yoon Shin] Hallym Univ, Dept Biomed Sci, Chunchon 200702, Gangwon Do, South Korea. [Glaser, Benjamin] Hadassah Hebrew Univ, Sch Med, Endocrinol & Metab Serv, IL-91120 Jerusalem, Israel. [Glaser, Benjamin] E Wolfson Med Ctr, IDRG, Diabet Unit, IL-58100 Holon, Israel. [Hanis, Craig] Univ Texas Hlth Sci Ctr Houston, Human Genet Ctr, Houston, TX 77030 USA. [Kooner, Jaspal] Univ London Imperial Coll Sci Technol & Med, Hammersmith Hosp, NHLI, London W12 0HS, England. [Laakso, Markku] Univ Eastern Finland, Dept Med, FI-70211 Kuopio, Finland. [Laakso, Markku] Kuopio Univ Hosp, FI-70211 Kuopio, Finland. [Lee, Jong-Young] Korea Natl Inst Hlth, Ctr Genome Sci, Chungcheongbuk Do 363951, South Korea. [Teo, Yik Ying] Natl Univ Singapore, Dept Epidemiol & Publ Hlth, Singapore 117597, Singapore. Natl Univ Singapore, Ctr Mol Epidemiol, Singapore 117456, Singapore. Agcy Sci Technol & Res, Genome Inst Singapore, Singapore 138672, Singapore. Natl Univ Singapore, Grad Sch Integrat Sci & Engn, Singapore 117456, Singapore. Natl Univ Singapore, Dept Stat & Appl Probabil, Singapore 117546, Singapore. [Wilson, James G.] Univ Mississippi, Med Ctr, Dept Physiol & Biophys, Jackson, MS 39216 USA. [Thameem, Farook; Abboud, Hanna E.] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, Div Nephrol, San Antonio, TX 78229 USA. [DeFronzo, Ralph A.; Jenkinson, Christopher P.] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, Div Diabet, San Antonio, TX 78229 USA. [Lehman, Donna M.] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, Div Clin Epidemiol, San Antonio, TX 78229 USA. [Cortes, Maria L.] Broad Inst Harvard & MIT, Cambridge, MA 02142 USA. RP Altshuler, D (reprint author), Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA 02142 USA. EM mttusie@gmail.com; altshuler@molbio.mgh.harvard.edu RI Fernandez, Juan Carlos/C-4976-2013; Chen, Peng/E-5546-2015; Derevianko, Anatoly/Q-5975-2016; OI Fernandez, Juan Carlos/0000-0003-3680-4193; Chen, Peng/0000-0002-1422-4641; Derevianko, Anatoly/0000-0003-1156-8331; Seielstad, Mark/0000-0001-5783-1401; Tai, E Shyong/0000-0003-2929-8966 FU Carlos Slim Health Institute; Consejo Nacional de Ciencia y Tecnologia [138826, 128877, 86867, 2092, M9303, F677-M9407, 251M, 2005-C01-14502, SALUD 2010-2-151165]; CONACyT-SALUD [2009-01-115250]; Direccion General de Asuntos del Personal Academico, UNAM [IT 214711]; Instituto Carlos Slim de la Salud; National Institutes of Health (NIH) [R01HL24799, CA164973, CA054281, CA063464, R01 CA55069, R35 CA53890, R01 CA80205, R01 CA144034, U01DK085526]; National Medical Research Council of Singapore; Veterans Administration Epidemiologic grant; National Institutes of Health Ruth L. Kirschstein National Research Service [F32 HG005944]; [R01 DK042273]; [R01 DK047482]; [R01 DK053889]; [R01 DK057295]; [P01 HL045522] FX We thank M. Daly, V. Mootha, E. Lander and K. Estrada for comments on the manuscript, B. Voight, A. Segre, J. Pickrell and the Scientific Advisory Board of the SIGMA Project (especially C. Bustamante) for useful discussions, and A. Subramanian and V. Rusu for assistance with expression analyses. This work was conducted as part of the Slim Initiative for Genomic Medicine, a joint US-Mexico project funded by the Carlos Slim Health Institute. The UNAM/INCMNSZ Diabetes Study was supported by Consejo Nacional de Ciencia y Tecnologia grants 138826, 128877, CONACyT-SALUD 2009-01-115250, and a grant from Direccion General de Asuntos del Personal Academico, 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 grant U01DK085526. The San Antonio Mexican American Family Studies (SAMAFS) were supported by R01 DK042273, R01 DK047482, R01 DK053889, R01 DK057295, P01 HL045522 and a Veterans Administration Epidemiologic grant to R.A.D. A.L.W. was supported by National Institutes of Health Ruth L. Kirschstein National Research Service Award number F32 HG005944. NR 29 TC 72 Z9 76 U1 2 U2 53 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD FEB 6 PY 2014 VL 506 IS 7486 BP 97 EP + DI 10.1038/nature12828 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 303BA UT WOS:000330648100039 ER PT J AU Peloso, GM Auer, PL Bis, JC Voorman, A Morrison, AC Stitziel, NO Brody, JA Khetarpal, SA Crosby, JR Fomage, M Isaacs, A Jakobsdottir, J Feitosa, MF Davies, G Huffman, JE Manichaikul, A Davis, B Lohman, K Joon, AY Smith, AV Grove, ML Zanoni, P Redon, V Demissie, S Lawson, K Peters, U Carlson, C Jackson, RD Ryckman, KK Mackey, RH Robinson, JG Siscovick, DS Schreiner, PJ Mychaleckyj, JC Pankow, JS Holman, A Uitterlinden, AG Harris, TB Taylor, KD Stafford, JM Reynolds, LM Marioni, RE Dehghan, A Franco, OH Patele, AP Lu, YC Hindy, G Gottesman, O Bottinger, EP Melander, O Orho-Melander, M Loos, RJF Duga, S Merlini, PA Farrall, M Goel, A Asselta, R Girelli, D Martinelli, N Shah, SH Kraus, WE Li, MY Rader, DJ Reilly, MP McPherson, R Watkins, H Ardissino, D Zhang, QY Wang, JD Tsai, MY Taylor, HA Correa, A Griswold, ME Lange, LA Starr, JM Rudan, I Eiriksdottir, G Launer, LJ Ordovas, JM Levy, D Chen, YDI Reiner, AP Hayward, C Polasek, O Deary, IJ Borecki, IB Liu, YM Gudnason, V Wilson, JG van Duijn, CM Kooperberg, C Rich, SS Psaty, BM Rotter, JI O'Donnell, CJ Rice, K Boerwinkle, E Kathiresan, S Cupples, LA AF Peloso, Gina M. Auer, Paul L. Bis, Joshua C. Voorman, Arend Morrison, Alanna C. Stitziel, Nathan O. Brody, Jennifer A. Khetarpal, Sumeet A. Crosby, Jacy R. Fomage, Myriam Isaacs, Aaron Jakobsdottir, Johanna Feitosa, Mary F. Davies, Gail Huffman, Jennifer E. Manichaikul, Ani Davis, Brian Lohman, Kurt Joon, Aron Y. Smith, Albert V. Grove, Megan L. Zanoni, Paolo Redon, Valeska Demissie, Serkalem Lawson, Kim Peters, Ulrike Carlson, Christopher Jackson, Rebecca D. Ryckman, Kelli K. Mackey, Rachel H. Robinson, Jennifer G. Siscovick, David S. Schreiner, Pamela J. Mychaleckyj, Josyf C. Pankow, James S. Holman, Albert Uitterlinden, Andre G. Harris, Tamara B. Taylor, Kent D. Stafford, Jeanette M. Reynolds, Lindsay M. Marioni, Riccardo E. Dehghan, Abbas Franco, Oscar H. Patele, Aniruddh P. Lu, Yingchang Hindy, George Gottesman, Omri Bottinger, Erwin P. Melander, Olle Orho-Melander, Marju Loos, Ruth J. F. Duga, Stefano Merlini, Piera Angelica Farrall, Martin Goel, Anuj Asselta, Rosanna Girelli, Domenico Martinelli, Nicola Shah, Svati H. Kraus, William E. Li, Mingyao Rader, Daniel J. Reilly, Muredach P. McPherson, Ruth Watkins, Hugh Ardissino, Diego Zhang, Qunyuan Wang, Judy Tsai, Michael Y. Taylor, Herman A. Correa, Adolfo Griswold, Michael E. Lange, Leslie A. Starr, John M. Rudan, Igor Eiriksdottir, Gudny Launer, Lenore J. Ordovas, Jose M. Levy, Daniel Chen, Y. -D. Ida Reiner, Alexander P. Hayward, Caroline Polasek, Ozren Deary, Ian J. Borecki, Ingrid B. Liu, Yongmei Gudnason, Vilmundur Wilson, James G. van Duijn, Cornelia M. Kooperberg, Charles Rich, Stephen S. Psaty, Bruce M. Rotter, Jerome I. O'Donnell, Christopher J. Rice, Kenneth Boerwinkle, Eric Kathiresan, Sekar Cupples, L. Adrienne CA NHLBI GO Exome Sequencing Project TI Association of Low-Frequency and Rare Coding-Sequence Variants with Blood Lipids and Coronary Heart Disease in 56,000 Whites and Blacks SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID PLATELET-ACTIVATING-FACTOR; DENSITY-LIPOPROTEIN CHOLESTEROL; FACTOR ACETYLHYDROLASES; PCSK9; PROTEIN; TRAITS; LDL AB Low-frequency coding DNA sequence variants in the proprotein convertase subtilisin/kexin type 9 gene (PCSK9) lower plasma low-density lipoprotein cholesterol (LDL-C), protect against risk of coronary heart disease (CHD), and have prompted the development of a new class of therapeutics. It is uncertain whether the PCSK9 example represents a paradigm or an isolated exception. We used the "Exome Array" to genotype >200,000 low-frequency and rare coding sequence variants across the genome in 56,538 individuals (42,208 European ancestry [EA] and 14,330 African ancestry [AA]) and tested these variants for association with LDL-C, high-density lipoprotein cholesterol (HDL-C), and triglycerides. Although we did not identify new genes associated with LDL-C, we did identify four low-frequency (frequencies between 0.1% and 2%) variants (ANGPTL8 rs145464906 [c.361C>T; p.Gln121*], PAFAH1B2 rs186808413 [c.482C>T; p.Ser161Leu], COL18A1 rs114139997 [c.331G>A; p.Gly111Arg], and PCSK7 rs142953140 [c.1511G>A; p.Arg504His]) with large effects on HDL-C and/or triglycerides. None of these four variants was associated with risk for CHD, suggesting that examples of low-frequency coding variants with robust effects on both lipids and CHD will be limited. C1 [Peloso, Gina M.; Patele, Aniruddh P.; Kathiresan, Sekar] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Peloso, Gina M.; Kathiresan, Sekar] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Peloso, Gina M.; O'Donnell, Christopher J.; Kathiresan, Sekar] Harvard Univ, Dept Med, Sch Med, Boston, MA 02115 USA. [Peloso, Gina M.; Patele, Aniruddh P.; Kathiresan, Sekar] Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA. [Auer, Paul L.; Peters, Ulrike; Carlson, Christopher; Reiner, Alexander P.; Kooperberg, Charles] Fred Hutchinson Canc Res Ctr, Publ Hlth Sci Div, Seattle, WA 98109 USA. [Auer, Paul L.] Univ Wisconsin, Sch Publ Hlth, Milwaukee, WI 53201 USA. [Bis, Joshua C.; Brody, Jennifer A.; Siscovick, David S.; Psaty, Bruce M.] Univ Washington, Cardiovasc Hlth Res Unit, Dept Med, Seattle, WA 98101 USA. [Voorman, Arend; Rice, Kenneth] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Morrison, Alanna C.; Crosby, Jacy R.; Fomage, Myriam; Davis, Brian; Grove, Megan L.; Lawson, Kim; Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Ctr Human Genet, Houston, TX 77030 USA. [Stitziel, Nathan O.] Washington Univ, Sch Med, Div Cardiovasc, Dept Med, St Louis, MO 63110 USA. [Stitziel, Nathan O.; Feitosa, Mary F.; Zhang, Qunyuan; Wang, Judy; Borecki, Ingrid B.] Washington Univ, Sch Med, Dept Genet, Div Stat Genom, St Louis, MO 63110 USA. [Khetarpal, Sumeet A.; Zanoni, Paolo; Redon, Valeska; Rader, Daniel J.; Reilly, Muredach P.] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Crosby, Jacy R.] Univ Texas Grad Sch Biomed Sci Houston, Dept Biostat Bioinformat & Syst Biol, Houston, TX 77030 USA. [Fomage, Myriam; Joon, Aron Y.] Univ Texas Hlth Sci Ctr Houston, Inst Mol Med, Houston, TX 77030 USA. [Isaacs, Aaron; van Duijn, Cornelia M.] Erasmus Univ, Med Ctr, Dept Epidemiol, Genet Epidemiol Unit, NL-3015 CN Rotterdam, Netherlands. [Jakobsdottir, Johanna; Smith, Albert V.; Eiriksdottir, Gudny; Gudnason, Vilmundur] Iceland Heart Assoc, IS-201 Kopavogur, Iceland. [Davies, Gail; Marioni, Riccardo E.; Starr, John M.; Deary, Ian J.] Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh EH8 9JZ, Midlothian, Scotland. [Davies, Gail; Marioni, Riccardo E.; Deary, Ian J.] Univ Edinburgh, Dept Psychol, Edinburgh EH8 9JZ, Midlothian, Scotland. [Huffman, Jennifer E.; Hayward, Caroline] Univ Edinburgh, MRC IGMM, MRC Human Genet, Edinburgh EH4 2XU, Midlothian, Scotland. [Manichaikul, Ani; Mychaleckyj, Josyf C.; Rich, Stephen S.] Univ Virginia, Ctr Publ Hlth Genom, Charlottesville, VA 22908 USA. [Manichaikul, Ani; Mychaleckyj, Josyf C.; Rich, Stephen S.] Univ Virginia, Dept Publ Hlth Sci, Charlottesville, VA 22908 USA. [Lohman, Kurt; Stafford, Jeanette M.; Reynolds, Lindsay M.; Liu, Yongmei] Wake Forest Sch Med, Winston Salem, NC 27106 USA. [Smith, Albert V.; Gudnason, Vilmundur] Univ Iceland, Fac Med, IS-101 Reykjavik, Iceland. [Demissie, Serkalem; Cupples, L. Adrienne] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA. [Demissie, Serkalem; Levy, Daniel; O'Donnell, Christopher J.; Cupples, L. Adrienne] NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. [Jackson, Rebecca D.] Ohio State Univ, Div Endocrinol Diabet & Metab, Dept Internal Med, Columbus, OH 43210 USA. [Ryckman, Kelli K.; Robinson, Jennifer G.] Univ Iowa, Coll Publ Hlth, Dept Epidemiol, Iowa City, IA 52242 USA. [Mackey, Rachel H.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15261 USA. [Siscovick, David S.; Reiner, Alexander P.; Psaty, Bruce M.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Schreiner, Pamela J.; Pankow, James S.] Univ Minnesota, Div Epidemiol & Community Hlth, Sch Publ Hlth, Minneapolis, MN 55454 USA. [Holman, Albert; Uitterlinden, Andre G.; Dehghan, Abbas; Franco, Oscar H.] Erasmus Univ, Med Ctr, Dept Epidemiol, NL-3015 CN Rotterdam, Netherlands. [Harris, Tamara B.; Launer, Lenore J.] NIA, NIH, Bethesda, MD 20892 USA. [Taylor, Kent D.; Chen, Y. -D. Ida; Rotter, Jerome I.] Harbor UCLA Med Ctr, Inst Translat Genom & Populat Sci, Los Angeles BioMed Res Inst, Torrance, CA 90502 USA. [Patele, Aniruddh P.] Yale Univ, Sch Med, New Haven, CT 06510 USA. [Lu, Yingchang; Gottesman, Omri; Bottinger, Erwin P.; Loos, Ruth J. F.] Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA. [Lu, Yingchang; Loos, Ruth J. F.] Icahn Sch Med Mt Sinai, Genet Obes & Related Metab Traits Program, New York, NY 10029 USA. [Hindy, George; Melander, Olle] Lund Univ, Dept Clin Sci Malmo, Clin Res Ctr, S-20502 Malmo, Sweden. [Orho-Melander, Marju] Lund Univ, Malmo Univ Hosp, Dept Clin Sci Diabet & Endocrinol, S-20502 Malmo, Sweden. [Loos, Ruth J. F.] Icahn Sch Med Mt Sinai, Mindich Child Hlth & Dev Inst, New York, NY 10029 USA. [Duga, Stefano; Asselta, Rosanna] Univ Milan, Dipartimento Biotecnol Med & Med Traslaz, I-20133 Milan, Italy. [Merlini, Piera Angelica; Ardissino, Diego] ASTC, I-27100 Pavia, Italy. [Merlini, Piera Angelica] Osped Maggiore Niguarda, Div Cardiol, I-20162 Milan, Italy. [Farrall, Martin; Goel, Anuj; Watkins, Hugh] Univ Oxford, Wellcome Trust Ctr Human Genet, Dept Cardiovasc Med, Oxford OX3 7BN, England. [Girelli, Domenico; Martinelli, Nicola] Univ Verona, Sch Med, Dept Med, I-37134 Verona, Italy. [Shah, Svati H.] Duke Univ, Div Urogynecol, Dept Obstet & Gynecol, Durham, NC 27710 USA. [Shah, Svati H.; Kraus, William E.] Duke Univ, Sch Med, Dept Med, Div Cardiol, Durham, NC 27710 USA. [Kraus, William E.] Duke Univ, Sch Med, Duke Mol Physiol Inst, Durham, NC 27701 USA. [Li, Mingyao] Univ Penn, Sch Med, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [McPherson, Ruth] Univ Ottawa, Inst Heart, Div Cardiol, Atherogen Lab, Ottawa, ON K1Y 4W7, Canada. [Watkins, Hugh] Merck Sharp & Dohme Corp, Rahway, NJ 07065 USA. [Ardissino, Diego] Azienda Osped Univ Parma, Div Cardiol, I-43100 Parma, Italy. [Tsai, Michael Y.] Univ Minnesota, Dept Lab Med & Pathol, Minneapolis, MN 55454 USA. [Taylor, Herman A.] Jackson State Univ, Jackson, MS 39217 USA. [Taylor, Herman A.] Tougaloo Coll, Tougaloo, MS 39174 USA. [Taylor, Herman A.; Correa, Adolfo; Griswold, Michael E.] Univ Mississippi, Med Ctr, Dept Med, Jackson, MS 39216 USA. [Lange, Leslie A.] Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA. [Starr, John M.] Univ Edinburgh, Alzheimer Scotland Dementia Res Ctr, Edinburgh EH8 9JZ, Midlothian, Scotland. [Rudan, Igor] Univ Edinburgh, Sch Med, Ctr Populat Hlth Sci, Edinburgh EH8 9AG, Midlothian, Scotland. [Rudan, Igor] Univ Split, Croatian Ctr Global Hlth, Fac Med, Split 21000, Croatia. [Ordovas, Jose M.] Natl Ctr Cardiovasc Investigat, Dept Cardiovasc Epidemiol & Populat Genet, Madrid 28049, Spain. [Ordovas, Jose M.] IMDEA Alimentac, Madrid 28049, Spain. [Ordovas, Jose M.] Tufts Univ, Jean Mayer USDA Human Nutr Res Ctr Aging, Nutr & Genom Lab, Medford, MA 02155 USA. [Ordovas, Jose M.] NHLBI, NIH, Bethesda, MD 20892 USA. [Polasek, Ozren] Univ Split, Fac Med, Dept Publ Hlth, Split 21000, Croatia. [Wilson, James G.] Univ Mississippi, Dept Physiol & Biophys, Med Ctr, Jackson, MS 39216 USA. [Psaty, Bruce M.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA 98101 USA. [Psaty, Bruce M.] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. [O'Donnell, Christopher J.; Kathiresan, Sekar] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Boerwinkle, Eric] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA. RP Kathiresan, S (reprint author), Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. EM skathiresan@partners.org; skathiresan@partners.org; adrienne@bu.edu RI Hindy, George/H-1864-2016; Duga, Stefano/F-8173-2014; Gudnason, Vilmundur/K-6885-2015; Polasek, Ozren/B-6002-2011; Rudan, Igor/I-1467-2012; Smith, Albert/K-5150-2015; Martinelli, Nicola/J-5622-2016; Hayward, Caroline/M-8818-2016; Feitosa, Mary/K-8044-2012; OI Mackey, Rachel/0000-0001-6088-2664; Hindy, George/0000-0002-7257-9299; Stitziel, Nathan/0000-0002-4963-8211; Manichaikul, Ani/0000-0002-5998-795X; Duga, Stefano/0000-0003-3457-1410; Watkins, Hugh/0000-0002-5287-9016; Pankow, James/0000-0001-7076-483X; Dehghan, Abbas/0000-0001-6403-016X; Gudnason, Vilmundur/0000-0001-5696-0084; Polasek, Ozren/0000-0002-5765-1862; Rudan, Igor/0000-0001-6993-6884; Smith, Albert/0000-0003-1942-5845; Martinelli, Nicola/0000-0001-6465-5119; Hayward, Caroline/0000-0002-9405-9550; Feitosa, Mary/0000-0002-0933-2410; Asselta, Rosanna/0000-0001-5351-0619; Reynolds, Lindsay/0000-0001-6157-0144 FU National Heart, Lung, and Blood Institute (NHLBI); NHLBI [RC2 HL-103010, RC2 HL-102923, RC2 HL-102924, RC2 HL-102925, RC2 HL-102926, T32HL007208]; National Heart, Lung, and Blood Institute [HL105756]; Massachusetts General Hospital (MGH); Howard Goodman Fellowship from MGH; Donovan Family Foundation [R01HL107816]; Fondation Leducq; NIH [RC2 HL-102925]; Merck; NIH/NHLBI [K08-HL114642]; NWO grant (veni) [916.12.154]; EUR Fellowship FX The authors wish to acknowledge the support of the National Heart, Lung, and Blood Institute (NHLBI) and the contributions of the research institutions, study investigators, field staff, and study participants in creating this resource for biomedical research. Funding for GO ESP was provided by NHLBI grants RC2 HL-103010 (HeartGO), RC2 HL-102923 (LungGO), and RC2 HL-102924 (WHISP). The exome sequencing was performed through NHLBI grants RC2 HL-102925 (BroadGO) and RC2 HL-102926 (SeattleGO). Infrastructure for the CHARGE Consortium is supported, in part, by the National Heart, Lung, and Blood Institute (grant HL105756). G.M.P. is supported by award number T32HL007208 from the NHLBI. S.K. is supported by a Research Scholar award from the Massachusetts General Hospital (MGH), the Howard Goodman Fellowship from MGH, the Donovan Family Foundation, R01HL107816, and a grant from Fondation Leducq. Exome Array genotyping in case-control studies of coronary heart disease was supported by NIH RC2 HL-102925 and an investigator-initiated research grant from Merck to S.K. N.O.S. is supported, in part, by a career development award from the NIH/NHLBI K08-HL114642. A.D. is supported by NWO grant (veni, 916.12.154) and the EUR Fellowship. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NHLBI or NIH. A full listing of acknowledgements is provided in Supplemental Data. NR 28 TC 99 Z9 100 U1 2 U2 23 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 FEB 6 PY 2014 VL 94 IS 2 BP 223 EP 232 DI 10.1016/j.ajhg.2014.01.009 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA AA9NF UT WOS:000331419500006 PM 24507774 ER PT J AU Lange, LA Hu, YN Zhang, H Xue, CY Schmidt, EM Tang, ZZ Bizon, C Lange, EM Smith, JD Turner, EH Jun, G Kang, HM Peloso, G Auer, P Li, KP Flannick, J Zhang, J Fuchsberger, C Gaulton, K Lindgren, C Locke, A Manning, A Sim, XL Rivas, MA Holmen, OL Gottesman, O Lu, YC Ruderfer, D Stah, EA Duan, Q Li, Y Durda, P Jiao, S Isaacs, A Hofman, A Bis, JC Correa, A Griswold, ME Jakobsdottir, J Smith, AV Schreiner, PJ Feitosa, ME Zhang, QY Huffman, JE Crosby, J Wasse, CL Do, R Franceschini, N Martin, LW Robinson, JG Assimes, TL Crosslin, DR Rosenthal, EA Tsai, M Rieder, MJ Farlow, DN Folsom, AR Lumley, T Fox, ER Carlson, CS Peters, U Jackson, RD Van Duijn, CM Uitterlinden, AG Levy, D Rotter, JI Taylor, HA Gudnason, V Siscovick, DS Fornage, M Borecki, IB Hayward, C Rudan, I Chen, YE Bottinger, EP Loos, RJF Strom, P Hveem, K Boehnke, M Groop, L McCarthy, M Meitinger, T Ballantyne, CM Gabriel, SB O'Donne, CJ Post, WS North, KE Reiner, AP Boerwinkle, E Psaty, BM Altshuler, D Kathiresan, S Lin, DY Jarvik, GP Cupples, LA Kooperberg, C Wilson, JG Nickerson, DA Abecasis, GR Rich, SS Tracy, RP Willer, CJ AF Lange, Leslie A. Hu, Youna Zhang, He Xue, Chenyi Schmidt, Ellen M. Tang, Zheng-Zheng Bizon, Chris Lange, Ethan M. Smith, Joshua D. Turner, Emily H. Jun, Goo Kang, Hyun Min Peloso, Gina Auer, Paul Li, Kuo-Ping Flannick, Jason Zhang, Ji Fuchsberger, Christian Gaulton, Kyle Lindgren, Cecilia Locke, Adam Manning, Alisa Sim, Xueling Rivas, Manuel A. Holmen, Oddgeir L. Gottesman, Omri Lu, Yingchang Ruderfer, Douglas Stah, Eli A. Duan, Qing Li, Yun Durda, Peter Jiao, Shuo Isaacs, Aaron Hofman, Albert Bis, Joshua C. Correa, Adolfo Griswold, Michael E. Jakobsdottir, Johanna Smith, Albert V. Schreiner, Pamela J. Feitosa, Mary E. Zhang, Qunyuan Huffman, Jennifer E. Crosby, Jacy Wasse, Christina L. Do, Ron Franceschini, Nora Martin, Lisa W. Robinson, Jennifer G. Assimes, Themistocles L. Crosslin, David R. Rosenthal, Elisabeth A. Tsai, Michael Rieder, Mark J. Farlow, Deborah N. Folsom, Aaron R. Lumley, Thomas Fox, Ervin R. Carlson, Christopher S. Peters, Ulrike Jackson, Rebecca D. Van Duijn, Cornelia M. Uitterlinden, Andre G. Levy, Daniel Rotter, Jerome I. Taylor, Herman A. Gudnason, Vilmundur, Jr. Siscovick, David S. Fornage, Myriam Borecki, Ingrid B. Hayward, Caroline Rudan, Igor Chen, Y. Eugene Bottinger, Erwin P. Loos, Ruth J. F. Strom, Pal Hveem, Kristian Boehnke, Michael Groop, Leif McCarthy, Mark Meitinger, Thomas Ballantyne, Christie M. Gabriel, Stacey B. O'Donne, Christopher J. Post, Wendy S. North, Kari E. Reiner, Alexander P. Boerwinkle, Eric Psaty, Bruce M. Altshuler, David Kathiresan, Sekar Lin, Dan-Yu Jarvik, Gail P. Cupples, L. Adrienne Kooperberg, Charles Wilson, James G. Nickerson, Deborah A. Abecasis, Goncalo R. Rich, Stephen S. Tracy, Russell P. Willer, Cristen J. CA NHLBI Grand Opportunity Exome Sequ TI Whole-Exome Sequencing Identifies Rare and Low-Frequency Coding Variants Associated with LDL Cholesterol SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID DENSITY-LIPOPROTEIN-CHOLESTEROL; HEART-DISEASE; DESIGN; PLASMA; OBJECTIVES; ATHEROSCLEROSIS; SUSCEPTIBILITY; ABSORPTION; SPECTRUM; RISK AB Elevated low-density lipoprotein cholesterol (LDL-C) is a treatable, heritable risk factor for cardiovascular disease. Genome-wide association studies (GWASs) have identified 157 variants associated with lipid levels but are not well suited to assess the impact of rare and low-frequency variants. To determine whether rare or low-frequency coding variants are associated with LDL-C, we exome sequenced 2,005 individuals, including 554 individuals selected for extreme LDL-C (>98th or <2nd percentile). Follow-up analyses included sequencing of 1,302 additional individuals and genotype-based analysis of 52,221 individuals. We observed significant evidence of association between LDL-C and the burden of rare or low-frequency variants in PNPLA5, encoding a phospholipase-domain-containing protein, and both known and previously unidentified variants in PCSK9, LDLR and APOB, three known lipid-related genes. The effect sizes for the burden of rare variants for each associated gene were substantially higher than those observed for individual SNPs identified from GWASs. We replicated the PNPLA5 signal in an independent large-scale sequencing study of 2,084 individuals. In conclusion, this large whole-exome-sequencing study for LDL-C identified a gene not known to be implicated in LDL-C and provides unique insight into the design and analysis of similar experiments. C1 [Lange, Leslie A.; Lange, Ethan M.; Duan, Qing; Li, Yun] Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA. [Hu, Youna; Jun, Goo; Kang, Hyun Min; Li, Kuo-Ping; Fuchsberger, Christian; Locke, Adam; Sim, Xueling; Boehnke, Michael; Abecasis, Goncalo R.] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA. [Zhang, He; Zhang, Ji; Chen, Y. Eugene; Willer, Cristen J.] Univ Michigan, Dept Internal Med, Div Cardiovasc Med, Ann Arbor, MI 48109 USA. [Xue, Chenyi; Schmidt, Ellen M.; Willer, Cristen J.] Univ Michigan, Dept Computat Med & Bioinformat, Ann Arbor, MI 48109 USA. [Tang, Zheng-Zheng; Lange, Ethan M.; Li, Yun; Lin, Dan-Yu] Univ N Carolina, Dept Biostat, Chapel Hill, NC 27599 USA. [Bizon, Chris] Renaissance Comp Inst, Chapel Hill, NC 27517 USA. [Smith, Joshua D.; Turner, Emily H.; Rieder, Mark J.; Jarvik, Gail P.; Nickerson, Deborah A.] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA. [Peloso, Gina; Do, Ron; Altshuler, David; Kathiresan, Sekar] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Peloso, Gina; Manning, Alisa; Do, Ron; Gabriel, Stacey B.; Altshuler, David; Kathiresan, Sekar] Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA 02141 USA. [Auer, Paul; Jiao, Shuo; Carlson, Christopher S.; Peters, Ulrike; Kooperberg, Charles] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA. [Auer, Paul; Manning, Alisa] Univ Wisconsin, Sch Publ Hlth, Milwaukee, WI 53201 USA. [Flannick, Jason; Manning, Alisa; Farlow, Deborah N.] Broad Inst Harvard & MIT, Cambridge, MA 02141 USA. [Flannick, Jason; Altshuler, David] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Gaulton, Kyle; Lindgren, Cecilia; Rivas, Manuel A.] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX1 2JD, England. [Manning, Alisa; Altshuler, David] Harvard Univ, Dept Genet, Sch Med, Boston, MA 02138 USA. [Holmen, Oddgeir L.; Hveem, Kristian] Norwegian Univ Sci & Technol, Dept Publ Hlth, HUNT Res Ctr, N-7600 Levanger, Norway. [Gottesman, Omri; Bottinger, Erwin P.] Charles Bronfman Inst Personalized Med, Icahn Sch Med Mt Sinai, New York, NY 10029 USA. [Lu, Yingchang; Loos, Ruth J. F.] Charles Bronfman Inst Personalized Med, Icahn Sch Med Mt Sinai, Genet Obes & Related Metab Traits Program, New York, NY 10029 USA. [Ruderfer, Douglas; Stah, Eli A.] Icahn Sch Med Mt Sinai, Dept Psychiat, Div Psychiat Genom, New York, NY 10029 USA. [Li, Yun] Univ N Carolina, Dept Comp Sci, Chapel Hill, NC 27599 USA. [Durda, Peter; Tracy, Russell P.] Univ Vermont, Dept Pathol, Colchester, VT 05446 USA. [Isaacs, Aaron; Van Duijn, Cornelia M.] Erasmus MC, Dept Epidemiol, Genet Epidemiol Unit, NL-3015 DR Rotterdam, Netherlands. [Hofman, Albert] Erasmus MC, Dept Epidemiol, NL-3000 DR Rotterdam, Netherlands. [Bis, Joshua C.; Siscovick, David S.; Psaty, Bruce M.] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Correa, Adolfo; Griswold, Michael E.; Fox, Ervin R.; Taylor, Herman A.] Univ Mississippi Med Ctr, Dept Med, Jackson, MS 39216 USA. [Jakobsdottir, Johanna; Smith, Albert V.; Gudnason, Vilmundur, Jr.] Iceland Heart Assoc, IS-201 Kopavogur, Iceland. [Smith, Albert V.; Gudnason, Vilmundur, Jr.] Univ Iceland, IS-101 Reykjavik, Iceland. [Schreiner, Pamela J.; Tsai, Michael; Folsom, Aaron R.] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN 55454 USA. [Feitosa, Mary E.; Zhang, Qunyuan; Borecki, Ingrid B.] Washington Univ, Div Stat Genom, Dept Genet, Sch Med, St Louis, MO 63110 USA. [Huffman, Jennifer E.; Hayward, Caroline] Univ Edinburgh, Med Res Ctr Human Genet, Med Res Ctr Inst Genet & Mol Med, Edinburgh EH4 2XU, Midlothian, Scotland. [Crosby, Jacy; Fornage, Myriam; Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Houston, TX 77030 USA. [Wasse, Christina L.] Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15261 USA. [Franceschini, Nora; North, Kari E.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27599 USA. [Martin, Lisa W.] George Washington Sch Med & Hlth Sci, Div Cardiol, Washington, DC 20037 USA. [Robinson, Jennifer G.] Univ Iowa, Dept Epidemiol, Iowa City, IA 52242 USA. [Robinson, Jennifer G.] Univ Iowa, Dept Med, Iowa City, IA 52242 USA. [Assimes, Themistocles L.] Stanford Univ, Dept Med, Sch Med, Stanford, CA 94305 USA. [Crosslin, David R.; Rosenthal, Elisabeth A.; Jarvik, Gail P.] Univ Washington, Dept Med, Div Med Genet, Seattle, WA 98195 USA. [Crosslin, David R.; Lumley, Thomas] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Lumley, Thomas] Univ Auckland, Dept Stat, Auckland 1142, New Zealand. [Jackson, Rebecca D.] Ohio State Univ, Div Endocrinol, Columbus, OH 43210 USA. [Uitterlinden, Andre G.] Erasmus MC, Dept Internal Med, NL-3000 DR Rotterdam, Netherlands. [Levy, Daniel; O'Donne, Christopher J.; Cupples, L. Adrienne] NHLBI, Ctr Populat Studies, Framingham, MA 01702 USA. [Levy, Daniel] NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. [Rotter, Jerome I.] Harbor UCLA Med Ctr, Inst Translat Genom & Populat Sci, Los Angeles BioMed Res Inst, Torrance, CA 90502 USA. [Rotter, Jerome I.] Harbor UCLA Med Ctr, Dept Pediat, Torrance, CA 90502 USA. [Taylor, Herman A.] Tougaloo Coll, Jackson, MS 39174 USA. [Taylor, Herman A.] Jackson State Univ, Jackson, MS 39217 USA. [Siscovick, David S.; Reiner, Alexander P.; Psaty, Bruce M.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Siscovick, David S.; Psaty, Bruce M.] Univ Washington, Dept Med, Med Ctr, Seattle, WA 98195 USA. [Fornage, Myriam] Univ Texas Hlth Sci Ctr Houston, Inst Mol Med, Houston, TX 77030 USA. [Rudan, Igor] Univ Edinburgh, Ctr Populat Hlth Sci, Sch Med, Edinburgh EH8 9YL, Midlothian, Scotland. [Strom, Pal] Norwegian Univ Sci & Technol, Dept Comp & Informat Sci, N-7491 Trondheim, Norway. [Strom, Pal] Norwegian Univ Sci & Technol, Dept Canc Res & Mol Med, N-7489 Trondheim, Norway. [Groop, Leif] Lund Univ, Dept Clin Sci Diabet & Endocrinol, Skane Univ Hosp, S-22100 Malmo, Sweden. [Groop, Leif] Glostrup Univ Hosp, Glostrup Res Inst, DK-2600 Glostrup, Denmark. [McCarthy, Mark] Univ Oxford, Churchill Hosp, Oxford Ctr Diabet Endocrinol & Metab, Oxford OX1 2JD, England. [McCarthy, Mark] Univ Oxford, Churchill Hosp, Oxford Natl Inst Hlth Res Biomed Res Ctr, Oxford OX1 2JD, England. [Meitinger, Thomas] German Res Ctr Environm Hlth, Helmholtz Ctr Munich, Inst Human Genet, D-85764 Neuherberg, Germany. [Meitinger, Thomas] Tech Univ Munich, Inst Human Genet, D-85764 Neuherberg, Germany. [Ballantyne, Christie M.] Baylor Coll Med, Houston, TX 77030 USA. [Ballantyne, Christie M.] Houston Methodist DeBakey Heart & Vasc Ctr, Houston, TX 77030 USA. [O'Donne, Christopher J.; Kathiresan, Sekar] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Post, Wendy S.] Johns Hopkins Univ, Dept Med, Sch Med, Baltimore, MD 21205 USA. [Psaty, Bruce M.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA 98195 USA. [Cupples, L. Adrienne] Boston Univ, Dept Biostat, Sch Publ Hlth, Boston, MA 02215 USA. [Wilson, James G.] Univ Mississippi, Med Ctr, Dept Physiol & Biophys, Jackson, MS 39216 USA. [Rich, Stephen S.] Univ Virginia, Ctr Publ Hlth Genom, Charlottesville, VA 22908 USA. [Tracy, Russell P.] Univ Vermont, Dept Biochem, Burlington, VT 05405 USA. [Willer, Cristen J.] Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA. RP Willer, CJ (reprint author), Univ Michigan, Dept Internal Med, Div Cardiovasc Med, Ann Arbor, MI 48109 USA. EM cristen@umich.edu RI Johnson, Andrew/G-6520-2013; Feitosa, Mary/K-8044-2012; Jun, Goo/F-1941-2017; Singleton, Andrew/C-3010-2009; Zhang, Ji/J-4009-2014; Jarvik, Gail/N-6476-2014; Altshuler, David/A-4476-2009; Hardy, John/C-2451-2009; Tang, Zheng-Zheng/F-6642-2014; de Bakker, Paul/B-8730-2009; Gudnason, Vilmundur/K-6885-2015; Meitinger, Thomas/O-1318-2015; Rudan, Igor/I-1467-2012; Smith, Albert/K-5150-2015; Ruderfer, Douglas/M-5795-2016; Hayward, Caroline/M-8818-2016 OI Martin, Lisa Warsinger/0000-0003-4352-0914; Locke, Adam/0000-0001-6227-198X; Turner, Emily/0000-0001-9040-9229; Saetrom, Pal/0000-0001-8142-7441; Shendure, Jay/0000-0002-1516-1865; Assimes, Themistocles/0000-0003-2349-0009; Feitosa, Mary/0000-0002-0933-2410; Jun, Goo/0000-0003-0891-0204; Quinlan, Aaron/0000-0003-1756-0859; Willer, Cristen/0000-0001-5645-4966; Seshadri, Sudha/0000-0001-6135-2622; Fuchsberger, Christian/0000-0002-5918-8947; Jarvik, Gail/0000-0002-6710-8708; Altshuler, David/0000-0002-7250-4107; Tang, Zheng-Zheng/0000-0003-3802-8087; de Bakker, Paul/0000-0001-7735-7858; Gudnason, Vilmundur/0000-0001-5696-0084; Rudan, Igor/0000-0001-6993-6884; Smith, Albert/0000-0003-1942-5845; Ruderfer, Douglas/0000-0002-2365-386X; Hayward, Caroline/0000-0002-9405-9550 FU NHLBI [RC2 HL-103010, RC2 HL-102923, RC2 HL-102924, RC2 HL-102925, RC2 HL-102926]; Northwest Institute of Genomic Medicine; Washington State Life Sciences Discovery Fund; National Institutes of Health [R01HL107816]; Amarin; Amgen; Astra-Zeneca; Daiichi-Sankyo; Esperion; F. Hoffman-La Roche; Glaxo-Smith Kline; Merck; Regeneron; Sanofi; Takeda; Zinfandel; [R01 HL67406]; [R00 HL94535]; [R01 HL109946] FX The authors wish to acknowledge the support of the NHLBI and the contributions of the research institutions, study investigators, field staff, and study participants in creating this resource for biomedical research. Funding for the NHLBI Grand Opportunity (GO) Exome Sequencing Project was provided by NHLBI grants RC2 HL-103010 (HeartGO), RC2 HL-102923 (LungGO), and RC2 HL-102924 (Women's Health Initiative Sequencing Project). Exome sequencing was performed through NHLBI grants RC2 HL-102925 (BroadGO) and RC2 HL-102926 (SeattleGO). G.J. is supported by R01 HL67406 and the Northwest Institute of Genomic Medicine, funded by the Washington State Life Sciences Discovery Fund. S.K.'s effort is funded through National Institutes of Health grant R01HL107816. C.J.W. is supported by R00 HL94535 and R01 HL109946. The University of Iowa receives financial support from Amarin, Amgen, Astra-Zeneca, Daiichi-Sankyo, Esperion, F. Hoffman-La Roche, Glaxo-Smith Kline, Merck, Regeneron and Sanofi, and Takeda and Zinfandel for J.G.R's research. B.M.P serves on the data and safety monitoring board of a clinical trial for Zoll LifeCor. Additional acknowledgements are provided in the Supplemental Data. NR 41 TC 87 Z9 89 U1 2 U2 19 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 FEB 6 PY 2014 VL 94 IS 2 BP 233 EP 245 DI 10.1016/j.ajhg.2014.01.010 PG 13 WC Genetics & Heredity SC Genetics & Heredity GA AA9NF UT WOS:000331419500007 PM 24507775 ER PT J AU Abdel-Kader, K Jhamb, M Mandich, LA Yabes, J Keene, RM Beach, S Buysse, DJ Unruh, ML AF Abdel-Kader, Khaled Jhamb, Manisha Mandich, Lee Anne Yabes, Jonathan Keene, Robert M. Beach, Scott Buysse, Daniel J. Unruh, Mark L. TI Ecological momentary assessment of fatigue, sleepiness, and exhaustion in ESKD SO BMC NEPHROLOGY LA English DT Article DE End-stage renal disease; Alertness; Fatigue; Symptoms; Ecological momentary assessment ID QUALITY-OF-LIFE; CHRONIC KIDNEY-DISEASE; POSTDIALYSIS FATIGUE; MAINTENANCE DIALYSIS; PHYSICAL-ACTIVITY; HEMODIALYSIS; EXPERIENCE; SYMPTOMS; ASSOCIATION; IMPACT AB Background: Many patients on maintenance dialysis experience significant sleepiness and fatigue. However, the influence of the hemodialysis (HD) day and circadian rhythms on patients' symptoms have not been well characterized. We sought to use ecological momentary assessment to evaluate day-to-day and diurnal variability of fatigue, sleepiness, exhaustion and related symptoms in thrice-weekly maintenance HD patients. Methods: Subjects used a modified cellular phone to access an interactive voice response system that administered the Daytime Insomnia Symptom Scale (DISS). The DISS assessed subjective vitality, mood, and alertness through 19 questions using 7-point Likert scales. Subjects completed the DISS 4 times daily for 7 consecutive days. Factor analysis was conducted and a mean composite score of fatigue-sleepiness-exhaustion was created. Linear mixed regression models (LMM) were used to examine the association of time of day, dialysis day and fatigue, sleepiness, and exhaustion composite scores. Results: The 55 participants completed 1,252 of 1,540 (81%) possible assessments over the 7 day period. Multiple symptoms related to mood (e.g., feeling sad, feeling tense), cognition (e. g., difficulty concentrating), and fatigue (e.g., exhaustion, feeling sleepy) demonstrated significant daily and diurnal variation, with higher overall symptom scores noted on hemodialysis days and later in the day. In factor analysis, 4 factors explained the majority of the observed variance for DISS symptoms. Fatigue, sleepiness, and exhaustion loaded onto the same factor and were highly intercorrelated. In LMM, mean composite fatigue-sleepiness-exhaustion scores were associated with dialysis day (coefficient and 95% confidence interval [CI] 0.21 [0.02 - 0.39]) and time of day (coefficient and 95% CI 0.33 [0.25 - 0.41]. Observed associations were minimally affected by adjustment for demographics and common confounders. Conclusions: Maintenance HD patients experience fatigue-sleepiness-exhaustion symptoms that demonstrate significant daily and diurnal variation. The variability in symptoms may contribute to poor symptom awareness by providers and greater misclassification bias of fatigue related symptoms in clinical studies. C1 [Abdel-Kader, Khaled] Vanderbilt Univ, Med Ctr, Div Nephrol & Hypertens, Nashville, TN 37232 USA. [Jhamb, Manisha] Univ Pittsburgh, Renal Electrolyte Div, Pittsburgh, PA USA. [Mandich, Lee Anne] VA Pittsburgh Healthcare Syst, Renal Sect, Pittsburgh, PA USA. [Yabes, Jonathan] Univ Pittsburgh, Ctr Res Hlth Care, Div Gen Internal Med, Pittsburgh, PA USA. [Keene, Robert M.; Beach, Scott] Univ Pittsburgh, Univ Ctr Social & Urban Res, Pittsburgh, PA USA. [Buysse, Daniel J.] Univ Pittsburgh, Sleep Med Inst, Dept Psychiat, Pittsburgh, PA USA. [Unruh, Mark L.] Univ New Mexico, Div Nephrol, Albuquerque, NM 87131 USA. RP Abdel-Kader, K (reprint author), Vanderbilt Univ, Med Ctr, Div Nephrol & Hypertens, 1161 21st Ave South,MCN S-3223, Nashville, TN 37232 USA. EM khaled.abdel-kader@vanderbilt.edu OI Abdel-Kader, Khaled/0000-0002-6412-8498 FU National Institutes of Health [K23DK090304, R01DK077785]; American Heart Association [11FTF7520014] FX This work was supported by National Institutes of Health grants K23DK090304 (Abdel-Kader) and R01DK077785 (Unruh) and American Heart Association grant 11FTF7520014 (Jhamb). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 47 TC 4 Z9 4 U1 2 U2 9 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 FEB 6 PY 2014 VL 15 AR 29 DI 10.1186/1471-2369-15-29 PG 8 WC Urology & Nephrology SC Urology & Nephrology GA AB9PV UT WOS:000332128500001 PM 24502751 ER PT J AU Shivdasani, RA AF Shivdasani, Ramesh A. TI Radiation Redux: Reserve Intestinal Stem Cells Miss the Call to Duty SO CELL STEM CELL LA English DT Editorial Material ID LGR5 AB Distinct stem cell populations in intestinal crypts mediate tissue homeostasis and responses to epithelial damage such as radiation. Now in Cell Stem Cell, Metcalfe et al. (2014) demonstrate that homeostatic, proliferative Lrg5(+) cells are necessary to regenerate the epithelium after radiation, whereas quiescent Lgr5(-) reserve stem cells are surprisingly radiosensitive. C1 [Shivdasani, Ramesh A.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Shivdasani, Ramesh A.] Dana Farber Canc Inst, Ctr Funct Canc Epigenet, Boston, MA 02215 USA. [Shivdasani, Ramesh A.] Brigham & Womens Hosp, Dept Med, Boston, MA 02215 USA. [Shivdasani, Ramesh A.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02215 USA. RP Shivdasani, RA (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. EM ramesh_shivdasani@dfci.harvard.edu FU NIDDK NIH HHS [R01 DK082889, R01 DK081113, R01DK081113, R01DK082889] NR 9 TC 2 Z9 2 U1 1 U2 3 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 FEB 6 PY 2014 VL 14 IS 2 BP 135 EP 136 DI 10.1016/j.stem.2014.01.015 PG 2 WC Cell & Tissue Engineering; Cell Biology SC Cell Biology GA AA1DF UT WOS:000330835800003 PM 24506878 ER PT J AU Zon, L AF Zon, Leonard TI Translational Research: The Path for Bringing Discovery to Patients SO CELL STEM CELL LA English DT Editorial Material AB Translating basic research findings into therapeutic settings presents many scientific, logistic, and financial challenges for academic researchers. Here, I highlight some key insights for navigating such challenges based on recent clinical trials initiated by basic research from my lab. C1 [Zon, Leonard] Harvard Univ, Sch Med, Childrens Hosp, Stem Cell Program & Hematol Oncol, Boston, MA 02115 USA. [Zon, Leonard] Harvard Univ, Sch Med, Dana Farber Canc Inst, HHMI,Harvard Stem Cell Inst, Boston, MA 02115 USA. RP Zon, L (reprint author), Harvard Univ, Sch Med, Childrens Hosp, Stem Cell Program & Hematol Oncol, Boston, MA 02115 USA. EM zon@enders.tch.harvard.edu FU Howard Hughes Medical Institute NR 4 TC 3 Z9 3 U1 0 U2 7 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 FEB 6 PY 2014 VL 14 IS 2 BP 146 EP 148 DI 10.1016/j.stem.2014.01.004 PG 3 WC Cell & Tissue Engineering; Cell Biology SC Cell Biology GA AA1DF UT WOS:000330835800007 PM 24506882 ER PT J AU Walensky, RP Cohen, MS Freedberg, KA AF Walensky, Rochelle P. Cohen, Myron S. Freedberg, Kenneth A. TI Cost-Effectiveness of HIV Treatment as Prevention in Serodiscordant Couples REPLY SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [Walensky, Rochelle P.; Freedberg, Kenneth A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Cohen, Myron S.] Univ N Carolina, Chapel Hill, NC USA. RP Walensky, RP (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. EM rwalensky@partners.org NR 0 TC 1 Z9 1 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 FEB 6 PY 2014 VL 370 IS 6 BP 581 EP 582 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA AA4NT UT WOS:000331073500029 PM 24499229 ER PT J AU Chaudhury, A Cristofaro, V Carew, JA Goyal, RK Sullivan, MP AF Chaudhury, Arun Cristofaro, Vivian Carew, Josephine A. Goyal, Raj K. Sullivan, Maryrose P. TI Myosin Va Plays a Role in Nitrergic Smooth Muscle Relaxation in Gastric Fundus and Corpora Cavernosa of Penis SO PLOS ONE LA English DT Article ID NITRIC-OXIDE SYNTHASE; INHIBITORY NEUROTRANSMISSION; ERECTILE DYSFUNCTION; PROTEIN INHIBITOR; MOUSE STRAINS; KNOCKOUT MICE; NEURONAL NOS; NNOS-ALPHA; RAT; EXPRESSION AB The intracellular motor protein myosin Va is involved in nitrergic neurotransmission possibly by trafficking of neuronal nitric oxide synthase (nNOS) within the nerve terminals. In this study, we examined the role of myosin Va in the stomach and penis, proto-typical smooth muscle organs in which nitric oxide (NO) mediated relaxation is critical for function. We used confocal microscopy and co-immunoprecipitation of tissue from the gastric fundus (GF) and penile corpus cavernosum (CCP) to localize myosin Va with nNOS and demonstrate their molecular interaction. We utilized in vitro mechanical studies to test whether smooth muscle relaxations during nitrergic neuromuscular neurotransmission is altered in DBA (dilute, brown, non-agouti) mice which lack functional myosin Va. Myosin Va was localized in nNOS-positive nerve terminals and was co-immunoprecipitated with nNOS in both GF and CCP. In comparison to C57BL/6J wild type (WT) mice, electrical field stimulation (EFS) of precontracted smooth muscles of GF and CCP from DBA animals showed significant impairment of nitrergic relaxation. An NO donor, Sodium nitroprusside (SNP), caused comparable levels of relaxation in smooth muscles of WT and DBA mice. These normal postjunctional responses to SNP in DBA tissues suggest that impairment of smooth muscle relaxation resulted from inhibition of NO synthesis in prejunctional nerve terminals. Our results suggest that normal physiological processes of relaxation of gastric and cavernosal smooth muscles that facilitate food accommodation and penile erection, respectively, may be disrupted under conditions of myosin Va deficiency, resulting in complications like gastroparesis and erectile dysfunction. C1 [Chaudhury, Arun] VA Boston Healthcare Syst, Div Surg, Boston, MA USA. [Chaudhury, Arun; Cristofaro, Vivian; Carew, Josephine A.; Goyal, Raj K.; Sullivan, Maryrose P.] Harvard Univ, Sch Med, Boston, MA USA. [Cristofaro, Vivian; Sullivan, Maryrose P.] VA Boston Healthcare Syst, Div Urol, Boston, MA 02130 USA. [Carew, Josephine A.; Goyal, Raj K.] VA Boston Healthcare Syst, Div Med, Boston, MA USA. RP Sullivan, MP (reprint author), VA Boston Healthcare Syst, Div Urol, Boston, MA 02130 USA. EM msullivan@rics.bwh.harvard.edu FU Public Health Service [DK062867]; Medical Research Service, Department of Veterans Affairs, Washington, D.C. [BX001790] FX The study was supported by a Public Health Service grant (DK062867, RKG) and Medical Research Service, Department of Veterans Affairs, Washington, D.C. (BX001790, MPS). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 39 TC 1 Z9 1 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 FEB 6 PY 2014 VL 9 IS 2 AR e86778 DI 10.1371/journal.pone.0086778 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AA1BH UT WOS:000330830700014 PM 24516539 ER PT J AU Toruno, C Carbonneau, S Stewart, RA Jette, C AF Toruno, Cristhian Carbonneau, Seth Stewart, Rodney A. Jette, Cicely TI Interdependence of Bad and Puma during Ionizing-Radiation-Induced Apoptosis SO PLOS ONE LA English DT Article ID DNA-DAMAGE RESPONSE; BCL-X-L; CELL-SURVIVAL; MEMBRANE PERMEABILIZATION; MITOCHONDRIAL APOPTOSIS; DEPENDENT APOPTOSIS; BH3 DOMAINS; PROTEINS; PHOSPHORYLATION; AKT AB Ionizing radiation (IR)-induced DNA double-strand breaks trigger an extensive cellular signaling response that involves the coordination of hundreds of proteins to regulate DNA repair, cell cycle arrest and apoptotic pathways. The cellular outcome often depends on the level of DNA damage as well as the particular cell type. Proliferating zebrafish embryonic neurons are highly sensitive to IR-induced apoptosis, and both p53 and its transcriptional target puma are essential mediators of the response. The BH3-only protein Puma has previously been reported to activate mitochondrial apoptosis through direct interaction with the pro-apoptotic Bcl-2 family proteins Bax and Bak, thus constituting the role of an "activator" BH3-only protein. This distinguishes it from BH3-only proteins like Bad that are thought to indirectly promote apoptosis through binding to anti-apoptotic Bcl-2 family members, thereby preventing the sequestration of activator BH3-only proteins and allowing them to directly interact with and activate Bax and Bak. We have shown previously that overexpression of the BH3-only protein Bad in zebrafish embryos supports normal embryonic development but greatly sensitizes developing neurons to IR-induced apoptosis. While Bad has previously been shown to play only a minor role in promoting IR-induced apoptosis of T cells in mice, we demonstrate that Bad is essential for robust IR-induced apoptosis in zebrafish embryonic neural tissue. Moreover, we found that both p53 and Puma are required for Bad-mediated radiosensitization in vivo. Our findings show the existence of a hierarchical interdependence between Bad and Puma whereby Bad functions as an essential sensitizer and Puma as an essential activator of IR-induced mitochondrial apoptosis specifically in embryonic neural tissue. C1 [Toruno, Cristhian; Stewart, Rodney A.; Jette, Cicely] Univ Utah, Huntsman Canc Inst, Dept Oncol Sci, Salt Lake City, UT 84112 USA. [Carbonneau, Seth] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Carbonneau, Seth] Harvard Univ, Sch Med, Boston, MA USA. RP Jette, C (reprint author), Univ Utah, Huntsman Canc Inst, Dept Oncol Sci, Salt Lake City, UT 84112 USA. EM Cicely.Jette@hci.utah.edu OI Stewart, Rodney/0000-0003-1220-1830 FU Huntsman Cancer Foundation; NIH [5K01DK074555-06] FX This work was supported by the Huntsman Cancer Foundation and NIH grant 5K01DK074555-06. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 43 TC 9 Z9 9 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 FEB 6 PY 2014 VL 9 IS 2 AR e88151 DI 10.1371/journal.pone.0088151 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AA1BH UT WOS:000330830700048 PM 24516599 ER PT J AU Gao, L Song, CM Gao, ZY Barabasi, AL Bagrow, JP Wang, DS AF Gao, Liang Song, Chaoming Gao, Ziyou Barabasi, Albert-Laszlo Bagrow, James P. Wang, Dashun TI Quantifying Information Flow During Emergencies SO SCIENTIFIC REPORTS LA English DT Article ID HUMAN MOBILITY; INFECTIOUS-DISEASES; HUMAN DYNAMICS; SCALING LAWS; NETWORKS; PATTERNS; PREDICTABILITY; RECIPROCITY; EPIDEMICS; BEHAVIOR AB Recent advances on human dynamics have focused on the normal patterns of human activities, with the quantitative understanding of human behavior under extreme events remaining a crucial missing chapter. This has a wide array of potential applications, ranging from emergency response and detection to traffic control and management. Previous studies have shown that human communications are both temporally and spatially localized following the onset of emergencies, indicating that social propagation is a primary means to propagate situational awareness. We study real anomalous events using country-wide mobile phone data, finding that information flow during emergencies is dominated by repeated communications. We further demonstrate that the observed communication patterns cannot be explained by inherent reciprocity in social networks, and are universal across different demographics. C1 [Gao, Liang; Gao, Ziyou] Beijing Jiaotong Univ, State Key Lab Rail Traff Control & Safety, Inst Syst Sci, Beijing 100044, Peoples R China. [Gao, Liang; Gao, Ziyou] Beijing Jiaotong Univ, MOE Key Lab Urban Transportat Complex Syst Theory, Beijing 100044, Peoples R China. [Gao, Liang; Barabasi, Albert-Laszlo] Northeastern Univ, Dept Phys, Ctr Complex Network Res, Boston, MA 02115 USA. [Song, Chaoming] Univ Miami, Dept Phys, Coral Gables, FL 33146 USA. [Barabasi, Albert-Laszlo] Dana Farber Canc Inst, Ctr Canc Syst Biol, Boston, MA 02115 USA. [Barabasi, Albert-Laszlo] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Med, Boston, MA 02115 USA. [Bagrow, James P.] Northwestern Univ, NW Inst Complex Syst, Dept Engn Sci & Appl Math, Evanston, IL 60208 USA. [Bagrow, James P.] Univ Vermont, Vermont Adv Comp Ctr, Ctr Complex Syst, Dept Math & Stat, Burlington, VT 05405 USA. [Wang, Dashun] IBM Corp, Thomas J Watson Res Ctr, Yorktown Hts, NY 10598 USA. RP Wang, DS (reprint author), IBM Corp, Thomas J Watson Res Ctr, Yorktown Hts, NY 10598 USA. EM dashun@us.ibm.com FU Network Science Collaborative Technology Alliance; US Army Research Laboratory [W911NF-09-2-0053]; Office of Naval Research [N000141010968]; Defense Threat Reduction Agency [WMDBRBAA07-J-2-0035, BRBAA08-Per4-C-2-0033]; James S. Mc-Donnell Foundation 21st Century Initiative in Studying Complex Systems; Major State Basic Research Development Program of China (973 Program) [2012CB725400]; China Scholarship Council; National Natural Science Foundation of China [71101009, 71131001]; Fundamental Research Funds for the Central Universities [2012JBM067] FX This work was supported by the Network Science Collaborative Technology Alliance sponsored by the US Army Research Laboratory under Agreement Number W911NF-09-2-0053; the Office of Naval Research under Agreement Number N000141010968; the Defense Threat Reduction Agency awards WMDBRBAA07-J-2-0035 and BRBAA08-Per4-C-2-0033; and the James S. Mc-Donnell Foundation 21st Century Initiative in Studying Complex Systems. L. Gao and Z. Gao thank the financial support from the Major State Basic Research Development Program of China (973 Program) No. 2012CB725400, the China Scholarship Council, the National Natural Science Foundation of China (71101009, 71131001), and the Fundamental Research Funds for the Central Universities No. 2012JBM067. NR 46 TC 15 Z9 15 U1 1 U2 60 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 FEB 6 PY 2014 VL 4 AR 3997 DI 10.1038/srep03997 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AA6QU UT WOS:000331223800001 PM 24499738 ER PT J AU Medina, I Friedel, P Rivera, C Kahle, KT Kourdougli, N Uvarov, P Pellegrino, C AF Medina, Igor Friedel, Perrine Rivera, Claudio Kahle, Kristopher T. Kourdougli, Nazim Uvarov, Pavel Pellegrino, Christophe TI Current view on the functional regulation of the neuronal K+-Cl- cotransporter KCC2 SO FRONTIERS IN CELLULAR NEUROSCIENCE LA English DT Review DE KCC2; intracellular chloride; GABA; neurons ID CATION-CHLORIDE COTRANSPORTERS; TRANSPORT-INDEPENDENT MECHANISM; DEVELOPMENTAL UP-REGULATION; GREEN FLUORESCENT PROTEIN; GAMMA-AMINOBUTYRIC-ACID; RAT HIPPOCAMPAL-NEURONS; TEMPORAL-LOBE EPILEPSY; AUDITORY BRAIN-STEM; INTRACELLULAR CHLORIDE; DOWN-REGULATION AB In the mammalian central nervous system (CNS), the inhibitory strength of chloride (Cl-)-permeable GABA(A) and glycine receptors (GABA(A)R and GlyR) depends on the intracellular Cl- concentration ([Cl-](i)). Lowering [Cl-](i) enhances inhibition, whereas raising [Cl-](i) facilitates neuronal activity. A neuron's basal level of [Cl-](i), as well as its Cl- extrusion capacity, is critically dependent on the activity of the electroneutral K+-Cl- cotransporter KCC2, a member of the SLC12 cation-Cl- cotransporter (CCC) family. KCC2 deficiency compromises neuronal migration, formation and the maturation of GABAergic and glutamatergic synaptic connections, and results in network hyperexcitability and seizure activity. Several neurological disorders including multiple epilepsy subtypes, neuropathic pain, and schizophrenia, as well as various insults such as trauma and ischemia, are associated with significant decreases in the Cl- extrusion capacity of KCC2 that result in increases of [Cl-](i) and the subsequent hyperexcitability of neuronal networks. Accordingly, identifying the key upstream molecular mediators governing the functional regulation of KCC2, and modifying these signaling pathways with small molecules, might constitute a novel neurotherapeutic strategy for multiple diseases. Here, we discuss recent advances in the understanding of the mechanisms regulating KCC2 activity, and of the role these mechanisms play in neuronal Cl homeostasis and GABAergic neurotransmission. As KCC2 mediates electroneutral transport, the experimental recording of its activity constitutes an important research challenge; we therefore also, provide an overview of the different methodological approaches utilized to monitor function of KCC2 in both physiological and pathological conditions. C1 [Medina, Igor; Friedel, Perrine; Rivera, Claudio; Kourdougli, Nazim; Pellegrino, Christophe] INSERM, Inst Neurobiol Mediterranee INMED, F-13273 Marseille, France. [Medina, Igor; Friedel, Perrine; Rivera, Claudio; Kourdougli, Nazim; Pellegrino, Christophe] Aix Marseille Univ, UMR901, Marseille, France. [Rivera, Claudio] Univ Helsinki, Ctr Neurosci, Helsinki, Finland. [Kahle, Kristopher T.] Boston Childrens Hosp, Howard Hughes Med Inst, Dept Cardiol, Manton Ctr Orphan Dis Res, Boston, MA USA. [Kahle, Kristopher T.] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. [Kahle, Kristopher T.] Harvard Univ, Sch Med, Boston, MA USA. [Uvarov, Pavel] Univ Helsinki, Inst Biomed, Helsinki, Finland. RP Medina, I (reprint author), INSERM, Inst Neurobiol Mediterranee INMED, U901, 163 Route Luminy, F-13273 Marseille, France. EM igor.medyna@inserm.fr RI Medina, Igor/O-5532-2016; Pellegrino, Christophe/P-5266-2016 OI Medina, Igor/0000-0001-6839-5414; NR 210 TC 31 Z9 31 U1 4 U2 42 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1662-5102 J9 FRONT CELL NEUROSCI JI Front. Cell. Neurosci. PD FEB 6 PY 2014 VL 8 AR 27 DI 10.3389/fncel.2014.00027 PG 18 WC Neurosciences SC Neurosciences & Neurology GA AA4JA UT WOS:000331060700001 PM 24567703 ER PT J AU Huang, TY Saxena, AR Isganaitis, E James-Todd, T AF Huang, Tianyi Saxena, Aditi R. Isganaitis, Elvira James-Todd, Tamarra TI Gender and racial/ethnic differences in the associations of urinary phthalate metabolites with markers of diabetes risk: national health and nutrition examination survey 2001-2008 SO ENVIRONMENTAL HEALTH LA English DT Article DE Di(2-ethylhexyl) phthalate; Mono-benzyl phthalate; Mono-(3-carboxypropyl) phthalate; Mono-ethyl phthalate; Mono-isobutyl phthalate; Mono-n-butyl phthalate; Insulin; Blood glucose; Gender differences; Race/ethnicity ID INSULIN-RESISTANCE; PPAR-GAMMA; HUMAN EXPOSURE; MEXICAN WOMEN; US POPULATION; ADULTS; ACTIVATION; MONOESTERS; ADIPOSITY; MELLITUS AB Background: Phthalates are ubiquitous endocrine disrupting chemicals associated with diabetes. Although women and minorities are more likely to be exposed to phthalates, no prior studies have examined phthalate exposure and markers of diabetes risk evaluating effect modification by gender and race/ethnicity. Methods: We analyzed CDC data for 8 urinary phthalate metabolites from 3,083 non-diabetic, non-pregnant participants aged 12- < 80 years in the National Health and Nutrition Examination Survey (NHANES) 2001-2008. We used median regression to assess the associations between urinary phthalate metabolites and fasting blood glucose (FBG), fasting insulin and Homeostatic Model Assessment of insulin resistance (HOMA-IR), controlling for urinary creatinine as well as several sociodemographic and behavioral factors. Stratified analyses were conducted to compare the gender-and race/ethnicity-specific patterns for the associations. Results: Urinary levels of several phthalate metabolites, including MBzP, MnBP, MiBP, MCPP and Sigma DEHP showed significant positive associations with FBG, fasting insulin and HOMA-IR. No clear difference was noted between men and women. Mexican-Americans and non-Hispanic blacks had stronger dose-response relationships for MnBP, MiBP, MCPP and Sigma DEHP compared to non-Hispanic whites. For example, the highest quartile of MiBP relative to its lowest quartile showed a median FBG increase of 5.82 mg/dL (95% CI: 3.77, 7.87) in Mexican-Americans, 3.63 mg/dL (95% CI: 1.23, 6.03) in blacks and 1.79 mg/dL (95% CI: -0.29, 3.87) in whites. Conclusions: The findings suggest that certain populations may be more vulnerable to phthalates with respect to disturbances in glucose homeostasis. Whether endocrine disrupting chemicals contribute to gender and racial/ethnic differences in diabetes risk will be an important area for further study. C1 [Huang, Tianyi; James-Todd, Tamarra] Brigham & Womens Hosp, Connors Ctr Womens Hlth & Gender Biol, Dept Med, Div Womens Hlth, Boston, MA 02120 USA. [Huang, Tianyi; James-Todd, Tamarra] Harvard Univ, Sch Med, Boston, MA 02120 USA. [Huang, Tianyi] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Saxena, Aditi R.] Brigham & Womens Hosp, Dept Med, Div Endocrinol, Boston, MA 02115 USA. [Saxena, Aditi R.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Isganaitis, Elvira] Joslin Diabet Ctr, Genet & Epidemiol Div, Boston, MA 02215 USA. [Isganaitis, Elvira] Joslin Diabet Ctr, Pediat Hlth Serv, Boston, MA 02215 USA. RP James-Todd, T (reprint author), Brigham & Womens Hosp, Connors Ctr Womens Hlth & Gender Biol, Dept Med, Div Womens Hlth, Boston, MA 02120 USA. EM tjames-todd@bics.bwh.harvard.edu OI Huang, Tianyi/0000-0001-8420-9167 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development [K12HD051959]; Harvard BIRCWH Scholars program [K12HD051959-07]; NIH Loan Repayment Award for Clinical Research; NICHD career development award [K99HD064793]; Clinical Scholar Award from the Pediatric Endocrine Society FX TJ was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (K12HD051959). ARS was supported by the Harvard BIRCWH Scholars program (K12HD051959-07) and the NIH Loan Repayment Award for Clinical Research. EI was supported by a NICHD career development award (K99HD064793) and the Clinical Scholar Award from the Pediatric Endocrine Society. NR 52 TC 14 Z9 14 U1 2 U2 19 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1476-069X J9 ENVIRON HEALTH-GLOB JI Environ. Health PD FEB 5 PY 2014 VL 13 AR 6 DI 10.1186/1476-069X-13-6 PG 10 WC Environmental Sciences; Public, Environmental & Occupational Health SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health GA AF2KL UT WOS:000334540900001 PM 24499162 ER PT J AU Brown, TI Whiteman, AS Aselcioglu, I Stern, CE AF Brown, Thackery I. Whiteman, Andrew S. Aselcioglu, Irem Stern, Chantal E. TI Structural Differences in Hippocampal and Prefrontal Gray Matter Volume Support Flexible Context-Dependent Navigation Ability SO JOURNAL OF NEUROSCIENCE LA English DT Article ID EPISODIC MEMORY; OVERLAPPING SEQUENCES; TEMPORAL CORTICES; PATH-INTEGRATION; CINGULATE CORTEX; AMYGDALA; RETRIEVAL; SYSTEMS; HUMANS; FMRI AB Spatial navigation is a fundamental part of daily life. Humans differ in their individual abilities to flexibly navigate their world, and a critical question is how this variability relates to differences in underlying brain structure. Our experiment examined individual differences in the ability to flexibly navigate routes that overlap with, and must be distinguished from, previously learned trajectories. We related differences in flexible navigation performance to differences in brain morphology in healthy young adults using voxel-based morphometry. Our findings provide novel evidence that individual differences in gray matter volume in the hippocampus and dorsolateral prefrontal cortex correlate with our ability rapidly to learn and flexibly navigate routes through our world. C1 [Brown, Thackery I.; Whiteman, Andrew S.; Aselcioglu, Irem; Stern, Chantal E.] Boston Univ, Dept Psychol & Brain Sci, Boston, MA 02215 USA. [Brown, Thackery I.; Whiteman, Andrew S.; Aselcioglu, Irem; Stern, Chantal E.] Boston Univ, Conte Ctr Memory & Brain, Boston, MA 02215 USA. [Brown, Thackery I.; Stern, Chantal E.] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. RP Stern, CE (reprint author), Boston Univ, Ctr Memory & Brain, 2 Cummington Mall, Boston, MA 02215 USA. EM chantal@bu.edu FU Office of Naval Research Multidisciplinary University Research Initiative grant [ONR MURI N00014-10-1-0936]; National Institutes of Health Silvio O. Conte Center for Neuroscience Research Grant [NIH P50 MH094263]; NIH National Center for Research Resources Shared Instrumentation Grant Program [NIH P41RR14075] FX This work was supported by an Office of Naval Research Multidisciplinary University Research Initiative grant (ONR MURI N00014-10-1-0936) and a National Institutes of Health Silvio O. Conte Center for Neuroscience Research Grant (NIH P50 MH094263) to the Cognitive Neuroimaging Lab, Center for Memory and Brain, Boston University. Imaging data were collected at the Athinoula A. Martinos Center for Biomedical Imaging in Charlestown, Massachusetts, which receives support from the NIH National Center for Research Resources Shared Instrumentation Grant Program (NIH P41RR14075). NR 50 TC 8 Z9 8 U1 1 U2 10 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 FEB 5 PY 2014 VL 34 IS 6 BP 2314 EP 2320 DI 10.1523/JNEUROSCI.2202-13.2014 PG 7 WC Neurosciences SC Neurosciences & Neurology GA AB0AW UT WOS:000331455200028 PM 24501370 ER PT J AU Blain, JC Ricardo, A Szostak, JW AF Blain, J. Craig Ricardo, Alonso Szostak, Jack W. TI Synthesis and Nonenzymatic Template-Directed Polymerization of 2 '-Amino-2 '-deoxythreose Nucleotides SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID ALTERNATIVE GENETIC SYSTEM; 4+2 CYCLOADDITION REACTION; NUCLEIC-ACID STRUCTURE; PHOSPHORAMIDATE LINKAGES; PAIRING PROPERTIES; CHEMICAL ETIOLOGY; PRIMER EXTENSION; TNA SYNTHESIS; RNA; DNA AB Threose nucleic acid (TNA) is a potential alternative genetic material that may have played a role in the early evolution of life. We have developed a novel synthesis of 2'-amino modified TNA nucleosides (2'-NH2-TNA) based on a cycloaddition reaction between a glycal and an azodicarboxylate, followed by direct nucleosidation of the cycloadduct. Using this route, we synthesized the thymine and guanine 2'-NH2-TNA nucleosides in seven steps with 24% and 12% overall yield, respectively. We then phosphorylated the guanine nucleoside on the 3'-hydroxyl, activated the phosphate as the 2-methylimidazolide, and tested the ability of the activated nucleotide to copy C-4 RNA, DNA, and TNA templates by nonenzymatic primer extension. We measured pseudo-first-order rate constants for the first nucleotide addition step of 1.5, 0.97, and 0.57 h on RNA, DNA, and TNA templates, respectively, at pH 7.5 and 4 degrees C with 150 mM NaCl, 100 mM N-(hydroxylethyl)imidazole catalyst, and 5 mM activated nucleotide. The activated nucleotide hydrolyzed with a rate constant of 0.39 h(-1), causing the polymerization reaction to stall before complete template copying could be achieved. These extension rates are more than 1 order of magnitude slower than those for amino-sugar ribonucleotides under the same conditions, and copying of the TNA template, which best represented a true self-copying reaction, was the slowest of all. The poor kinetics of 2'-NH2-TNA template copying could give insight into why TNA was ultimately not used as a genetic material by biological systems. C1 [Szostak, Jack W.] Massachusetts Gen Hosp, Howard Hughes Med Inst, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Boston, MA 02114 USA. RP Szostak, JW (reprint author), Massachusetts Gen Hosp, Howard Hughes Med Inst, 185 Cambridge St, Boston, MA 02114 USA. EM szostak@molbio.mgh.harvard.edu FU National Sciences Foundation [CHE-0809413] FX We thank Dr. John Chaput for the TNA template, Dr. Sergei Gryaznov for the primer oligonucleotide, and members of our laboratory for helpful discussions and comments on the manuscript. We also thank Dr. Shao-Liang Zheng for his help with X-ray data collection and structure determination. This research was funded in part by grant CHE-0809413 from the National Sciences Foundation. J.W.S. is an Investigator of the Howard Hughes Medical Institute. NR 50 TC 5 Z9 5 U1 5 U2 45 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD FEB 5 PY 2014 VL 136 IS 5 BP 2033 EP 2039 DI 10.1021/ja411950n PG 7 WC Chemistry, Multidisciplinary SC Chemistry GA AB0PD UT WOS:000331493700055 PM 24409991 ER PT J AU Alami, NH Smith, RB Carrasco, MA Williams, LA Winborn, CS Han, SSW Kiskinis, E Winborn, B Freibaum, BD Kanagaraj, A Clare, AJ Badders, NM Bilican, B Chaum, E Chandran, S Shaw, CE Eggan, KC Maniatis, T Taylor, JP AF Alami, Nael H. Smith, Rebecca B. Carrasco, Monica A. Williams, Luis A. Winborn, Christina S. Han, Steve S. W. Kiskinis, Evangelos Winborn, Brett Freibaum, Brian D. Kanagaraj, Anderson Clare, Alison J. Badders, Nisha M. Bilican, Bilada Chaum, Edward Chandran, Siddharthan Shaw, Christopher E. Eggan, Kevin C. Maniatis, Tom Taylor, J. Paul TI Axonal Transport of TDP-43 mRNA Granules Is Impaired by ALS-Causing Mutations SO NEURON LA English DT Article ID AMYOTROPHIC-LATERAL-SCLEROSIS; PLURIPOTENT STEM-CELLS; MOTOR-NEURONS; LIVING CELLS; PROTEIN; FUS/TLS; NEURODEGENERATION; VULNERABILITY; TRANSLATION; STABILITY AB The RNA-binding protein TDP-43 regulates RNA metabolism at multiple levels, including transcription, RNA splicing, and mRNA stability. TDP-43 is a major component of the cytoplasmic inclusions characteristic of amyotrophic lateral sclerosis and some types of frontotemporal lobar degeneration. The importance of TDP-43 in disease is underscored by the fact that dominant missense mutations are sufficient to cause disease, although the role of TDP-43 in pathogenesis is unknown. Here we show that TDP-43 forms cytoplasmic mRNP granules that undergo bidirectional, microtubule-dependent transport in neurons in vitro and in vivo and facilitate delivery of target mRNA to distal neuronal compartments. TDP-43 mutations impair this mRNA transport function in vivo and in vitro, including in stem cell-derived motor neurons from ALS patients bearing any one of three different TDP-43 ALS-causing mutations. Thus, TDP-43 mutations that cause ALS lead to partial loss of a novel cytoplasmic function of TDP-43. C1 [Alami, Nael H.; Smith, Rebecca B.; Winborn, Brett; Freibaum, Brian D.; Kanagaraj, Anderson; Clare, Alison J.; Badders, Nisha M.; Taylor, J. Paul] St Jude Childrens Res Hosp, Dept Dev Neurobiol, Memphis, TN 38105 USA. [Carrasco, Monica A.; Maniatis, Tom] Columbia Univ, Med Ctr, Dept Biochem & Mol Biophys, New York, NY 10032 USA. [Williams, Luis A.; Han, Steve S. W.; Kiskinis, Evangelos; Eggan, Kevin C.] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. [Winborn, Christina S.; Chaum, Edward] Univ Tennessee, Hlth Sci Ctr, Dept Ophthalmol, Memphis, TN 38163 USA. [Han, Steve S. W.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Bilican, Bilada; Chandran, Siddharthan] Univ Edinburgh, Euan MacDonald Ctr Motor Neurone Dis Res, Med Res Council Ctr Regenerat Med, Ctr Neuroregenerat, Edinburgh EH16 4SB, Midlothian, Scotland. [Shaw, Christopher E.] Kings Coll London, Dept Clin Neurosci, London SE5 8AF, England. [Shaw, Christopher E.] Kings Coll London, Dept Neurodegenerat & Brain Injury, London SE5 8AF, England. [Shaw, Christopher E.] Kings Hlth Partners, MRC Ctr Neurodegenerat Res, London SE5 8AF, England. RP Taylor, JP (reprint author), St Jude Childrens Res Hosp, Dept Dev Neurobiol, 332 N Lauderdale St, Memphis, TN 38105 USA. EM jpaul.taylor@stjude.org FU Packard Foundation; Target ALS; ALS Association; NIH [NS053825, AG031587, 8DP1NS082099] FX We thank H. Mitsumoto and C. Henderson (Project A.L.S./Columbia) and R. Brown (UMass Medical School) for collection of Patient 47 and Patient RB20 material. We also thank D. Zarnescu for providing the UAS-YFP-TDP-43(A315T) Drosophila lines and C. Gu and D. Solecki for provision of YFP-EB1 and pCIG2-GFP expression plasmids, respectively. This work was supported by grants from the Packard Foundation, Target ALS, the ALS Association, and NIH grants NS053825 and AG031587 to J.P.T., and an NIH Director's Pioneer Award to T. M. (8DP1NS082099). Images were acquired in the Cell & Tissue Imaging Center at St. Jude, which is supported by the American-Lebanese-Syrian Associated Charities and NCI P30 CA021765-34. NR 36 TC 106 Z9 107 U1 5 U2 38 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 FEB 5 PY 2014 VL 81 IS 3 BP 536 EP 543 DI 10.1016/j.neuron.2013.12.018 PG 8 WC Neurosciences SC Neurosciences & Neurology GA AA3AO UT WOS:000330965500009 PM 24507191 ER PT J AU Silbereis, JC Nobuta, H Tsai, HH Heine, VM McKinsey, GL Meijer, DH Howard, MA Petryniak, MA Potter, GB Alberta, JA Baraban, SC Stiles, CD Rubenstein, JLR Rowitch, DH AF Silbereis, John C. Nobuta, Hiroko Tsai, Hui-Hsin Heine, Vivi M. McKinsey, Gabriel L. Meijer, Dimphna H. Howard, MacKenzie A. Petryniak, Magda A. Potter, Gregory B. Alberta, John A. Baraban, Scott C. Stiles, Charles D. Rubenstein, John L. R. Rowitch, David H. TI Olig1 Function Is Required to Repress Dlx1/2 and Interneuron Production in Mammalian Brain SO NEURON LA English DT Article ID CORTICAL INTERNEURONS; GABAERGIC INTERNEURONS; TRANSCRIPTION FACTORS; PREFRONTAL CORTEX; BASAL FOREBRAIN; GENE-EXPRESSION; STEM-CELLS; INHIBITORY SYNAPSES; TOURETTE-SYNDROME; GLYCINE RECEPTOR AB Abnormal GABAergic interneuron density, and imbalance of excitatory versus inhibitory tone, is thought to result in epilepsy, neurodevelopmental disorders, and psychiatric disease. Recent studies indicate that interneuron cortical density is determined primarily by the size of the precursor pool in the embryonic telencephalon. However, factors essential for regulating interneuron allocation from telencephalic multipotent precursors are poorly understood. Here we report that Olig1 represses production of GABAergic interneurons throughout the mouse brain. Olig1 deletion in mutant mice results in ectopic expression and upregulation of Dlx1/2 genes in the ventral medial ganglionic eminences and adjacent regions of the septum, resulting in an similar to 30% increase in adult cortical interneuron numbers. We show that Olig1 directly represses the Dlx1/2 I12b intergenic enhancer and that Dlx1/2 functions genetically downstream of Olig1. These findings establish Olig1 as an essential repressor of Dlx1/2 and interneuron production in developing mammalian brain. C1 [Silbereis, John C.; Nobuta, Hiroko; Tsai, Hui-Hsin; Heine, Vivi M.; Petryniak, Magda A.; Potter, Gregory B.; Rowitch, David H.] Univ Calif San Francisco, Dept Pediat, San Francisco, CA 94143 USA. [Silbereis, John C.; Nobuta, Hiroko; Tsai, Hui-Hsin; Heine, Vivi M.; Petryniak, Magda A.; Potter, Gregory B.; Rowitch, David H.] Univ Calif San Francisco, Eli & Edythe Broad Inst Stem Cell Res & Regenerat, San Francisco, CA 94143 USA. [Silbereis, John C.; Nobuta, Hiroko; Tsai, Hui-Hsin; Heine, Vivi M.; Howard, MacKenzie A.; Baraban, Scott C.; Rowitch, David H.] Univ Calif San Francisco, Dept Neurosurg, San Francisco, CA 94143 USA. [Silbereis, John C.; McKinsey, Gabriel L.] Univ Calif San Francisco, Neurosci Grad Program, San Francisco, CA 94143 USA. [McKinsey, Gabriel L.; Rubenstein, John L. R.] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94143 USA. [Meijer, Dimphna H.; Alberta, John A.; Stiles, Charles D.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Silbereis, John C.; Nobuta, Hiroko; Tsai, Hui-Hsin; Rowitch, David H.] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. RP Rowitch, DH (reprint author), Univ Calif San Francisco, Dept Pediat, San Francisco, CA 94143 USA. EM rowitchd@peds.ucsf.edu RI Heine, Vivi/F-1741-2011 FU NIGMS [T32 GM007449-36]; Ruth Kirschstein NRSA fellowship from the NINDS [F31 NS076254-03]; European Leukodystrophy Association; NINDS [NS047572, NS040511, R01-NS-048528]; NIMH [MH049428] FX We are grateful to Michael Wong and Sandra Chang for expert technical help. J. S. acknowledges support from training grant T32 GM007449-36 from the NIGMS and the Ruth Kirschstein NRSA fellowship F31 NS076254-03 from the NINDS. G. P. and H.N acknowledge postdoctoral fellowship support from the European Leukodystrophy Association. This work has been supported by grants to C. D. S. (NS047572) and D. H. R. (NS040511) from the NINDS, to J. L. R. R. (MH049428) from NIMH, and to S. C. B (R01-NS-048528) from NINDS. D. H. R. is an Howard Hughes Medical Institute Investigator. NR 88 TC 17 Z9 18 U1 2 U2 5 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 EI 1097-4199 J9 NEURON JI Neuron PD FEB 5 PY 2014 VL 81 IS 3 BP 574 EP 587 DI 10.1016/j.neuron.2013.11.024 PG 14 WC Neurosciences SC Neurosciences & Neurology GA AA3AO UT WOS:000330965500012 PM 24507192 ER PT J AU Knudsen, S Jensen, T Hansen, A Mazin, W Lindemann, J Kuter, I Laing, N Anderson, E AF Knudsen, Steen Jensen, Thomas Hansen, Anker Mazin, Wiktor Lindemann, Justin Kuter, Irene Laing, Naomi Anderson, Elizabeth TI Development and Validation of a Gene Expression Score That Predicts Response to Fulvestrant in Breast Cancer Patients SO PLOS ONE LA English DT Article ID PHASE-II; SIGNALING PATHWAYS; PROTEIN EXPRESSION; CELLS; APOPTOSIS; CHEMOSENSITIVITY; METASTASIS; INHIBITOR; MUTATIONS; SUBTYPES AB Fulvestrant is a selective estrogen receptor antagonist. Based on the measured growth inhibition of 60 human cancer cell lines (NCI60) in the presence of fulvestrant, as well as the baseline gene expression of the 60 cell lines, a gene expression score that predicts response to fulvestrant was developed. The score is based on 414 genes, 103 of which show increased expression in sensitive cell lines, while 311 show increased expression in the non-responding cell lines. The sensitivity genes primarily sense signaling through estrogen receptor alpha, whereas the resistance genes modulate the PI3K signaling pathway. The latter genes suggest that resistance to fulvestrant can be overcome by drugs targeting the PI3K pathway. The level of this gene expression score and its correlation with fulvestrant response was measured in a panel of 20 breast cancer cell lines. The predicted sensitivity matched the measured sensitivity well (CC = -0.63, P = 0.003). The predictor was applied to tumor biopies obtained from a Phase II clinical trial. The sensitivity of each patient to treatment with fulvestrant was predicted based on the RNA profile of the biopsy taken before neoadjuvant treatment and without knowledge of the subsequent response. The prediction was then compared to clinical response to show that the responders had a significantly higher sensitivity prediction than the non-responders (P = 0.01). When clinical covariates, tumor grade and estrogen receptor H-score, were included in the prediction, the difference in predicted senstivity between responders and non-responders improved (P = 0.003). Using a pre-defined cutoff to separate patients into predicted sensitive and predicted resistant yielded a positive predictive value of 88% and a negative predictive value of 100% when compared to clinical data. We conclude that pre-screening patients with the new gene expression predictor has the potential to identify those postmenopausal women with locally advanced, estrogen-receptor-positive breast cancer most likely to respond to fulvestrant. C1 [Knudsen, Steen; Jensen, Thomas; Hansen, Anker; Mazin, Wiktor] Med Prognosis Inst, Horsholm, Denmark. [Lindemann, Justin; Anderson, Elizabeth] Astrazeneca UK Ltd, Oncol iMED, Alderley Pk, Cheshire, England. [Laing, Naomi] Astrazeneca R&D Boston, Waltham, MA USA. [Kuter, Irene] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Knudsen, S (reprint author), Med Prognosis Inst, Horsholm, Denmark. EM steen@medical-prognosis.com FU Astrazeneca; Medical Prognosis Institute FX The work has been funded entirely by Astrazeneca and Medical Prognosis Institute. The funders had a role in study design, data collection and analysis, decision to publish, and preparation of the manuscript. NR 41 TC 7 Z9 7 U1 0 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 FEB 5 PY 2014 VL 9 IS 2 AR e87415 DI 10.1371/journal.pone.0087415 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AA1AT UT WOS:000330829200046 PM 24505287 ER PT J AU Mananga, ES El Fakhri, G Schaefferkoetter, J Bonab, AA Ouyang, JS AF Mananga, Eugene S. El Fakhri, Georges Schaefferkoetter, Joshua Bonab, Ali A. Ouyang, Jinsong TI Myocardial Defect Detection Using PET-CT: Phantom Studies SO PLOS ONE LA English DT Article ID TIME-OF-FLIGHT; LESION DETECTION; HUMAN-OBSERVER; PERFUSION; SPECT; MODEL; VIABILITY; TRACER; RB-82; NOISE AB It is expected that both noise and activity distribution can have impact on the detectability of a myocardial defect in a cardiac PET study. In this work, we performed phantom studies to investigate the detectability of a defect in the myocardium for different noise levels and activity distributions. We evaluated the performance of three reconstruction schemes: Filtered Back-Projection (FBP), Ordinary Poisson Ordered Subset Expectation Maximization (OP-OSEM), and Point Spread Function corrected OSEM (PSF-OSEM). We used the Channelized Hotelling Observer (CHO) for the task of myocardial defect detection. We found that the detectability of a myocardial defect is almost entirely dependent on the noise level and the contrast between the defect and its surroundings. C1 [Mananga, Eugene S.; El Fakhri, Georges; Bonab, Ali A.; Ouyang, Jinsong] Massachusetts Gen Hosp, Div Nucl Med & Mol Imaging, Ctr Adv Med Imaging Sci, Boston, MA 02114 USA. [Mananga, Eugene S.; El Fakhri, Georges; Bonab, Ali A.; Ouyang, Jinsong] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Schaefferkoetter, Joshua] A STAR NUS Clin Imaging & Res Ctr CIRC, Singapore, Singapore. RP Ouyang, JS (reprint author), Massachusetts Gen Hosp, Div Nucl Med & Mol Imaging, Ctr Adv Med Imaging Sci, Boston, MA 02114 USA. EM ouyang.jinsong@mgh.harvard.edu FU National Institutes of Health (NIH) [R01-HL110241, T32-EB013180] FX This research was supported in part by the National Institutes of Health (NIH) Grants R01-HL110241 and T32-EB013180. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 16 TC 0 Z9 0 U1 1 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD FEB 5 PY 2014 VL 9 IS 2 AR e88200 DI 10.1371/journal.pone.0088200 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AA1AT UT WOS:000330829200135 PM 24505429 ER PT J AU Cohen, SP Mao, JR AF Cohen, Steven P. Mao, Jianren TI Neuropathic pain: mechanisms and their clinical implications SO BMJ-BRITISH MEDICAL JOURNAL LA English DT Article ID NECROSIS-FACTOR-ALPHA; LOW-BACK-PAIN; SPINAL GLUTAMATE TRANSPORTERS; PERIPHERAL-NERVE INJURY; QUALITY-OF-LIFE; GENERAL-POPULATION; NMDA RECEPTOR; PROINFLAMMATORY CYTOKINES; PHARMACOLOGICAL-TREATMENT; GABAERGIC INHIBITION AB Neuropathic pain can develop after nerve injury, when deleterious changes occur in injured neurons and along nociceptive and descending modulatory pathways in the central nervous system. The myriad neurotransmitters and other substances involved in the development and maintenance of neuropathic pain also play a part in other neurobiological disorders. This might partly explain the high comorbidity rates for chronic pain, sleep disorders, and psychological conditions such as depression, and why drugs that are effective for one condition may benefit others. Neuropathic pain can be distinguished from non-neuropathic pain by two factors. Firstly, in neuropathic pain there is no transduction (conversion of a nociceptive stimulus into an electrical impulse). Secondly, the prognosis is worse: injury to major nerves is more likely than injury to non-nervous tissue to result in chronic pain. In addition, neuropathic pain tends to be more refractory than non-neuropathic pain to conventional analgesics, such as nonsteroidal anti-inflammatory drugs and opioids. However, because of the considerable overlap between neuropathic and nociceptive pain in terms of mechanisms and treatment modalities, it might be more constructive to view these entities as different points on the same continuum. This review focuses on the mechanisms of neuropathic pain, with special emphasis on clinical implications. C1 [Cohen, Steven P.] Johns Hopkins Sch Med, Dept Anesthesiol & Crit Care Med, Baltimore, MD 21029 USA. [Cohen, Steven P.] Johns Hopkins Sch Med, Dept Phys Med & Rehabil, Baltimore, MD 21029 USA. [Cohen, Steven P.] Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. [Mao, Jianren] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. RP Cohen, SP (reprint author), Johns Hopkins Sch Med, Dept Anesthesiol & Crit Care Med, Baltimore, MD 21029 USA. EM scohen40@jhmi.edu FU Centers for Rehabilitation Sciences Research, Uniformed Services University of the Health Sciences, Bethesda, MD, USA FX Funded in part by the Centers for Rehabilitation Sciences Research, Uniformed Services University of the Health Sciences, Bethesda, MD, USA. NR 105 TC 70 Z9 73 U1 5 U2 37 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 FEB 5 PY 2014 VL 348 AR f7656 DI 10.1136/bmj.f7656 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA AA4JK UT WOS:000331061700001 PM 24500412 ER PT J AU Gradl, G de Witte, PB Evans, BT Hornicek, F Raskin, K Ring, D AF Gradl, Gertraud de Witte, Pieter Bas Evans, Brady T. Hornicek, Francis Raskin, Kevin Ring, David TI Surgical Site Infection in Orthopaedic Oncology SO JOURNAL OF BONE AND JOINT SURGERY-AMERICAN VOLUME LA English DT Article ID RISK-FACTORS; SURGERY; INDEX; HIP; REPLACEMENT; PREDICTION; SYSTEM; SPINE AB Background: This study addressed risk factors for surgical site infection in patients who had undergone orthopaedic oncology surgical procedures. Methods: We retrospectively reviewed data on 1521 orthopaedic oncologic surgical procedures in 1304 patients. We assessed patient demographics, updated Charlson comorbidity index, surgery-specific data, and treatment-related data and attempted to identify predictors of surgical site infection with bivariate and multivariable analysis. Results: Eight factors independently predicted surgical site infection: body mass index (odds ratio [OR]:, 1.03, 95% confidence interval [Cl]: 1.00 to 1.07), age (OR: 1.18, 95% Cl: 1.05 to 1.33), total number of preceding procedures (OR: 1.19, 95% Cl: 1.07 to 1.34), preexisting implants (OR: 1.94, 95% Cl: 1.17 to 3.21), infection at another site on the date of the surgery (OR: 4.13, 95% Cl: 1.57 to 10.85), malignant disease (OR: 1.46, 95% Cl: 0.94 to 2.26), hip region affected (OR: 1.96, 95% Cl: 1.35 to 2.84), and duration of the procedure (OR: 1.16, 95% Cl: 1:07 to 1.25). Conclusions: These factors can inform patients and surgeons of the probability of surgical site infection after orthopaedic oncologic surgery. While most risk factors are unmodifiable or related to the complexity of the case, infection at another site on the date of the surgery is one factor amenable to intervention. C1 [Gradl, Gertraud; de Witte, Pieter Bas; Evans, Brady T.; Hornicek, Francis; Raskin, Kevin; Ring, David] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Gradl, G (reprint author), Univ Aachen, Dept Trauma & Reconstruct Surg, Pauwelstr 30, D-52074 Aachen, Germany. EM DRING@PARTNERS.ORG NR 30 TC 5 Z9 6 U1 0 U2 1 PU JOURNAL BONE JOINT SURGERY INC PI NEEDHAM PA 20 PICKERING ST, NEEDHAM, MA 02192 USA SN 0021-9355 J9 J BONE JOINT SURG AM JI J. Bone Joint Surg.-Am. Vol. PD FEB 5 PY 2014 VL 96A IS 3 BP 223 EP 230 DI 10.2106/JBJS.L.01514 PG 8 WC Orthopedics; Surgery SC Orthopedics; Surgery GA 301PW UT WOS:000330545400007 PM 24500584 ER PT J AU Peterson, ED Gaziano, JM Greenland, P AF Peterson, Eric D. Gaziano, J. Michael Greenland, Philip TI Recommendations for Treating Hypertension What Are the Right Goals and Purposes? SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material ID ISOLATED SYSTOLIC HYPERTENSION; AMERICAN-HEART-ASSOCIATION; COLLEGE-OF-CARDIOLOGY; BLOOD-PRESSURE; CARDIOVASCULAR-DISEASE; CLINICAL-PRACTICE; PREVENTION; COMMITTEE; STROKE C1 [Peterson, Eric D.] Duke Univ, Med Ctr, Duke Clin Res Inst, Durham, NC USA. [Gaziano, J. Michael] VA Boston Healthcare Syst, Boston, MA USA. [Gaziano, J. Michael] Brigham & Womens Hosp, Div Aging, Boston, MA 02115 USA. [Greenland, Philip] Northwestern Univ, Chicago, IL 60611 USA. RP Peterson, ED (reprint author), Duke Clin Res Inst, 2400 Pratt St,Room 0311,Terrace Level, Durham, NC 27705 USA. EM eric.peterson@duke.edu NR 13 TC 23 Z9 27 U1 0 U2 3 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD FEB 5 PY 2014 VL 311 IS 5 BP 474 EP 476 DI 10.1001/jama.2013.284430 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 302GF UT WOS:000330589800019 PM 24352710 ER PT J AU Marrouche, NF Wilber, D Hindricks, G Jais, P Akoum, N Marchlinski, F Kholmovski, E Burgon, N Hu, N Mont, L Deneke, T Duytschaever, M Neumann, T Mansour, M Mahnkopf, C Herweg, B Daoud, E Wissner, E Bansmann, P Brachmann, J AF Marrouche, Nassir F. Wilber, David Hindricks, Gerhard Jais, Pierre Akoum, Nazem Marchlinski, Francis Kholmovski, Eugene Burgon, Nathan Hu, Nan Mont, Lluis Deneke, Thomas Duytschaever, Mattias Neumann, Thomas Mansour, Moussa Mahnkopf, Christian Herweg, Bengt Daoud, Emile Wissner, Erik Bansmann, Paul Brachmann, Johannes TI Association of Atrial Tissue Fibrosis Identified by Delayed Enhancement MRI and Atrial Fibrillation Catheter Ablation The DECAAF Study SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID RADIOFREQUENCY ABLATION; ANTIARRHYTHMIC-DRUGS; IRREVERSIBLE INJURY; PULMONARY VEIN; BLOOD-PRESSURE; MECHANISMS; TRIAL; RISK; CONTRACTILE; ARRHYTHMIAS AB IMPORTANCE Left atrial fibrosis is prominent in patients with atrial fibrillation (AF). Extensive atrial tissue fibrosis identified by delayed enhancement magnetic resonance imaging (MRI) has been associated with poor outcomes of AF catheter ablation. OBJECTIVE To characterize the feasibility of atrial tissue fibrosis estimation by delayed enhancement MRI and its association with subsequent AF ablation outcome. DESIGN, SETTING, AND PARTICIPANTS Multicenter, prospective, observational cohort study of patients diagnosed with paroxysmal and persistent AF (undergoing their first catheter ablation) conducted between August 2010 and August 2011 at 15 centers in the United States, Europe, and Australia. Delayed enhancement MRI images were obtained up to 30 days before ablation. MAIN OUTCOMES AND MEASURES Fibrosis quantificationwas performed at a core laboratory blinded to the participating center, ablation approach, and procedure outcome. Fibrosis blinded to the treating physicians was categorized as stage 1 (<10% of the atrial wall), 2 (>= 10%-<20%), 3 (>= 20%-<30%), and 4 (>= 30%). Patients were followed up for recurrent arrhythmia per current guidelines using electrocardiography or ambulatory monitor recording and results were analyzed at a core laboratory. Cumulative incidence of recurrence was estimated by stage at days 325 and 475 after a 90-day blanking period (standard time allowed for arrhythmias related to ablation-induced inflammation to subside) and the risk of recurrence was estimated (adjusting for 10 demographic and clinical covariates). RESULTS Atrial tissue fibrosis estimation by delayed enhancement MRI was successfully quantified in 272 of 329 enrolled patients (57 patients [17%] were excluded due to poor MRI quality). There were 260 patients who were followed up after the blanking period (mean [SD] age of 59.1 [10.7] years, 31.5% female, 64.6% with paroxysmal AF). For recurrent arrhythmia, the unadjusted overall hazard ratio per 1% increase in left atrial fibrosis was 1.06 (95% CI, 1.03-1.08; P<.001). Estimated unadjusted cumulative incidence of recurrent arrhythmia by day 325 for stage 1 fibrosis was 15.3%(95% CI, 7.6%-29.6%); stage 2, 32.6%(95% CI, 24.3%-42.9%); stage 3, 45.9%(95% CI, 35.5%-57.5%); and stage 4, 51.1% (95% CI, 32.8%-72.2%) and by day 475 was 15.3%(95% CI, 7.6%-29.6%), 35.8% (95% CI, 26.2%-47.6%), 45.9%(95% CI, 35.6%-57.5%), and 69.4%(95% CI, 48.6%-87.7%), respectively. Similar results were obtained after covariate adjustment. The addition of fibrosis to a recurrence prediction model that includes traditional clinical covariates resulted in an improved predictive accuracy with the C statistic increasing from 0.65 to 0.69 (risk difference of 0.05; 95% CI, 0.01-0.09). CONCLUSIONS AND RELEVANCE Among patients with AF undergoing catheter ablation, atrial tissue fibrosis estimated by delayed enhancement MRI was independently associated with likelihood of recurrent arrhythmia. The clinical implications of this association warrant further investigation. C1 [Marrouche, Nassir F.; Akoum, Nazem; Kholmovski, Eugene; Burgon, Nathan; Hu, Nan] Univ Utah, Sch Med, Comprehens Arrhythmia & Res Management Ctr, Salt Lake City, UT 84132 USA. [Wilber, David] Loyola Univ, Med Ctr, Maywood, IL 60153 USA. [Hindricks, Gerhard] Univ Leipzig, D-04109 Leipzig, Germany. [Jais, Pierre] Ctr Hosp Univ Bordeaux, Bordeaux, France. [Marchlinski, Francis] Hosp Univ Penn, Philadelphia, PA 19104 USA. [Mont, Lluis] Univ Barcelona, Barcelona, Spain. [Deneke, Thomas] Ruhr Univ Bochum, BG Kliniken Bergmannsheil, Bochum, Germany. [Duytschaever, Mattias] Univ Hosp Ghent, Ghent, Belgium. [Neumann, Thomas] Kerckhoff Heart Ctr, Bad Nauheim, Germany. [Mansour, Moussa] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Mahnkopf, Christian; Brachmann, Johannes] Klinikum Coburg GmbH, Med Klin, Coburg, Germany. [Herweg, Bengt] Univ S Florida, Morsani Coll Med, Tampa, FL USA. [Daoud, Emile] Ohio State Univ, Columbus, OH 43210 USA. [Wissner, Erik] Asklepios Klin St Georg, Hamburg, Germany. [Bansmann, Paul] Med Ctr Porz Rhein, Cologne, Germany. RP Marrouche, NF (reprint author), Univ Utah, Hlth Sci Ctr, 30 N 1900 E,Room 4A100, Salt Lake City, UT 84132 USA. EM nassir.marrouche@hsc.utah.edu FU Comprehensive Arrhythmia and Research Management Center (CARMA) Center at the University of Utah; George S. and Dolores Dore Eccles Foundation FX The Comprehensive Arrhythmia and Research Management Center (CARMA) Center at the University of Utah provided funding for the study. The George S. and Dolores Dore Eccles Foundation funded part of the DECAAF study. NR 38 TC 170 Z9 175 U1 5 U2 19 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD FEB 5 PY 2014 VL 311 IS 5 BP 498 EP 506 DI 10.1001/jama.2014.3 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 302GF UT WOS:000330589800023 PM 24496537 ER PT J AU Rassi, AN Yeh, RW AF Rassi, Andrew N. Yeh, Robert W. TI Cardiovascular Event Risk After Noncardiac Surgery SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter ID CORONARY STENTS C1 [Rassi, Andrew N.; Yeh, Robert W.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02108 USA. RP Rassi, AN (reprint author), Massachusetts Gen Hosp, 55 Fruit St, Boston, MA 02108 USA. EM arassi@partners.org NR 5 TC 1 Z9 1 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD FEB 5 PY 2014 VL 311 IS 5 BP 525 EP 525 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 302GF UT WOS:000330589800027 PM 24496540 ER PT J AU Wagner, SL Zhang, C Cheng, S Nguyen, P Zhang, XL Rynearson, KD Wang, R Li, YM Sisodia, SS Mobley, WC Tanzi, RE AF Wagner, Steven L. Zhang, Can Cheng, Soan Phuong Nguyen Zhang, Xulun Rynearson, Kevin D. Wang, Rong Li, Yueming Sisodia, Sangram S. Mobley, William C. Tanzi, Rudolph E. TI Soluble gamma-Secretase Modulators Selectively Inhibit the Production of the 42-Amino Acid Amyloid beta Peptide Variant and Augment the Production of Multiple Carboxy-Truncated Amyloid beta Species SO BIOCHEMISTRY LA English DT Article ID FAMILIAL ALZHEIMER-DISEASE; PRESENILIN MUTATIONS; A-BETA-40; PROTEIN; TRIAL; DEPOSITION; MECHANISM AB Alzheimer's disease (AD) is characterized pathologically by an abundance of extracellular neuritic plaques composed primarily of the 42-amino acid amyloid beta peptide variant (A beta 42). In the majority of familial AD (FAD) cases, e.g., those harboring mutations in presenilin 1 (PS1), there is a relative increase in the levels of A beta 42 compared to the levels of A beta 40. We previously reported the characterization of a series of aminothiazole-bridged aromates termed aryl aminothiazole gamma-secretase modulators or AGSMs [Kounnas, M. Z., et al. (2010) Neuron 67, 769-780] and showed their potential for use in the treatment of FAD [Wagner, S. L., et al. (2012) Arch. Neurol. 69, 1255-1258]. Here we describe a series of GSMs with physicochemical properties improved compared to those of AGSMs. Specific heterocycle replacements of the phenyl rings in AGSMs provided potent molecules with improved aqueous solubilities. A number of these soluble gamma-secretase modulators (SGSMs) potently lowered A beta 42 levels without inhibiting proteolysis of Notch or causing accumulation of amyloid precursor protein carboxyterminal fragments, even at concentrations approximately 1000-fold greater than their IC50 values for reducing A beta 42 levels. The effects of one potent SGSM on A beta peptide production were verified by matrix-assisted laser desorption ionization time-of-flight mass spectrometry, showing enhanced production of a number of carboxy-truncated A beta species. This SGSM also inhibited A beta 42 peptide production in a highly purified reconstituted gamma-secretase in vitro assay system and retained the ability to modulate gamma-secretase-mediated proteolysis in a stably transfected cell culture model overexpressing a human PS1 mutation validating the potential for use in FAD. C1 [Wagner, Steven L.; Cheng, Soan; Phuong Nguyen; Rynearson, Kevin D.; Mobley, William C.] Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA. [Zhang, Can; Tanzi, Rudolph E.] Massachusetts Gen Hosp, Dept Neurol, Genet & Aging Res Unit, Charlestown, MA 02129 USA. [Wang, Rong] Icahn Inst, Dept Genet & Genom Sci, New York, NY 10029 USA. [Li, Yueming] Mem Sloan Kettering Canc Ctr, Mol Pharmacol & Chem Program, New York, NY 10065 USA. [Zhang, Xulun; Sisodia, Sangram S.] Univ Chicago, Ctr Mol Neurobiol, Chicago, IL 60637 USA. RP Wagner, SL (reprint author), Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA. EM SLWagner@ucsd.edu RI Wang, Rong/A-8721-2009 FU Cure Alzheimer's Fund; Down Syndrome Research and Treatment Foundation; Thrasher Foundation; National Institutes of Health [U01-NS074501] FX This work was supported by grants from the Cure Alzheimer's Fund to S.L.W. and R.E.T., grants from the Down Syndrome Research and Treatment Foundation and the Thrasher Foundation to W.C.M., and National Institutes of Health Grant U01-NS074501 to S.L.W. NR 35 TC 14 Z9 14 U1 0 U2 10 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD FEB 4 PY 2014 VL 53 IS 4 BP 702 EP 713 DI 10.1021/bi401537v PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AA3TN UT WOS:000331015400011 PM 24401146 ER PT J AU Humphrey, LL Deffebach, M Pappas, M Zakher, B Slatore, CG AF Humphrey, Linda L. Deffebach, Mark Pappas, Miranda Zakher, Bernadette Slatore, Christopher G. TI Screening for Lung Cancer With Low-Dose Computed Tomography Response SO ANNALS OF INTERNAL MEDICINE LA English DT Letter ID CT C1 [Humphrey, Linda L.; Deffebach, Mark; Slatore, Christopher G.] Portland VA Med Ctr, Portland, OR 97239 USA. [Pappas, Miranda; Zakher, Bernadette] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. RP Humphrey, LL (reprint author), Portland VA Med Ctr, Portland, OR 97239 USA. NR 4 TC 3 Z9 3 U1 0 U2 2 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 FEB 4 PY 2014 VL 160 IS 3 BP 212 EP 212 DI 10.7326/L14-5003-3 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA AA2VE UT WOS:000330951500015 PM 24493448 ER PT J AU Sawada, N Jiang, A Takizawa, F Safdar, A Manika, A Tesmenitsky, Y Kang, KT Bischoff, J Kalwa, H Sartoretto, JL Kamei, Y Benjamin, LE Watada, H Ogawa, Y Higashikuni, Y Kessinger, CW Jaffer, FA Michel, T Sata, M Croce, K Tanaka, R Arany, Z AF Sawada, Naoki Jiang, Aihua Takizawa, Fumihiko Safdar, Adeel Manika, Andre Tesmenitsky, Yevgenia Kang, Kyu-Tae Bischoff, Joyce Kalwa, Hermann Sartoretto, Juliano L. Kamei, Yasutomi Benjamin, Laura E. Watada, Hirotaka Ogawa, Yoshihiro Higashikuni, Yasutomi Kessinger, Chase W. Jaffer, Farouc A. Michel, Thomas Sata, Masataka Croce, Kevin Tanaka, Rica Arany, Zolt TI Endothelial PGC-1 alpha Mediates Vascular Dysfunction in Diabetes SO CELL METABOLISM LA English DT Article ID TRANSCRIPTIONAL COACTIVATOR PGC-1-ALPHA; PROGENITOR CELLS; UP-REGULATION; INSULIN-RESISTANCE; SKELETAL-MUSCLE; BONE-MARROW; IN-VIVO; NOTCH; ANGIOGENESIS; MECHANISMS AB Endothelial dysfunction is a central hallmark of diabetes. The transcriptional coactivator PGC-1 alpha is a powerful regulator of metabolism, but its role in endothelial cells remains poorly understood. We show here that endothelial PGC-1 alpha expression is high in diabetic rodents and humans and that PGC-1 alpha powerfully blocks endothelial migration in cell culture and vasculogenesis in vivo. Mechanistically, PGC-1 alpha induces Notch signaling, blunts activation of Rac/Akt/eNOS signaling, and renders endothelial cells unresponsive to established angiogenic factors. Transgenic overexpression of PGC-1 alpha in the endothelium mimics multiple diabetic phenotypes, including aberrant re-endothelialization after carotid injury, blunted wound healing, and reduced blood flow recovery after hindlimb ischemia. Conversely, deletion of endothelial PGC-1 alpha rescues the blunted wound healing and recovery from hindlimb ischemia seen in type 1 and type 2 diabetes. Endothelial PGC-1 alpha thus potently inhibits endothelial function and angiogenesis, and induction of endothelial PGC-1 alpha contributes to multiple aspects of vascular dysfunction in diabetes. C1 [Sawada, Naoki; Takizawa, Fumihiko; Kamei, Yasutomi; Ogawa, Yoshihiro] Tokyo Med & Dent Univ, Dept Mol Endocrinol & Metab, Tokyo 1138510, Japan. [Sawada, Naoki; Takizawa, Fumihiko; Ogawa, Yoshihiro] Tokyo Med & Dent Univ, Global COE Program, Tokyo 1138510, Japan. [Takizawa, Fumihiko] Tokyo Med & Dent Univ, Dept Pediat & Dev Biol, Tokyo 1138510, Japan. [Sawada, Naoki; Jiang, Aihua; Safdar, Adeel; Benjamin, Laura E.; Arany, Zolt] Beth Israel Deaconess Med Ctr, Cardiovasc Inst, Boston, MA 02215 USA. [Sawada, Naoki; Jiang, Aihua; Safdar, Adeel; Benjamin, Laura E.; Arany, Zolt] Beth Israel Deaconess Med Ctr, Vasc Biol Res Ctr, Boston, MA 02215 USA. [Sawada, Naoki] Univ Chicago, Dept Med, Cardiol Sect, Chicago, IL 60637 USA. [Manika, Andre; Tesmenitsky, Yevgenia; Kalwa, Hermann; Sartoretto, Juliano L.; Michel, Thomas; Croce, Kevin] Brigham & Womens Hosp, Div Cardiovasc, Boston, MA 02115 USA. [Manika, Andre] Fundacao Univ Cardiol, Inst Cardiol Rio Grande Sul, Porto Alegre, RS, Brazil. [Kang, Kyu-Tae; Bischoff, Joyce] Childrens Hosp, Vasc Biol Program, Boston, MA 02115 USA. [Kang, Kyu-Tae; Bischoff, Joyce] Childrens Hosp, Dept Surg, Boston, MA 02115 USA. [Kamei, Yasutomi] Kyoto Prefectural Univ, Lab Mol Nutr, Grad Sch Environm & Life Sci, Kyoto 6068522, Japan. [Watada, Hirotaka] Juntendo Univ, Grad Sch Med, Dept Metab & Endocrinol, Tokyo 1138421, Japan. [Higashikuni, Yasutomi] Univ Tokyo, Grad Sch Med, Dept Cardiovasc Med, Tokyo 1138655, Japan. [Kessinger, Chase W.; Jaffer, Farouc A.] Massachusetts Gen Hosp, Div Cardiol, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Sata, Masataka] Univ Tokushima, Grad Sch, Inst Hlth Biosci, Dept Cardiovasc Med, Tokushima 7708503, Japan. [Tanaka, Rica] Juntendo Univ, Grad Sch Med, Dept Plast & Reconstruct Surg, Tokyo 1138421, Japan. RP Sawada, N (reprint author), Tokyo Med & Dent Univ, Dept Mol Endocrinol & Metab, Tokyo 1138510, Japan. EM nsawada@medicine.bsd.uchicago.edu; zarany@bidmc.harvard.edu FU Ministry of Education, Culture, Sports, Science, and Technology; Takeda Science Foundation; Japan Vascular Disease Research Foundation; Astra Zeneca Research Grant; Suzuken Memorial Foundation; AHA; CAPES foundation; NHLBI; NIGMS; ADA; Ellison Medical Foundation; [HL094262]; [HL076136]; [HL108229] FX N.S. was supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology; the Takeda Science Foundation; the Japan Vascular Disease Research Foundation; the Astra Zeneca Research Grant; and the Suzuken Memorial Foundation. H. K. and A.J. were supported by postdoctoral fellowships from the AHA. J.B. was supported by HL094262. A. M. was supported by the CAPES foundation. C. W. K. was supported by HL076136. F. A.J. was supported by HL108229. T. M. was supported by grants from the NHLBI and NIGMS, and Z.A. was supported by the ADA, the Ellison Medical Foundation, and the NHLBI. NR 65 TC 37 Z9 39 U1 1 U2 21 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1550-4131 EI 1932-7420 J9 CELL METAB JI Cell Metab. PD FEB 4 PY 2014 VL 19 IS 2 BP 246 EP 258 DI 10.1016/j.cmet.2013.12.014 PG 13 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 304CE UT WOS:000330722600010 PM 24506866 ER PT J AU Gimenez-Cassina, A Garcia-Haro, L Choi, CS Osundiji, MA Lane, EA Huang, H Yildirim, MA Szlyk, B Fisher, JK Polak, K Patton, E Wiwczar, J Godes, M Lee, DH Robertson, K Kim, S Kulkarni, A Distefano, A Samuel, V Cline, G Kim, YB Shulman, GI Danial, NN AF Gimenez-Cassina, Alfredo Garcia-Haro, Luisa Choi, Cheol Soo Osundiji, Mayowa A. Lane, Elizabeth A. Huang, Hu Yildirim, Muhammed A. Szlyk, Benjamin Fisher, Jill K. Polak, Klaudia Patton, Elaura Wiwczar, Jessica Godes, Marina Lee, Dae Ho Robertson, Kirsten Kim, Sheene Kulkarni, Ameya Distefano, Alberto Samuel, Varman Cline, Gary Kim, Young-Bum Shulman, Gerald I. Danial, Nika N. TI Regulation of Hepatic Energy Metabolism and Gluconeogenesis by BAD SO CELL METABOLISM LA English DT Article ID REQUIRES GLUCOSE-METABOLISM; GLUCOKINASE GENE-EXPRESSION; INSULIN SENSITIVITY; PHOSPHOENOLPYRUVATE CARBOXYKINASE; HORMONAL-REGULATION; FLUX CONTROL; FATTY LIVER; DUAL ROLE; HEPATOCYTES; MICE AB The homeostatic balance of hepatic glucose utilization, storage, and production is exquisitely controlled by hormonal signals and hepatic carbon metabolism during fed and fasted states. How the liver senses extracellular glucose to cue glucose utilization versus production is not fully understood. We show that the physiologic balance of hepatic glycolysis and gluconeogenesis is regulated by Bcl-2-associated agonist of cell death (BAD), a protein with roles in apoptosis and metabolism. BAD deficiency reprograms hepatic substrate and energy metabolism toward diminished glycolysis, excess fatty acid oxidation, and exaggerated glucose production that escapes suppression by insulin. Genetic and biochemical evidence suggests that BAD's suppression of gluconeogenesis is actuated by phosphorylation of its BCL-2 homology (BH)-3 domain and subsequent activation of glucokinase. The physiologic relevance of these findings is evident from the ability of a BAD phosphomimic variant to counteract unrestrained gluconeogenesis and improve glycemia in leptin-resistant and high-fat diet models of diabetes and insulin resistance. C1 [Gimenez-Cassina, Alfredo; Garcia-Haro, Luisa; Osundiji, Mayowa A.; Lane, Elizabeth A.; Yildirim, Muhammed A.; Szlyk, Benjamin; Fisher, Jill K.; Polak, Klaudia; Patton, Elaura; Wiwczar, Jessica; Godes, Marina; Robertson, Kirsten; Danial, Nika N.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA. [Gimenez-Cassina, Alfredo; Garcia-Haro, Luisa; Osundiji, Mayowa A.; Lane, Elizabeth A.; Danial, Nika N.] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. [Choi, Cheol Soo; Kim, Sheene; Kulkarni, Ameya; Distefano, Alberto; Samuel, Varman; Cline, Gary; Shulman, Gerald I.] Yale Univ, Sch Med, Dept Internal Med, New Haven, CT 06510 USA. [Choi, Cheol Soo] Gachon Univ, Div Endocrinol, Lee Gil Ya Canc & Diabet Inst, Gil Med Ctr, Inchon 405760, South Korea. [Huang, Hu; Lee, Dae Ho; Kim, Young-Bum] Beth Israel Deaconess Med Ctr, Div Endocrinol Diabet & Metab, Dept Med, Boston, MA 02115 USA. [Huang, Hu; Lee, Dae Ho; Kim, Young-Bum] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Shulman, Gerald I.] Yale Univ, Sch Med, Howard Hughes Med Inst, New Haven, CT 06510 USA. RP Danial, NN (reprint author), Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA. EM nika_danial@dfci.harvard.edu RI Yildirim, Muhammed/J-3695-2014; OI Yildirim, Muhammed/0000-0003-2826-1766; Gimenez-Cassina, Alfredo/0000-0002-2768-2350 FU Ministerio de Educacion y Ciencia (MEC, Spain); Juvenile Diabetes Research Foundation; Burroughs Wellcome Fund; US National Institutes of Health [K01CA10659, R01DK078081, R01 DK-40936, U24 DK-059635, R01DK083567]; Ministry for Health, Welfare & Family Affairs, Republic of Korea [A102060] FX We thank J. Quijada for technical assistance and animal husbandry; J. Lemasters for advice on OCR studies; and B. Lowell, P. Puigserver, members of the Spiegelman laboratory, L. Agius, and F. Matschinsky for helpful discussions. A. G.-C. and L. G.-H. were supported by postdoctoral fellowships from the Ministerio de Educacion y Ciencia (MEC, Spain). M.A.O. was supported by a postdoctoral fellowship from the Juvenile Diabetes Research Foundation. N.N.D. is a recipient of the Burroughs Wellcome Fund Career Award in Biomedical Sciences. This work was supported by the US National Institutes of Health grants K01CA10659 (N.N.D.), R01DK078081 (N.N.D.), R01 DK-40936 (G. I. S.), U24 DK-059635 (G. I. S.), and R01DK083567 (Y.-B.K.) and the Korea Healthcare technology R&D Project A102060, Ministry for Health, Welfare & Family Affairs, Republic of Korea (C.S.C.). NR 42 TC 17 Z9 18 U1 2 U2 20 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1550-4131 EI 1932-7420 J9 CELL METAB JI Cell Metab. PD FEB 4 PY 2014 VL 19 IS 2 BP 272 EP 284 DI 10.1016/j.cmet.2013.12.001 PG 13 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 304CE UT WOS:000330722600012 PM 24506868 ER PT J AU Koldewyn, K Yendiki, A Weigelt, S Gweon, H Julian, J Richardson, H Malloy, C Saxe, R Fischl, B Kanwisher, N AF Koldewyn, Kami Yendiki, Anastasia Weigelt, Sarah Gweon, Hyowon Julian, Joshua Richardson, Hilary Malloy, Caitlin Saxe, Rebecca Fischl, Bruce Kanwisher, Nancy TI Differences in the right inferior longitudinal fasciculus but no general disruption of white matter tracts in children with autism spectrum disorder SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE diffusion-weighted imaging; connectivity ID FUNCTIONAL CONNECTIVITY MRI; MOTION CORRECTION; SUBJECT MOTION; HEAD MOTION; HUMAN BRAIN; CORTEX; REGISTRATION; PERCEPTION; DTI AB One of the most widely cited features of the neural phenotype of autism is reduced "integrity" of long-range white matter tracts, a claim based primarily on diffusion imaging studies. However, many prior studies have small sample sizes and/or fail to address differences in data quality between those with autism spectrum disorder (ASD) and typical participants, and there is little consensus on which tracts are affected. To overcome these problems, we scanned a large sample of children with autism (n = 52) and typically developing children (n = 73). Data quality was variable, and worse in the ASD group, with some scans unusable because of head motion artifacts. When we follow standard data analysis practices (i.e., without matching head motion between groups), we replicate the finding of lower fractional anisotropy (FA) in multiple white matter tracts. However, when we carefully match data quality between groups, all these effects disappear except in one tract, the right inferior longitudinal fasciculus (ILF). Additional analyses showed the expected developmental increases in the FA of fiber tracts within ASD and typical groups individually, demonstrating that we had sufficient statistical power to detect known group differences. Our data challenge the widely claimed general disruption of white matter tracts in autism, instead implicating only one tract, the right ILF, in the ASD phenotype. C1 [Koldewyn, Kami; Weigelt, Sarah; Gweon, Hyowon; Julian, Joshua; Richardson, Hilary; Malloy, Caitlin; Saxe, Rebecca; Kanwisher, Nancy] MIT, Dept Brain & Cognit Sci, Cambridge, MA 02139 USA. [Koldewyn, Kami] Bangor Univ, Sch Psychol, Bangor LL57 2AS, Gwynedd, Wales. [Yendiki, Anastasia; Fischl, Bruce] Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Yendiki, Anastasia; Fischl, Bruce] Harvard Univ, Sch Med, Charlestown, MA 02129 USA. [Weigelt, Sarah] Ruhr Univ Bochum, Fak Psychol, D-44801 Bochum, Germany. [Fischl, Bruce] MIT, Comp Sci & Artificial Intelligence Lab, Cambridge, MA 02139 USA. RP Koldewyn, K (reprint author), MIT, Dept Brain & Cognit Sci, E25-618, Cambridge, MA 02139 USA. EM k.koldewyn@bangor.ac.uk; ngk@mit.edu OI Koldewyn, Kami/0000-0003-3588-6449 FU Ellison Medical Foundation; Simons Foundation; National Center for Research Resources Grant [U24 RR021382]; National Institute for Biomedical Imaging and Bioengineering [5P41EB015896-15, R01EB006758]; National Institute on Aging [AG022381, 5R01AG008122-22]; National Institutes of Health Blueprint for Neuroscience Research Grant [5U01-MH093765]; multiinstitutional Human Connectome Project; [1S10RR023401]; [1S10RR019307]; [1S10RR023043] FX The authors thank the study participants and their families, including those participating in the SFARI Simplex Collection and the Autism Consortium, as well as the principle investigators at SFARI SSC sites. We also thank the team at the Athinoula A. Martinos Imaging Center at McGovern Institute for Brain Research, Massachusetts Institute of Technology for their excellent technical support. This study was supported by the Ellison Medical Foundation; a grant from the Simons Foundation to the Simons Center for the Social Brain at Massachusetts Institute of Technology; National Center for Research Resources Grant U24 RR021382; National Institute for Biomedical Imaging and Bioengineering Grants 5P41EB015896-15 and R01EB006758; National Institute on Aging Grants AG022381 and 5R01AG008122-22; resources provided by Shared Instrumentation Grants 1S10RR023401, 1S10RR019307, and 1S10RR023043; and National Institutes of Health Blueprint for Neuroscience Research Grant 5U01-MH093765, part of the multiinstitutional Human Connectome Project. NR 42 TC 32 Z9 32 U1 2 U2 13 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 4 PY 2014 VL 111 IS 5 BP 1981 EP 1986 DI 10.1073/pnas.1324037111 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 302FL UT WOS:000330587600075 PM 24449864 ER PT J AU Kalia, A Lesmes, LA Dorr, M Gandhi, T Chatterjee, G Ganesh, S Bex, PJ Sinha, P AF Kalia, Amy Lesmes, Luis Andres Dorr, Michael Gandhi, Tapan Chatterjee, Garga Ganesh, Suma Bex, Peter J. Sinha, Pawan TI Development of pattern vision following early and extended blindness SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE brain plasticity; sensitive periods; sight restoration; visual impairment; childhood blindness ID CONTRAST SENSITIVITY FUNCTION; MACAQUES VISUAL-SYSTEM; EARLY UNILATERAL BLUR; CRITICAL PERIOD; HUMAN INFANTS; DEPRIVATION; CORTEX; PLASTICITY; AMBLYOPIA; SELECTIVITY AB Visual plasticity peaks during early critical periods of normal visual development. Studies in animals and humans provide converging evidence that gains in visual function are minimal and deficits are most severe when visual deprivation persists beyond the critical period. Here we demonstrate visual development in a unique sample of patients who experienced extended early-onset blindness (beginning before 1 y of age and lasting 8-17 y) before removal of bilateral cataracts. These patients show surprising improvements in contrast sensitivity, an assay of basic spatial vision. We find that contrast sensitivity development is independent of the age of sight onset and that individual rates of improvement can exceed those exhibited by normally developing infants. These results reveal that the visual system can retain considerable plasticity, even after early blindness that extends beyond critical periods. C1 [Kalia, Amy; Gandhi, Tapan; Chatterjee, Garga; Sinha, Pawan] MIT, Dept Brain & Cognit Sci, Cambridge, MA 02139 USA. [Lesmes, Luis Andres; Dorr, Michael; Bex, Peter J.] Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, Schepens Eye Res Inst, Boston, MA 02114 USA. [Lesmes, Luis Andres] Adapt Sensory Technol, Boston, MA 02114 USA. [Gandhi, Tapan] Govt India, Def Inst Physiol & Allied Sci, New Delhi 110016, India. [Ganesh, Suma] Dr Shroffs Char Eye Hosp, Dept Pediat Ophthalmol, New Delhi 110002, India. RP Kalia, A (reprint author), MIT, Dept Brain & Cognit Sci, E25-618, Cambridge, MA 02139 USA. EM akalia@mit.edu FU National Institutes of Health [R01EY019281, R01EY020517] FX We thank Piyush Swami for help with data collection, the staff and outreach team at the Dr. Shroff's Charity Eye Hospital (Delhi, India) for providing additional support for this study, and Drs. Frank Thorn and Anne Fulton for helpful comments on the manuscript. This research was supported by National Institutes of Health Grants R01EY019281 (to P.J.B.) and R01EY020517 (to P.S.). NR 47 TC 15 Z9 15 U1 0 U2 13 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 4 PY 2014 VL 111 IS 5 BP 2035 EP 2039 DI 10.1073/pnas.1311041111 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 302FL UT WOS:000330587600084 PM 24449865 ER PT J AU Kwon, OJ Zhang, L Ittmann, MM Xin, L AF Kwon, Oh-Joon Zhang, Li Ittmann, Michael M. Xin, Li TI Prostatic inflammation enhances basal-to-luminal differentiation and accelerates initiation of prostate cancer with a basal cell origin SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE prostate stem cells; cells-of-origin for cancer ID ACUTE BACTERIAL PROSTATITIS; EPITHELIAL STEM-CELLS; MURINE PROSTATE; AUTOIMMUNE PROSTATITIS; MOUSE PROSTATE; IN-VITRO; MODEL; TISSUE; CARCINOGENESIS; EXPRESSION AB Chronic inflammation has been shown to promote the initiation and progression of diverse malignancies by inducing genetic and epigenetic alterations. In this study, we investigate an alternative mechanism through which inflammation promotes the initiation of prostate cancer. Adult murine prostate epithelia are composed predominantly of basal and luminal cells. Previous studies revealed that the two lineages are largely self-sustained when residing in their native microenvironment. To interrogate whether tissue inflammation alters the differentiation program of basal cells, we conducted lineage tracing of basal cells using a K14-CreER; mTmG model in concert with a murine model of prostatitis induced by infection from the uropathogenic bacteria CP9. We show that acute prostatitis causes tissue damage and creates a tissue microenvironment that induces the differentiation of basal cells into luminal cells, an alteration that rarely occurs under normal physiological conditions. Previously we showed that a mouse model with prostate basal cell-specific deletion of Phosphatase and tensin homolog (K14-CreER; Ptenfl/fl) develops prostate cancer with a long latency, because disease initiation in this model requires and is limited by the differentiation of transformation-resistant basal cells into transformation-competent luminal cells. Here, we show that CP9-induced prostatitis significantly accelerates the initiation of prostatic intraepithelial neoplasia in this model. Our results demonstrate that inflammation results in a tissue microenvironment that alters the normal prostate epithelial cell differentiation program and that through this cellular process inflammation accelerates the initiation of prostate cancer with a basal cell origin. C1 [Kwon, Oh-Joon; Zhang, Li; Xin, Li] Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA. [Ittmann, Michael M.; Xin, Li] Baylor Coll Med, Dept Pathol & Immunol, Houston, TX 77030 USA. [Xin, Li] Baylor Coll Med, Dan L Duncan Canc Ctr, Houston, TX 77030 USA. [Ittmann, Michael M.] Michael E DeBakey VA Med Ctr, US Dept Vet Affairs, Houston, TX 77030 USA. RP Xin, L (reprint author), Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA. EM xin@bcm.edu FU National Institutes of Health (NIH) [AI036211, CA125123, RR024574]; NIH [R00 CA125937, R01 DK092202, U01 CA141497, P20DK097775]; NIH Cancer Center Shared Resources [P30 CA125123] FX We thank Dr. Allison O'Brien for providing the CP9 bacterial strain; Drs. Julienne Carstens and Jonathan Levitt for technical advice on transurethral instillation of bacteria; Drs. Jeffrey Rosen and Amy Shore for critical comments; Joel M. Sederstrom for expert assistance with flow cytometry; and the Cytometry and Cell Sorting Core at Baylor College of Medicine [National Institutes of Health (NIH) Grants AI036211, CA125123, and RR024574] for technical support. This work was supported by NIH Grants R00 CA125937 and R01 DK092202 (to L.X.), U01 CA141497 and P20DK097775 (to M.M.I.), and NIH Cancer Center Shared Resources Grant P30 CA125123. NR 64 TC 39 Z9 39 U1 0 U2 12 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 FEB 4 PY 2014 VL 111 IS 5 BP E592 EP E600 DI 10.1073/pnas.1318157111 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 302FL UT WOS:000330587600012 PM 24367088 ER PT J AU Stanton, RC AF Stanton, Robert C. TI Sodium Glucose Transport 2 (SGLT2) Inhibition Decreases Glomerular Hyperfiltration Is There a Role for SGLT2 Inhibitors in Diabetic Kidney Disease? SO CIRCULATION LA English DT Editorial Material DE Editorials; diabetes mellitus; kidney; sodium glucose cotransporters ID FILTRATION-RATE; ALBUMINURIA; MORTALITY; OUTCOMES; RISK C1 [Stanton, Robert C.] Joslin Diabet Ctr, Boston, MA 02215 USA. [Stanton, Robert C.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Stanton, Robert C.] Harvard Univ, Sch Med, Boston, MA USA. RP Stanton, RC (reprint author), Joslin Diabet Ctr, Kidney & Hypertens Sect, One Joslin Pl, Boston, MA 02215 USA. EM robert.stanton@joslin.harvard.edu NR 16 TC 16 Z9 16 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 FEB 4 PY 2014 VL 129 IS 5 BP 542 EP 544 DI 10.1161/CIRCULATIONAHA.113.007071 PG 3 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 302EA UT WOS:000330583300009 PM 24334174 ER PT J AU Stimberg, M Goodman, DFM Benichoux, V Brette, R AF Stimberg, Marcel Goodman, Dan F. M. Benichoux, Victor Brette, Romain TI Equation-oriented specification of neural models for simulations SO FRONTIERS IN NEUROINFORMATICS LA English DT Article DE python; neuroscience; computational neuroscience; simulation; software ID PLASTICITY; NETWORKS; NEURONS AB Simulating biological neuronal networks is a core method of research in computational neuroscience. A full specification of such a network model includes a description of the dynamics and state changes of neurons and synapses, as well as the synaptic connectivity patterns and the initial values of all parameters. A standard approach in neuronal modeling software is to build network models based on a library of pre-defined components and mechanisms; if a model component does not yet exist, it has to be defined in a special-purpose or general low-level language and potentially be compiled and linked with the simulator. Here we propose an alternative approach that allows flexible definition of models by writing textual descriptions based on mathematical notation. We demonstrate that this approach allows the definition of a wide range of models with minimal syntax. Furthermore, such explicit model descriptions allow the generation of executable code for various target languages and devices, since the description is not tied to an implementation. Finally, this approach also has advantages for readability and reproducibility, because the model description is fully explicit, and because it can be automatically parsed and transformed into formatted descriptions. The presented approach has been implemented in the Brian2 simulator. C1 [Stimberg, Marcel; Benichoux, Victor; Brette, Romain] CNRS, Lab Psychol Percept, Paris, France. [Stimberg, Marcel; Benichoux, Victor; Brette, Romain] Univ Paris 05, Paris, France. [Stimberg, Marcel; Benichoux, Victor; Brette, Romain] Ecole Normale Super, Dept Etud Cognit, F-75230 Paris 05, France. [Goodman, Dan F. M.] Massachusetts Eye & Ear Infirm, Eaton Peabody Lab, Boston, MA 02114 USA. [Goodman, Dan F. M.] Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. RP Stimberg, M (reprint author), Ecole Normale Super, Equipe Audit, Dept Etud Cognit, 29 Rue Ulm, F-75230 Paris 05, France. EM marcel.stimberg@ens.fr RI Brette, Romain/I-7120-2016; OI Stimberg, Marcel/0000-0002-2648-4790; Brette, Romain/0000-0003-0110-1623 FU ERC [StG 240132]; [ANR-11-0001-02 PSL*]; [ANR-10-LABX-0087] FX This work was supported by ANR-11-0001-02 PSL*, ANR-10-LABX-0087 and ERC StG 240132. NR 26 TC 14 Z9 14 U1 1 U2 4 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1662-5196 J9 FRONT NEUROINFORM JI Front. Neuroinformatics PD FEB 4 PY 2014 VL 8 AR 6 DI 10.3389/fninf.2014.00006 PG 14 WC Mathematical & Computational Biology; Neurosciences SC Mathematical & Computational Biology; Neurosciences & Neurology GA AZ3CG UT WOS:000348104800001 PM 24550820 ER PT J AU Martinez, CH Moy, ML Nguyen, HQ Cohen, M Kadri, R Roman, P Holleman, RG Kim, HM Goodrich, DE Giardino, ND Richardson, CR AF Martinez, Carlos H. Moy, Marilyn L. Nguyen, Huong Q. Cohen, Miriam Kadri, Reema Roman, Pia Holleman, Robert G. Kim, Hyungjin Myra Goodrich, David E. Giardino, Nicholas D. Richardson, Caroline R. TI Taking Healthy Steps: rationale, design and baseline characteristics of a randomized trial of a pedometer-based internet-mediated walking program in veterans with chronic obstructive pulmonary disease SO BMC PULMONARY MEDICINE LA English DT Article DE COPD; Chronic bronchitis; Emphysema; Quality of life; Exercise; Physical activity; Internet; Pedometer; Walking; Veterans ID CHRONIC LUNG-DISEASE; PHYSICAL-ACTIVITY; SELF-MANAGEMENT; DIAGNOSED COPD; REHABILITATION; DYSPNEA; PARTICIPATION; MORTALITY; DECLINE; LIFE AB Background: Low levels of physical activity are common in patients with chronic obstructive pulmonary disease (COPD), and a sedentary lifestyle is associated with poor outcomes including increased mortality, frequent hospitalizations, and poor health-related quality of life. Internet-mediated physical activity interventions may increase physical activity and improve health outcomes in persons with COPD. Methods/Design: This manuscript describes the design and rationale of a randomized controlled trial that tests the effectiveness of Taking Healthy Steps, an Internet-mediated walking program for Veterans with COPD. Taking Healthy Steps includes an uploading pedometer, a website, and an online community. Eligible and consented patients wear a pedometer to obtain one week of baseline data and then are randomized on a 2:1 ratio to Taking Healthy Steps or to a wait list control. The intervention arm receives iterative step-count feedback; individualized step-count goals, motivational and informational messages, and access to an online community. Wait list controls are notified that they are enrolled, but that their intervention will start in one year; however, they keep the pedometer and have access to a static webpage. Discussion: Participants include 239 Veterans (mean age 66.7 years, 93.7% male) with 155 randomized to Taking Healthy Steps and 84 to the wait list control arm; rural-living (45.2%); ever-smokers (93.3%); and current smokers (25.1%). Baseline mean St. George's Respiratory Questionnaire Total Score was 46.0; 30.5% reported severe dyspnea; and the average number of comorbid conditions was 4.9. Mean baseline daily step counts was 3497 (+/- 2220). Veterans with COPD can be recruited to participate in an online walking program. We successfully recruited a cohort of older Veterans with a significant level of disability including Veterans who live in rural areas using a remote national recruitment strategy. C1 [Martinez, Carlos H.] Univ Michigan Hlth Syst, Div Pulm & Crit Care, Ann Arbor, MI 48104 USA. [Moy, Marilyn L.] VA Boston Healthcare Syst, Pulm & Crit Care Med Sect, West Roxbury, MA 02132 USA. [Moy, Marilyn L.] Brigham & Womens Hosp, Dept Med, Div Pulm & Crit Care Med, Boston, MA 02115 USA. [Nguyen, Huong Q.] Kaiser Permanente So Calif, Dept Res & Evaluat, Pasadena, CA 91102 USA. [Cohen, Miriam] VA New York Harbor, Patient Serv, Brooklyn, NY 11209 USA. [Kadri, Reema; Roman, Pia; Holleman, Robert G.; Kim, Hyungjin Myra; Goodrich, David E.; Richardson, Caroline R.] VA Ann Arbor Healthcare Syst, Ctr Clin Management Res, Ann Arbor, MI 48105 USA. [Kim, Hyungjin Myra] Univ Michigan, Sch Publ Hlth, Ann Arbor, MI 48109 USA. [Giardino, Nicholas D.] Univ Michigan, Dept Psychiat, Ann Arbor, MI 48109 USA. [Richardson, Caroline R.] Univ Michigan, Dept Family Med, Ann Arbor, MI 48104 USA. RP Richardson, CR (reprint author), VA Ann Arbor Healthcare Syst, Ctr Clin Management Res, Ann Arbor, MI 48105 USA. EM caroli@umich.edu OI Goodrich, David/0000-0003-3232-2189 FU Department of Veterans Affairs, Health Services Research and Development [IIR 09-366]; NIH Heart, Lung and Blood Institute [T32 HL007749-20]; VA Rehabilitation R&D Service Career Development Award [F6847W]; Robert Wood Johnson Foundation [57408]; NIH-NHLBI [K23 HL075098]; Michigan Diabetes Research and Training Center [P60 DK020572]; Center for Health Communications Research [P50 CA101451]; Michigan Institute for Clinical and Health Research (NIH) [UL1RR024986] FX This project is funded through the Department of Veterans Affairs, Health Services Research and Development (IIR 09-366, Richardson), NIH Heart, Lung and Blood Institute (T32 HL007749-20, Martinez), and VA Rehabilitation R&D Service Career Development Award (F6847W, Moy). The Stepping Up to Health platform was funded by Dr Richardson's Physician Faculty Scholars Program award from the Robert Wood Johnson Foundation (57408). Additional funding was provided by awards from NIH-NHLBI (K23 HL075098, Richardson), the Michigan Diabetes Research and Training Center (P60 DK020572), the Center for Health Communications Research (P50 CA101451), the Michigan Institute for Clinical and Health Research (NIH #UL1RR024986). None of the funding bodies had any role in the design, collection, analysis or interpretation of the data; in writing the manuscript or in the decision to submit the manuscript for publication. NR 60 TC 4 Z9 4 U1 4 U2 9 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2466 J9 BMC PULM MED JI BMC Pulm. Med. PD FEB 3 PY 2014 VL 14 AR 12 DI 10.1186/1471-2466-14-12 PG 13 WC Respiratory System SC Respiratory System GA AF3UL UT WOS:000334637700001 PM 24491137 ER PT J AU Schwarz, BA Bar-Nur, O Silva, JCR Hochedlinger, K AF Schwarz, Benjamin A. Bar-Nur, Ori Silva, Jose C. R. Hochedlinger, Konrad TI Nanog Is Dispensable for the Generation of Induced Pluripotent Stem Cells SO CURRENT BIOLOGY LA English DT Article ID TRANSCRIPTIONAL NETWORK; MOUSE EPIBLAST; SOMATIC-CELLS; GROUND-STATE; ES CELLS; FIBROBLASTS; EXPRESSION AB Cellular reprogramming from somatic cells to induced pluripotent stem cells (iPSCs) can be achieved through forced expression of the transcription factors Oct4, Klf4, Sox2, and c-Myc (OKSM) [1-4]. These factors, in combination with environmental cues, induce a stable intrinsic pluripotency network that confers indefinite self-renewal capacity on iPSCs. In addition to Oct4 and Sox2, the homeodomain-containing transcription factor Nanog is an integral part of the pluripotency network [5-11]. Although Nanog expression is not required for the maintenance of pluripotent stem cells, it has been reported to be essential for the establishment of both embryonic stem cells (ESCs) from blastocysts and iPSCs from somatic cells [10, 12]. Here we revisit the role of Nanog in direct reprogramming. Surprisingly, we find that Nanog is dispensable for iPSC formation under optimized culture conditions. We further document that Nanog-deficient iPSCs are transcriptionally highly similar to wild-type iPSCs and support the generation of teratomas and chimeric mice. Lastly, we provide evidence that the presence of ascorbic acid in the culture media is critical for overcoming the previously observed reprogramming block of Nanog knockout cells. C1 [Schwarz, Benjamin A.; Bar-Nur, Ori; Hochedlinger, Konrad] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Schwarz, Benjamin A.; Bar-Nur, Ori; Hochedlinger, Konrad] Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA. [Schwarz, Benjamin A.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Schwarz, Benjamin A.; Bar-Nur, Ori; Hochedlinger, Konrad] Harvard Stem Cell Inst, Cambridge, MA 02138 USA. [Silva, Jose C. R.] Univ Cambridge, Wellcome Trust Med Res Council, Cambridge Stem Cell Inst, Cambridge CB2 1QR, England. [Silva, Jose C. R.] Univ Cambridge, Dept Biochem, Cambridge CB2 1QR, England. [Hochedlinger, Konrad] Harvard Univ, Howard Hughes Med Inst, Cambridge, MA 02138 USA. [Hochedlinger, Konrad] Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. RP Hochedlinger, K (reprint author), Massachusetts Gen Hosp, Ctr Canc, 185 Cambridge St, Boston, MA 02114 USA. EM khochedlinger@helix.mgh.harvard.edu RI Silva, Jose/G-1920-2014 OI Silva, Jose/0000-0001-5487-1117 FU MGH Pathology Department grant [NIH 5-T32-CA-9216-33]; Gruss Lipper postdoctoral fellowship; NIH [R01-HD-058013] FX We thank members of the Hochedlinger lab for their help and support, as well as the MGH CRM/HSCI flow cytometry core, the Harvard University Genome Modification Facility, and the Partners Center for Personalized Genetic Medicine core microarray facility. B.A.S. was supported through an MGH Pathology Department grant (NIH 5-T32-CA-9216-33), O.B. was supported by the Gruss Lipper postdoctoral fellowship, and K.H. was supported by the NIH (R01-HD-058013). NR 26 TC 27 Z9 30 U1 0 U2 19 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0960-9822 EI 1879-0445 J9 CURR BIOL JI Curr. Biol. PD FEB 3 PY 2014 VL 24 IS 3 BP 347 EP 350 DI 10.1016/j.cub.2013.12.050 PG 4 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AA2IS UT WOS:000330918900032 PM 24461999 ER PT J AU Mitsis, EM Bender, HA Kostakoglu, L Machac, J Martin, J Woehr, JL Sewell, MC Aloysi, A Goldstein, MA Li, C Sano, M Gandy, S AF Mitsis, Effie M. Bender, Heidi A. Kostakoglu, Lale Machac, Josef Martin, Jane Woehr, Jennifer L. Sewell, Margaret C. Aloysi, Amy Goldstein, Martin A. Li, Clara Sano, Mary Gandy, Sam TI A consecutive case series experience with [F-18] florbetapir PET imaging in an urban dementia center: impact on quality of life, decision making, and disposition SO MOLECULAR NEURODEGENERATION LA English DT Article DE Amyvid (TM); Florbetapir; PET; Clinical series; Alzheimer's disease; Neuroimaging ID POSITRON-EMISSION-TOMOGRAPHY; MILD COGNITIVE IMPAIRMENT; ALZHEIMER-DISEASE; F 18; AMYLOID DEPOSITION; INDIVIDUALS; F-18-AV-45; MEMORY; CARE AB Background: Identification and quantification of fibrillar amyloid in brain using positron emission tomography (PET) imaging and Amyvid (TM) ([F-18] Amyvid, [F-18] florbetapir, F-18-AV-45) was recently approved by the US Food and Drug Administration as a clinical tool to estimate brain amyloid burden in patients being evaluated for cognitive impairment or dementia. Imaging with [F-18] florbetapir offers in vivo confirmation of the presence of cerebral amyloidosis and may increase the accuracy of the diagnosis and likely cause of cognitive impairment (CI) or dementia. Most importantly, amyloid imaging may improve certainty of etiology in situations where the differential diagnosis cannot be resolved on the basis of standard clinical and laboratory criteria. Results: A consecutive case series of 30 patients (age 50-89; 16 M/14 F) were clinically evaluated at a cognitive evaluation center of urban dementia center and referred for [F-18] florbetapir PET imaging as part of a comprehensive dementia workup. Evaluation included neurological examination and neuropsychological assessment by dementia experts. [F-18] florbetapir PET scans were read by trained nuclear medicine physicians using the qualitative binary approach. Scans were rated as either positive or negative for the presence of cerebral amyloidosis. In addition to a comprehensive dementia evaluation, post [F-18] florbetapir PET imaging results caused diagnoses to be changed in 10 patients and clarified in 9 patients. Four patients presenting with SCI were negative for amyloidosis. These results show that [F-18] florbetapir PET imaging added diagnostic clarification and discrimination in over half of the patients evaluated. Conclusions: Amyloid imaging provided novel and essential data that: (1) caused diagnosis to be revised; and/or (2) prevented the initiation of incorrect or suboptimal treatment; and/or (3) avoided inappropriate referral to an anti-amyloid clinical trial. C1 [Mitsis, Effie M.; Bender, Heidi A.; Martin, Jane; Sewell, Margaret C.; Aloysi, Amy; Li, Clara; Sano, Mary; Gandy, Sam] Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA. [Bender, Heidi A.; Woehr, Jennifer L.; Aloysi, Amy; Goldstein, Martin A.; Gandy, Sam] Mt Sinai Med Ctr, Dept Neurol, New York, NY 10029 USA. [Kostakoglu, Lale; Machac, Josef] Dept Nucl Med, New York, NY 10029 USA. [Mitsis, Effie M.; Sewell, Margaret C.; Li, Clara; Sano, Mary; Gandy, Sam] Icahn Sch Med Mt Sinai, Alzheimers Dis Res Ctr, New York, NY 10029 USA. [Mitsis, Effie M.; Gandy, Sam] James J Peters Vet Affairs Med Ctr, Bronx, NY 10468 USA. RP Mitsis, EM (reprint author), Icahn Sch Med Mt Sinai, Dept Psychiat, One Gustave L Levy Pl,Box 1230, New York, NY 10029 USA. EM effie.mitsis@mssm.edu FU Baxter Pharmaceuticals; Polyphenolics, Inc.; Amicus Pharmaceuticals; Icahn School of Medicine Alzheimer's Disease Research Center [P50 AG05138] FX The Authors gratefully acknowledge Ash Rafique and Corey Fernandez for technical and administrative support, respectively. SG thanks NIA, NINDS, the Cure Alzheimer's Fund, the Department of Veteran Affairs, the Gideon and Sarah Gartner Foundation, and the Louis B. Mayer Foundation. Within the past 5 years, SG has received grants from Baxter Pharmaceuticals, Polyphenolics, Inc., and Amicus Pharmaceuticals. He has served as a member of the Data and Safety Monitoring Board for the Pfizer-Janssen Alzheimer's Immunotherapy Alliance, as a member of the Scientific Advisory Board of DiaGenic, and as a consultant to Amicus Pharmaceuticals and to Cerora, Inc. This research was supported in part by the Icahn School of Medicine Alzheimer's Disease Research Center grant P50 AG05138. NR 20 TC 8 Z9 8 U1 1 U2 7 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1750-1326 J9 MOL NEURODEGENER JI Mol. Neurodegener. PD FEB 3 PY 2014 VL 9 AR 10 DI 10.1186/1750-1326-9-10 PG 6 WC Neurosciences SC Neurosciences & Neurology GA AB1JX UT WOS:000331548800001 PM 24484858 ER PT J AU Angin, M Klarenbeek, PL King, M Sharma, SM Moodley, ES Rezai, A Piechocka-Trocha, A Toth, I Chan, AT Goulder, PJ Ndung'u, T Kwon, DS Addo, MM AF Angin, Mathieu Klarenbeek, Paul L. King, Melanie Sharma, Siddhartha M. Moodley, Eshia S. Rezai, Ashley Piechocka-Trocha, Alicja Toth, Ildiko Chan, Andrew T. Goulder, Philip J. Ndung'u, Thumbi Kwon, Douglas S. Addo, Marylyn M. TI Regulatory T Cells Expanded from HIV-1-Infected Individuals Maintain Phenotype, TCR Repertoire and Suppressive Capacity SO PLOS ONE LA English DT Article ID IMMUNODEFICIENCY-VIRUS-INFECTION; IN-VITRO EXPANSION; HIV-INFECTION; ALLOGRAFT-REJECTION; IMMUNE SUPPRESSION; PERIPHERAL-BLOOD; DNA METHYLATION; RHESUS MACAQUES; MURINE MODEL; ANTIGEN 4 AB While modulation of regulatory T cell (Treg) function and adoptive Treg transfer are being explored as therapeutic modalities in the context of autoimmune diseases, transplantation and cancer, their role in HIV-1 pathogenesis remains less well defined. Controversy persists regarding their beneficial or detrimental effects in HIV-1 disease, which warrants further detailed exploration. Our objectives were to investigate if functional CD4(+) Tregs can be isolated and expanded from HIV-1-infected individuals for experimental or potential future therapeutic use and to determine phenotype and suppressive capacity of expanded Tregs from HIV-1 positive blood and tissue. Tregs and conventional T cell controls were isolated from blood and gut-associated lymphoid tissue of individuals with HIV-1 infection and healthy donors using flow-based cell-sorting. The phenotype of expanded Tregs was assessed by flow-cytometry and quantitative PCR. T-cell receptor beta-chain (TCR-beta) repertoire diversity was investigated by deep sequencing. Flow-based T-cell proliferation and chromium release cytotoxicity assays were used to determine Treg suppressive function. Tregs from HIV-1 positive individuals, including infants, were successfully expanded from PBMC and GALT. Expanded Tregs expressed high levels of FOXP3, CTLA4, CD39 and HELIOS and exhibited a highly demethylated TSDR (Treg-specific demethylated region), characteristic of Treg lineage. The TCR beta repertoire was maintained following Treg expansion and expanded Tregs remained highly suppressive in vitro. Our data demonstrate that Tregs can be expanded from blood and tissue compartments of HIV-1+ donors with preservation of Treg phenotype, function and TCR repertoire. These results are highly relevant for the investigation of potential future therapeutic use, as currently investigated for other disease states and hold great promise for detailed studies on the role of Tregs in HIV-1 infection. C1 [Angin, Mathieu; King, Melanie; Sharma, Siddhartha M.; Rezai, Ashley; Piechocka-Trocha, Alicja; Toth, Ildiko; Ndung'u, Thumbi; Kwon, Douglas S.; Addo, Marylyn M.] Ragon Inst MGH MIT & Harvard, Boston, MA USA. [Klarenbeek, Paul L.] Univ Amsterdam, Acad Med Ctr, Dept Clin Immunol & Rheumatol, NL-1105 AZ Amsterdam, Netherlands. [Moodley, Eshia S.; Goulder, Philip J.; Ndung'u, Thumbi] Univ KwaZulu Natal, HIV Pathogenesis Programme, Doris Duke Med Res Inst, Durban, South Africa. [Moodley, Eshia S.; Goulder, Philip J.; Ndung'u, Thumbi] Univ KwaZulu Natal, KwaZulu Natal Res Inst TB & HIV, Durban, South Africa. [Chan, Andrew T.] Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. [Goulder, Philip J.] Univ Oxford, Dept Paediat, Oxford, England. [Kwon, Douglas S.; Addo, Marylyn M.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Addo, Marylyn M.] Univ Med Ctr Hamburg Eppendorf, Dept Med, Hamburg, Germany. RP Addo, MM (reprint author), Ragon Inst MGH MIT & Harvard, Boston, MA USA. EM maddo@partners.org OI Ndung'u, Thumbi/0000-0003-2962-3992; Angin, Mathieu/0000-0002-6867-4680 FU Elisabeth Glaser Pediatric AIDS Foundation (Pediatric HIV Vaccine Program Award) [MV-00-9-900-1429-0-00]; MGH/ECOR (Physician Scientist Development Award); NIH NIAID [KO8 AI074405, AI074405-03S1]; Milton Fund; Bill & Melinda Gates Foundation; Terry and Susan Ragon Foundation; Harvard University Center for AIDS Research (CFAR); NIH [5P30AI060354-09]; NIH; NIAID; NCI; NICHD; NHLBI; NIDA; NIMH; NIA; NCCAM; FIC; OAR; International Early Career Scientist award from the Howard Hughes Medical Institute; South African Department of Science and Technology/National Research Foundation Research Chairs Initiative; MGH Center for the Study Inflammatory Bowel Disease [P30DK043351] FX This work was supported in part by research funding from the Elisabeth Glaser Pediatric AIDS Foundation (Pediatric HIV Vaccine Program Award MV-00-9-900-1429-0-00 to MMA), MGH/ECOR (Physician Scientist Development Award to MMA), NIH NIAID (KO8 AI074405 and AI074405-03S1 to MMA) and the Milton Fund (MMA). The studies were furthermore supported by the Bill & Melinda Gates Foundation and the Terry and Susan Ragon Foundation. This publication resulted in part from research supported by the Harvard University Center for AIDS Research (CFAR) (including a CFAR scholar award to MA), an NIH funded program (5P30AI060354-09), which is supported by the following NIH Co-Funding and Participating Institutes and Centers: NIAID, NCI, NICHD, NHLBI, NIDA, NIMH, NIA, NCCAM, FIC, and OAR. The research of TN and EM was supported in part by an International Early Career Scientist award from the Howard Hughes Medical Institute and by the South African Department of Science and Technology/National Research Foundation Research Chairs Initiative. ATC was supported by funding from MGH Center for the Study Inflammatory Bowel Disease (P30DK043351). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 65 TC 3 Z9 4 U1 3 U2 13 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD FEB 3 PY 2014 VL 9 IS 2 AR e86920 DI 10.1371/journal.pone.0086920 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 302TD UT WOS:000330626900033 PM 24498287 ER PT J AU Kilic, G Alvarez-Mercado, AI Zarrouki, B Opland, D Liew, CW Alonso, LC Myers, MG Jonas, JC Poitout, V Kulkarni, RN Mauvais-Jarvis, F AF Kilic, Gamze Alvarez-Mercado, Ana I. Zarrouki, Bader Opland, Darren Liew, Chong Wee Alonso, Laura C. Myers, Martin G., Jr. Jonas, Jean-Christophe Poitout, Vincent Kulkarni, Rohit N. Mauvais-Jarvis, Franck TI The Islet Estrogen Receptor-alpha Is Induced by Hyperglycemia and Protects Against Oxidative Stress-Induced Insulin-Deficient Diabetes SO PLOS ONE LA English DT Article ID PANCREATIC BETA-CELLS; GLUCOSE-HOMEOSTASIS; INDUCED APOPTOSIS; ACTIVATION; MICE; MECHANISMS; EXPRESSION; SURVIVAL; ENERGY; MODEL AB The female steroid, 17 beta-estradiol (E2), is important for pancreatic beta-cell function and acts via at least three estrogen receptors (ER), ER alpha, ER beta, and the G-protein coupled ER (GPER). Using a pancreas-specific ER alpha knockout mouse generated using the Cre-lox-P system and a Pdx1-Cre transgenic line (PER alpha KO-/-), we previously reported that islet ER alpha suppresses islet glucolipotoxicity and prevents beta-cell dysfunction induced by high fat feeding. We also showed that E2 acts via ER alpha to prevent beta-cell apoptosis in vivo. However, the contribution of the islet ER alpha to beta-cell survival in vivo, without the contribution of ER alpha in other tissues is still unclear. Using the PER alpha KO-/- mouse, we show that ER alpha mRNA expression is only decreased by 20% in the arcuate nucleus of the hypothalamus, without a parallel decrease in the VMH, making it a reliable model of pancreas-specific ER alpha elimination. Following exposure to alloxan-induced oxidative stress in vivo, female and male PER alpha KO-/- mice exhibited a predisposition to beta-cell destruction and insulin deficient diabetes. In male PER alpha KO-/- mice, exposure to E2 partially prevented alloxan-induced beta-cell destruction and diabetes. ER alpha mRNA expression was induced by hyperglycemia in vivo in islets from young mice as well as in cultured rat islets. The induction of ER alpha mRNA by hyperglycemia was retained in insulin receptor-deficient beta-cells, demonstrating independence from direct insulin regulation. These findings suggest that induction of ER alpha expression acts to naturally protect beta-cells against oxidative injury. C1 [Kilic, Gamze; Mauvais-Jarvis, Franck] Northwestern Univ, Dept Med, Feinberg Sch Med, Div Endocrinol Metab & Mol Med, Chicago, IL 60611 USA. [Alvarez-Mercado, Ana I.; Mauvais-Jarvis, Franck] Tulane Univ, Sch Med, Dept Med, Div Endocrinol & Metab,Hlth Sci Ctr, New Orleans, LA 70112 USA. [Zarrouki, Bader; Poitout, Vincent] Univ Montreal, CRCHUM, Montreal Diabet Res Ctr, Montreal, PQ, Canada. [Zarrouki, Bader; Poitout, Vincent] Univ Montreal, Dept Med, Montreal, PQ H3C 3J7, Canada. [Opland, Darren; Myers, Martin G., Jr.] Univ Michigan, Dept Internal Med, Div Metab Endocrinol & Diabet, Ann Arbor, MI 48109 USA. [Liew, Chong Wee; Kulkarni, Rohit N.] Joslin Diabet Ctr, Sect Islet Cell Biol & Regenerat Med, Boston, MA 02215 USA. [Liew, Chong Wee; Kulkarni, Rohit N.] Harvard Univ, Sch Med, Boston, MA USA. [Alonso, Laura C.] Univ Massachusetts, Sch Med, Dept Med, Div Diabet, Worcester, MA USA. [Jonas, Jean-Christophe] Catholic Univ Louvain, Inst Clin & Expt Res, Brussels, Belgium. RP Mauvais-Jarvis, F (reprint author), Northwestern Univ, Dept Med, Feinberg Sch Med, Div Endocrinol Metab & Mol Med, Chicago, IL 60611 USA. EM fmauvais@tulane.edu RI Jonas, Jean-Christophe/C-6766-2011; OI Jonas, Jean-Christophe/0000-0001-9882-5438; Poitout, Vincent/0000-0002-6555-5053 FU National Institutes of Health [RO1 DK074970]; Canadian Institutes of Health Research [MOP 77686]; Eli Lilly; Fonds de la Recherche Scientifique-FNRS, Belgium; [R01DK58096]; [RO1DK095140]; [RO1DK67536] FX This study was funded by National Institutes of Health (RO1 DK074970) to FMJ. Fig. 5A was funded by R01DK58096 to VP and the Canadian Institutes of Health Research (MOP 77686 to VP) and a postdoctoral fellowship from Eli Lilly to BZ. Fig. 5 C was supported by the Fonds de la Recherche Scientifique-FNRS, Belgium to JCJ. Fig. 5B was supported by RO1DK095140 to LCA. Fig. 5D was supported by RO1DK67536 to RNK. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 25 TC 7 Z9 7 U1 3 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD FEB 3 PY 2014 VL 9 IS 2 AR e87941 DI 10.1371/journal.pone.0087941 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 302TD UT WOS:000330626900154 PM 24498408 ER PT J AU Pieroh, P Koch, M Wagner, DC Boltze, J Ehrlich, A Ghadban, C Hobusch, C Birkenmeier, G Dehghani, F AF Pieroh, Philipp Koch, Marco Wagner, Daniel-Christoph Boltze, Johannes Ehrlich, Angela Ghadban, Chalid Hobusch, Constance Birkenmeier, Gerd Dehghani, Faramarz TI Temporal Dynamics of Glyoxalase 1 in Secondary Neuronal Injury SO PLOS ONE LA English DT Article ID METHYL-D-ASPARTATE; RAT HIPPOCAMPAL-NEURONS; ACUTE ISCHEMIC-STROKE; NITRIC-OXIDE; GLUCOSE-METABOLISM; CEREBRAL-ISCHEMIA; INDUCED APOPTOSIS; CORTICAL-NEURONS; OXIDATIVE STRESS; S-NITROSYLATION AB Background: Enhanced glycolysis leads to elevated levels of the toxic metabolite methylglyoxal which contributes to loss of protein-function, metabolic imbalance and cell death. Neurons were shown being highly susceptible to methylglyoxal toxicity. Glyoxalase 1 as an ubiquitous enzyme reflects the main detoxifying enzyme of methylglyoxal and underlies changes during aging and neurodegeneration. However, little is known about dynamics of Glyoxalase 1 following neuronal lesions so far. Methods: To determine a possible involvement of Glyoxalase 1 in acute brain injury, we analysed the temporal dynamics of Glyoxalase 1 distribution and expression by immunohistochemistry and Western Blot analysis. Organotypic hippocampal slice cultures were excitotoxically (N-methyl-D-aspartate, 50 mu M for 4 hours) lesioned in vitro (5 minutes to 72 hours). Additionally, permanent middle cerebral artery occlusion was performed (75 minutes to 60 days). Results: We found (i) a predominant localisation of Glyoxalase 1 in endothelial cells in non-lesioned brains (ii) a time-dependent up-regulation and re-distribution of Glyoxalase 1 in neurons and astrocytes and (iii) a strong increase in Glyoxalase 1 dimers after neuronal injury (24 hours to 72 hours) when compared to monomers of the protein. Conclusions: The high dynamics of Glyoxalase 1 expression and distribution following neuronal injury may indicate a novel role of Glyoxalase 1. C1 [Pieroh, Philipp; Ghadban, Chalid; Dehghani, Faramarz] Univ Halle Wittenberg, Dept Anat & Cell Biol, D-06108 Halle, Saale, Germany. [Pieroh, Philipp; Koch, Marco; Ehrlich, Angela; Ghadban, Chalid; Hobusch, Constance; Dehghani, Faramarz] Univ Leipzig, Inst Anat, D-04109 Leipzig, Germany. [Wagner, Daniel-Christoph; Boltze, Johannes] Fraunhofer Inst Cell Therapy & Immunol, Leipzig, Germany. [Wagner, Daniel-Christoph; Boltze, Johannes] Translat Ctr Regenerat Med, Leipzig, Germany. [Boltze, Johannes] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Boltze, Johannes] Harvard Univ, Sch Med, Boston, MA USA. [Birkenmeier, Gerd] Univ Leipzig, Inst Biochem, D-04109 Leipzig, Germany. RP Dehghani, F (reprint author), Univ Halle Wittenberg, Dept Anat & Cell Biol, D-06108 Halle, Saale, Germany. EM Dehghani@medizin.uni-halle.de NR 54 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 FEB 3 PY 2014 VL 9 IS 2 AR e87364 DI 10.1371/journal.pone.0087364 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 302TD UT WOS:000330626900061 PM 24498315 ER PT J AU Liao, GX O'Keeffe, MS Wang, GX van Driel, B Moiety, RD Reinecker, HC Herzog, RW Terhorst, C AF Liao, Gongxian O'Keeffe, Michael S. Wang, Guoxing van Driel, Boaz Moiety, Rene de Waal Reinecker, Hans-Christian Herzog, Roland W. Terhorst, Cox TI Glucocorticoid-induced TNF receptor family-related protein ligand is requisite for optimal functioning of regulatory CD4(+) T cells SO FRONTIERS IN IMMUNOLOGY LA English DT Article DE GITR-L; TNFSF18; FIt3L; Treg; CX3CR1 ID GENE-TRANSFER; IN-VIVO; IMMUNE TOLERANCE; CUTTING EDGE; GITR; EFFECTOR; ANTIGEN; SUPPRESSION; INDUCTION; MICE AB Glucocorticoid-induced tumor necrosis factor receptor family-related protein (TNFRSF18, CD357) is constitutively expressed on regulatory T cells (Tregs) and is inducible on effector T cells. In this report, we examine the role of glucocorticoid-induced TNF receptor family related protein ligand (GITR-L), which is expressed by antigen presenting cells, on the development and expansion of Tregs. We found that GITR-L is dispensable for the development of naturally occurring FoxP3(+) Treg cells in the thymus. However, the expansion of Treg in GITR-L-/- mice is impaired after injection of the dendritic cells (DCs) inducing factor Flt3 ligand. Furthermore, DCs from the liver of GITR-L-/- mice were less efficient in inducing proliferation of antigen specific Treg cells in vitro than the same cells from WT littermates. Upon gene transfer of ovalbumin into hepatocytes of GITR-L(-/-)FoxP3 (GFP) reporter mice using adeno-associated virus (AAV8-OVA) the number of antigen-specific Treg in liver and spleen is reduced. The reduced number of Tregs resulted in an increase in the number of ovalbumin specific CD8(+) T effector cells. This is highly significant because proliferation of antigen-specific CD8(+) cells itself is dependent on the presence of GITR-L, as shown by in vitro experiments and by adoptive transfers into GITR-L / Rag / and Rag / mice that had received AAV8-OVA. Surprisingly, administering alpha CD3 significantly reduced the numbers of FoxP3(+) Treg cells in the liver and spleen of GITR-L-/- but not WT mice. Because soluble Fc-GITR-L partially rescues alpha CD3 induced in vitro depletion of the CD103(+) subset of FoxP3(+)CD4(+) Treg cells, we conclude that expression of GITR-L by antigen presenting cells is requisite for optimal Treg mediated regulation of immune responses including those in response during gene transfer. C1 [Liao, Gongxian; O'Keeffe, Michael S.; Wang, Guoxing; van Driel, Boaz; Terhorst, Cox] Harvard Univ, Div Immunol, Beth Israel Deaconess Med Ctr, Sch Med, Boston, MA 02115 USA. [Moiety, Rene de Waal] Merck Res Labs, Biol Discovery, Palo Alto, CA USA. [Reinecker, Hans-Christian] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Gastrointestinal Unit, Boston, MA 02115 USA. [Reinecker, Hans-Christian] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Study Inflammatory Bowel Dis,Dept Med, Boston, MA 02115 USA. [Herzog, Roland W.] Univ Florida, Dept Pediat, Gainesville, FL USA. RP Liao, GX (reprint author), Harvard Univ, Div Immunol, Beth Israel Deaconess Med Ctr, Sch Med, 3 Blackfan Circle,CLS 928, Boston, MA 02115 USA. EM gliao@bidmc.harvard.edu; cterhors@bidmc.harvard.edu FU National Institutes of Health [P01 HL078810, R01 DK-52510, P30 DK-43351] FX this work was sponsored by National Institutes of Health (P01 HL078810 to Roland W. Herzog and Cox Terhorst, and R01 DK-52510 and P30 DK-43351 to Cox Terhorst). NR 41 TC 10 Z9 11 U1 0 U2 4 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1664-3224 J9 FRONT IMMUNOL JI Front. Immunol. PD FEB 3 PY 2014 VL 5 BP 1 EP 7 AR 35 DI 10.3389/fimmu.2014.00035 PG 7 WC Immunology SC Immunology GA CI0VP UT WOS:000354457500001 PM 24550919 ER PT J AU Lange, RA Levine, GN AF Lange, Richard A. Levine, Glenn N. TI Sexual Activity and Ischemic Heart Disease SO CURRENT CARDIOLOGY REPORTS LA English DT Article DE Sexual activity; Coital angina; Coital MI; Ischemic heart disease ID CORONARY-ARTERY-DISEASE; ACUTE MYOCARDIAL-INFARCTION; CASE-CROSSOVER ANALYSIS; ERECTILE DYSFUNCTION; SILDENAFIL-CITRATE; CARDIOVASCULAR-DISEASE; HYPERTENSIVE MEN; CARDIAC RISK; ANTIHYPERTENSIVE DRUGS; DEPRESSIVE SYMPTOMS AB Human sexuality is an important aspect of health and quality of life. Many patients with ischemic heart disease - and their partners - are concerned that sexual activity could exacerbate their cardiac condition, possibly causing myocardial infarction or cardiac death. Patients with ischemic heart disease who wish to initiate or resume sexual activity should be evaluated with a thorough medical history and physical examination. Sexual activity is reasonable for individuals with no or mild angina and those who can exercise >= 3-5 METS without angina, excessive dyspnea, or ischemic ST segment changes. For the patient who is considered not be at low cardiovascular (CV) risk or in whom the CV risk is unknown, an exercise stress test is reasonable in order to determine his or her exercise capacity and to ascertain if symptoms or ischemia may occur. Regular exercise and cardiac rehabilitation can be effective in reducing the risk of CV complications associated with sexual activity for the patient with ischemic heart disease. C1 [Lange, Richard A.] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA. [Levine, Glenn N.] Baylor Coll Med, Dept Med, Michael E DeBakey Med Ctr, Cardiol Sect, Houston, TX 77030 USA. RP Lange, RA (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Med, 7703 Floyd Curl Dr,MC 7870, San Antonio, TX 78229 USA. EM Langera@uthscsa.edu NR 97 TC 6 Z9 8 U1 0 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1523-3782 EI 1534-3170 J9 CURR CARDIOL REP JI Curr. Cardiol. Rep. PD FEB PY 2014 VL 16 IS 2 AR 445 DI 10.1007/s11886-013-0445-4 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AT6ZC UT WOS:000345084500002 PM 24408673 ER PT J AU Chenevert, TL Malyarenko, DI Newitt, D Li, X Jayatilake, M Tudorica, A Fedorov, A Kikinis, R Liu, TT Muzi, M Oborski, M Laymon, CM Li, X Thomas, Y Jayashree, KC Mountz, JM Kinahan, PE Rubin, DL Fennessy, F Huang, W Hylton, N Ross, BD AF Chenevert, Thomas L. Malyarenko, Dariya I. Newitt, David Li, Xin Jayatilake, Mohan Tudorica, Alina Fedorov, Andriy Kikinis, Ron Liu, Tiffany Ting Muzi, Mark Oborski, MatthewJ. Laymon, Charles M. Li, Xia Thomas, Yankeelov Jayashree, Kalpathy-Cramer Mountz, James M. Kinahan, Paul E. Rubin, Daniel L. Fennessy, Fiona Huang, Wei Hylton, Nola Ross, Brian D. TI Errors in Quantitative Image Analysis due to Platform-Dependent Image Scaling SO TRANSLATIONAL ONCOLOGY LA English DT Article ID INTENSITY NONUNIFORMITY CORRECTION; CLINICAL-TRIALS; CALIBRATION; UNCERTAINTY; MRI AB PURPOSE: To evaluate the ability of various software (SW) tools used for quantitative image analysis to properly account for source-specific image scaling employed by magnetic resonance imaging manufacturers. METHODS: A series of gadoteridol-doped distilled water solutions (0%, 0.5%, 1%, and 2% volume concentrations) was prepared for manual substitution into one (of three) phantom compartments to create "variable signal," whereas the other two compartments (containing mineral oil and 0.25% gadoteriol) were held unchanged. Pseudodynamic images were acquired over multiple series using four scanners such that the histogram of pixel intensities varied enough to provoke variable image scaling from series to series. Additional diffusion-weighted images were acquired of an ice-water phantom to generate scanner-specific apparent diffusion coefficient (ADC) maps. The resulting pseudo-dynamic images and ADC maps were analyzed by eight centers of the Quantitative Imaging Network using 16 different SW tools to measure compartment-specific region-of-interest intensity. RESULTS: Images generated by one of the scanners appeared to have additional intensity scaling that was not accounted for by the majority of tested quantitative image analysis SW tools. Incorrect image scaling leads to intensity measurement bias near 100%, compared to nonscaled images. CONCLUSION: Corrective actions for image scaling are suggested for manufacturers and quantitative imaging community. C1 [Chenevert, Thomas L.; Malyarenko, Dariya I.; Ross, Brian D.] Univ Michigan Hosp, Dept Radiol, Ann Arbor, MI 48109 USA. [Newitt, David; Hylton, Nola] Univ Calif San Francisco, Dept Radiol & Biomed Imaging, San Francisco, CA 94143 USA. [Li, Xin; Jayatilake, Mohan; Tudorica, Alina; Huang, Wei] Univ Portland, Oregon Hlth & Sci, Portland, OR 97203 USA. [Fedorov, Andriy; Kikinis, Ron; Fennessy, Fiona] Brigham & Womens Hosp, Boston, MA 02115 USA. [Fedorov, Andriy; Kikinis, Ron; Fennessy, Fiona] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Liu, Tiffany Ting; Rubin, Daniel L.] Stanford Univ, Stanford, CA 94305 USA. [Muzi, Mark; Kinahan, Paul E.] Univ Washington, Seattle, WA USA. [Oborski, MatthewJ.; Laymon, Charles M.; Mountz, James M.] Univ Pittsburgh, Pittsburgh, PA USA. [Li, Xia; Thomas, Yankeelov] Vanderbilt Univ, Inst Imaging Sci, Nashville, TN 37235 USA. [Jayashree, Kalpathy-Cramer] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Chenevert, TL (reprint author), Univ Michigan Hosp, B2A209,1500 E Med Ctr Dr, Ann Arbor, MI 48109 USA. EM tlchenev@umich.edu OI Kalpathy-Cramer, Jayashree/0000-0001-8906-9618; Fedorov, Andrey/0000-0003-4806-9413 FU Quantitative Imaging Network; National Institutes of Health [U01CA166104, U01CA151235, U01CA154602, U01CA142555, U01CA154601, U01CA140204, U01CA142565, U01CA148131, U01CA172320, U01CA140230, U54EB005149, R01CA136892, 1S10OD012240-01A1] FX Quantitative Imaging Network and National Institutes of Health funding: U01CA166104, U01CA151235, U01CA154602, U01CA142555, U01CA154601, U01CA140204, U01CA142565, U01CA148131, U01CA172320, U01CA140230, U54EB005149, R01CA136892 and 1S10OD012240-01A1. NR 18 TC 5 Z9 5 U1 0 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1944-7124 EI 1936-5233 J9 TRANSL ONCOL JI Transl. Oncol. PD FEB PY 2014 VL 7 IS 1 BP 65 EP 71 DI 10.1593/tlo.13811 PG 7 WC Oncology SC Oncology GA AQ3ID UT WOS:000342684300009 PM 24772209 ER PT J AU Fennessy, FM Mckay, RR Beard, CJ Taplin, ME Tempany, CM AF Fennessy, Fiona M. Mckay, Rana R. Beard, Clair J. Taplin, Mary-Ellen Tempany, Clare M. TI Dynamic Contrast-Enhanced Magnetic Resonance Imaging in Prostate Cancer Clinical Trials: Potential Roles and Possible Pitfalls SO TRANSLATIONAL ONCOLOGY LA English DT Article ID APPARENT DIFFUSION-COEFFICIENT; ENDOTHELIAL GROWTH-FACTOR; ARTERIAL INPUT FUNCTION; PHASE-III TRIAL; BREAST-CANCER; DOUBLE-BLIND; DCE-MRI; SEMIQUANTITATIVE ANALYSIS; ANTIVASCULAR THERAPIES; RADICAL PROSTATECTOMY AB Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) evaluates the tissue microvasculature and may have a role in assessing and predicting therapeutic response in prostate cancer (PCa). In this review, we review principles of DCE-MRI and present the potential quantitative information that can be obtained. We discuss how it may be used as a biomarker for treatment with antiangiogenic and antivascular agents and potentially identify patients with PCa who may benefit from this form of therapy. Likewise, DCE-MRI may play a role in assessing response to combined androgen deprivation therapy and radiation therapy and theoretically could be a prognostic biomarker in evaluating second-generation hormone therapies. We also address the challenges of using DCE-MRI in PCa clinical trials and discuss the difficulties with standardization of this methodology to allow for biomarker validation, with particular reference to PCa. C1 [Fennessy, Fiona M.; Tempany, Clare M.] Brigham & Womens Hosp, Dept Radiol, Boston, MA 02115 USA. [Fennessy, Fiona M.] Dana Farber Canc Inst, Dept Radiol, Boston, MA 02115 USA. [Mckay, Rana R.; Taplin, Mary-Ellen] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Beard, Clair J.] Brigham & Womens Hosp, Dept Radiat Oncol, Boston, MA 02115 USA. RP Fennessy, FM (reprint author), Brigham & Womens Hosp, Dept Radiol, 45 Francis St, Boston, MA 02115 USA. EM ffennessy@partners.org FU National Cancer Institute (NCI) [U01CA151261] FX We acknowledge National Cancer Institute (NCI) funding through U01CA151261 and thank Andriy Fedorov, PhD, and Tobias Penzkoffer, MD, for their help with figures for this paper. NR 86 TC 4 Z9 4 U1 0 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1944-7124 EI 1936-5233 J9 TRANSL ONCOL JI Transl. Oncol. PD FEB PY 2014 VL 7 IS 1 BP 120 EP 129 DI 10.1593/tlo.13922 PG 10 WC Oncology SC Oncology GA AQ3ID UT WOS:000342684300015 PM 24772215 ER PT J AU Kalpathy-Cramer, J Freymann, JB Kirby, JS Kinahan, PE Prior, FW AF Kalpathy-Cramer, Jayashree Freymann, John Blake Kirby, Justin Stephen Kinahan, Paul Eugene Prior, Fred William TI Quantitative Imaging Network: Data Sharing and Competitive Algorithm Validation Leveraging The Cancer Imaging Archive SO TRANSLATIONAL ONCOLOGY LA English DT Article ID RESOURCE; THERAPY; SYSTEMS AB The Quantitative Imaging Network (QIN), supported by the National Cancer Institute, is designed to promote research and development of quantitative imaging methods and candidate biomarkers for the measurement of tumor response in clinical trial settings. An integral aspect of the QIN mission is to facilitate collaborative activities that seek to develop best practices for the analysis of cancer imaging data. The QIN working groups and teams are developing new algorithms for image analysis and novel biomarkers for the assessment of response to therapy. To validate these algorithms and biomarkers and translate them into clinical practice, algorithms need to be compared and evaluated on large and diverse data sets. Analysis competitions, or "challenges," are being conducted within the QIN as a means to accomplish this goal. The QIN has demonstrated, through its leveraging of The Cancer Imaging Archive (TCIA), that data sharing of clinical images across multiple sites is feasible and that it can enable and support these challenges. In addition to Digital Imaging and Communications in Medicine (DICOM) imaging data, many TCIA collections provide linked clinical, pathology, and "ground truth" data generated by readers that could be used for further challenges. The TCIA-QIN partnership is a successful model that provides resources for multisite sharing of clinical imaging data and the implementation of challenges to support algorithm and biomarker validation. C1 [Kalpathy-Cramer, Jayashree] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 01940 USA. [Kalpathy-Cramer, Jayashree] Harvard Univ, Sch Med, Boston, MA USA. [Freymann, John Blake; Kirby, Justin Stephen] Frederick Natl Lab Canc Res, Leidos Biomed Res Inc, CMRP, Clin Res Directorate, Frederick, MD USA. [Kinahan, Paul Eugene] Univ Washington, Dept Radiol, Seattle, WA 98195 USA. [Prior, Fred William] Washington Univ, Sch Med, Mallinckrodt Inst Radiol, St Louis, MO USA. RP Kalpathy-Cramer, J (reprint author), Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, 149 13th St, Charlestown, MA 01940 USA. EM kalpathy@nmr.mgh.harvard.edu OI Kalpathy-Cramer, Jayashree/0000-0001-8906-9618 FU National Cancer Institute, National Institutes of Health (NIH) [HHSN261200800001E]; NIH grants [U01CA154602, R00LM009889, ST13-4130]; NIH grant [U01CA148131, 24XS036-004] FX This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health (NIH), under Contract No. HHSN261200800001E. 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. J.K.-C. is funded in part by the NIH grants U01CA154602 and R00LM009889 and a contract ST13-4130. P.E.K. is funded in part by the NIH grant U01CA148131 and Contract 24XS036-004. NR 33 TC 8 Z9 8 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1944-7124 EI 1936-5233 J9 TRANSL ONCOL JI Transl. Oncol. PD FEB PY 2014 VL 7 IS 1 BP 147 EP 152 DI 10.1593/tlo.13862 PG 6 WC Oncology SC Oncology GA AQ3ID UT WOS:000342684300018 PM 24772218 ER PT J AU Huang, W Li, X Chen, YY Li, X Chang, MC Oborski, MJ Malyarenko, DI Muzi, M Jajamovich, GH Fedorov, A Tudorica, A Gupta, SN Laymon, CM Marro, KI Dyvorne, HA Miller, JV Barbodiak, DP Chenevert, TL Yankeelov, TE Mountz, JM Kinahan, PE Kikinis, R Taouli, B Fennessy, F Kalpathy-Cramer, J AF Huang, Wei Li, Xin Chen, Yiyi Li, Xia Chang, Ming-Ching Oborski, Matthew J. Malyarenko, Dariya I. Muzi, Mark Jajamovich, Guido H. Fedorov, Andriy Tudorica, Alina Gupta, Sandeep N. Laymon, Charles M. Marro, Kenneth I. Dyvorne, Hadrien A. Miller, James V. Barbodiak, Daniel P. Chenevert, Thomas L. Yankeelov, Thomas E. Mountz, James M. Kinahan, Paul E. Kikinis, Ron Taouli, Bachir Fennessy, Fiona Kalpathy-Cramer, Jayashree TI Variations of Dynamic Contrast-Enhanced Magnetic Resonance Imaging in Evaluation of Breast Cancer Therapy Response: A Multicenter Data Analysis Challenge SO TRANSLATIONAL ONCOLOGY LA English DT Article ID TRANSCYTOLEMMAL WATER EXCHANGE; CLINICAL-TRIALS; SHUTTER-SPEED; DCE-MRI; TUMOR RESPONSE; NEOADJUVANT CHEMOTHERAPY; ANTIVASCULAR THERAPIES; TRACER KINETICS; PERMEABILITY; REPRODUCIBILITY AB Pharmacokinetic analysis of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) time-course data allows estimation of quantitative parameters such as K-trans (rate constant for plasma/interstitium contrast agent transfer), v(e) (extravascular extracellular volume fraction), and v(p) (plasma volume fraction). A plethora of factors in DCE-MRI data acquisition and analysis can affect accuracy and precision of these parameters and, consequently, the utility of quantitative DCE-MRI for assessing therapy response. In this multicenter data analysis challenge, DCE-MRI data acquired at one center from 10 patients with breast cancer before and after the first cycle of neoadjuvant chemotherapy were shared and processed with 12 software tools based on the Tofts model (TM), extended TM, and Shutter-Speed model. Inputs of tumor region of interest definition, pre-contrast T-1, and arterial input function were controlled to focus on the variations in parameter value and response prediction capability caused by differences in models and associated algorithms. Considerable parameter variations were observed with the within-subject coefficient of variation (wCV) values for K-trans and v(p) being as high as 0.59 and 0.82, respectively. Parameter agreement improved when only algorithms based on the same model were compared, e.g., the K-trans intraclass correlation coefficient increased to as high as 0.84. Agreement in parameter percentage change was much better than that in absolute parameter value, e.g., the pairwise concordance correlation coefficient improved from 0.047 (for K-trans) to 0.92 (for K-trans percentage change) in comparing two TM algorithms. Nearly all algorithms provided good to excellent (univariate logistic regression c-statistic value ranging from 0.8 to 1.0) early prediction of therapy response using the metrics of mean tumor K-trans and k(ep) (=K-trans/v(e), intravasation rate constant) after the first therapy cycle and the corresponding percentage changes. The results suggest that the interalgorithm parameter variations are largely systematic, which are not likely to significantly affect the utility of DCE-MRI for assessment of therapy response. C1 [Huang, Wei; Li, Xin; Chen, Yiyi] Oregon Hlth & Sci Univ, Portland, OR 97239 USA. [Li, Xia; Yankeelov, Thomas E.] Vanderbilt Univ, Nashville, TN 37235 USA. [Chang, Ming-Ching; Gupta, Sandeep N.; Miller, James V.] Gen Elect Global Res, Niskayuna, NY USA. [Oborski, Matthew J.; Laymon, Charles M.; Mountz, James M.] Univ Pittsburgh, Pittsburgh, PA USA. [Malyarenko, Dariya I.] Univ Michigan, Ann Arbor, MI 48109 USA. [Muzi, Mark; Marro, Kenneth I.; Kinahan, Paul E.] Univ Washington, Seattle, WA 98195 USA. [Jajamovich, Guido H.; Dyvorne, Hadrien A.; Taouli, Bachir] Icahn Sch Med Mt Sinai, New York, NY 10029 USA. [Fedorov, Andriy; Kikinis, Ron; Fennessy, Fiona] Brigham & Womens Hosp, Boston, MA 02115 USA. [Fedorov, Andriy; Kikinis, Ron; Fennessy, Fiona; Kalpathy-Cramer, Jayashree] Harvard Univ, Sch Med, Boston, MA USA. [Barbodiak, Daniel P.] Duke Univ, Durham, NC USA. [Kalpathy-Cramer, Jayashree] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Huang, W (reprint author), Oregon Hlth & Sci Univ, Adv Imaging Res Ctr, 3181 SW Sam Jackson Pk Rd, Portland, OR 97239 USA. EM huangwe@ohsu.edu OI Kalpathy-Cramer, Jayashree/0000-0001-8906-9618; Fedorov, Andrey/0000-0003-4806-9413 FU NIH/National Institute of Biomedical Imaging and Bioengineering (NIBIB) [HHSN268201000050C] FX The authors thank William Woodward for assistance in breast DCE-MRI data acquisition, Aneela Afzal for preparation of the raw breast DCE-MRI data for sharing by participating QIN centers, and Karen Oh and Nicole Roy for drawing tumor ROIs. The authors acknowledge and appreciate the Radiological Society of North America and NIH/National Institute of Biomedical Imaging and Bioengineering (NIBIB) Contract No. HHSN268201000050C for supporting development and evaluation of the DCE-MRI DROs. NR 40 TC 28 Z9 28 U1 4 U2 19 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1944-7124 EI 1936-5233 J9 TRANSL ONCOL JI Transl. Oncol. PD FEB PY 2014 VL 7 IS 1 BP 153 EP 166 DI 10.1593/tlo.13838 PG 14 WC Oncology SC Oncology GA AQ3ID UT WOS:000342684300019 PM 24772219 ER PT J AU Goldman, RH Batsis, M Hacker, MR Souter, I Petrozza, J AF Goldman, Randi H. Batsis, Maria Hacker, Michele R. Souter, Irene Petrozza, John TI The Impact of Provider Type on the Success of Intrauterine Inseminations SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT 62nd Annual Meeting of the Pacific-Coast-Reproductive-Society (PCRS) CY MAR 19-23, 2014 CL Indian Wells, CA SP Pacific Coast Reprod Soc C1 [Goldman, Randi H.; Souter, Irene; Petrozza, John] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Vincent Dept Obstet & Gynecol, Boston, MA USA. [Batsis, Maria; Souter, Irene; Petrozza, John] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Fertil Ctr,Vincent Dept Obstet & Gynecol, Boston, MA USA. [Hacker, Michele R.] Harvard Univ, Beth Israel Deaconess Med Ctr, Dept Obstet Gynecol & Reprod Biol, Dept Obstet & Gynecol,Med Sch, Boston, MA 02215 USA. 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 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD FEB PY 2014 VL 101 IS 2 SU S MA P-53 BP E29 EP E30 PG 2 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA AP8SX UT WOS:000342350300061 ER PT J AU Souter, I Batsis, M Petrozza, J Karmon, A AF Souter, I. Batsis, M. Petrozza, J. Karmon, A. TI Are Levothyroxine-Treated Women with Hypothyroidism at Increased Risk for IVF Failure and Adverse Pregnancy Outcomes? SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT 62nd Annual Meeting of the Pacific-Coast-Reproductive-Society (PCRS) CY MAR 19-23, 2014 CL Indian Wells, CA SP Pacific Coast Reprod Soc C1 [Souter, I.; Batsis, M.; Petrozza, J.; Karmon, A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Fertil Ctr,Dept Obstet Gynecol,Div Reprod Endocri, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD FEB PY 2014 VL 101 IS 2 SU S MA P-26 BP E18 EP E19 PG 2 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA AP8SX UT WOS:000342350300035 ER PT J AU Roghmann, F Trinh, QD Braun, K von Bodman, C Brock, M Noldus, J Palisaar, J AF Roghmann, Florian Quoc-Dien Trinh Braun, Katharina von Bodman, Christian Brock, Marko Noldus, Joachim Palisaar, Jueri TI Standardized assessment of complications in a contemporary series of European patients undergoing radical cystectomy SO INTERNATIONAL JOURNAL OF UROLOGY LA English DT Article DE Clavien; complication; cystectomy; risk factor; urinary diversion ID URINARY-DIVERSION; BLADDER-CANCER; PERIOPERATIVE COMPLICATIONS; REPORTING METHODOLOGY; RISK-FACTORS; MORTALITY; MORBIDITY; CLASSIFICATION AB Objectives: To examine postoperative complications in a contemporary series of patients after radical cystectomy using a standardized reporting system, and to identify readily available preoperative risk factors. Methods: Using the modified Clavien-Dindo classification, we assessed the 90-day postoperative clinical course of 535 bladder cancer patients who underwent radical cystectomy and urinary diversion (ileal conduit n = 349, ileal neobladder n = 186) between June 2003 and February 2012 at a single institution. All Martin criteria for standardized reporting of complications were met. Uni- and multivariable analyses for prediction of complications were carried out; covariates included body mass index, Charlson Comorbidity Index, age, sex, American Society of Anesthesiologists Score, neoadjuvant chemotherapy, prior abdominal or pelvic surgery, localized tumor and urinary diversion type. Results: The 90-day rates for overall (Clavien-Dindo classification I-V) and high-grade complications (Clavien-Dindo classification III-V), as well as mortality (Clavien-Dindo classification V), were 56.4, 18.7 and 3.9%, respectively. Infections (16.4%), bleeding (14.2%) and gastrointestinal complications (10.7%) were the most common adverse outcomes. Independent risk factors for overall complications were body mass index (odds ratio 1.08) and Charlson Comorbidity Index >= 3 (odds ratio 1.93). Risk factors for high-grade complications were Charlson Comorbidity Index >= 3 (odds ratio 1.86), American Society of Anesthesiologists Score >= 3 (odds ratio 1.92) and body mass index (odds ratio 1.07, all P < 0.03). Conclusions: Radical cystectomy is associated with significant morbidity; nevertheless, the majority of complications are minor. Charlson Comorbidity Index, American Society of Anesthesiologists Score and body mass index might help to identify patients at risk for high-grade complications after radical cystectomy. C1 [Roghmann, Florian; Braun, Katharina; von Bodman, Christian; Brock, Marko; Noldus, Joachim; Palisaar, Jueri] Ruhr Univ Bochum, Marienhosp, Dept Urol, D-44627 Herne, Germany. [Roghmann, Florian; Quoc-Dien Trinh] Univ Montreal, Ctr Hlth, Canc Prognost & Hlth Outcomes Unit, Montreal, PQ, Canada. [Quoc-Dien Trinh] Harvard Univ, Brigham & Womens Hosp, Dana Farber Canc Inst, Dept Surg,Div Urol,Med Sch, Boston, MA 02115 USA. RP Roghmann, F (reprint author), Ruhr Univ Bochum, Marienhosp, Dept Urol, Widumer Str 8, D-44627 Herne, Germany. EM f.roghmann@gmail.com NR 29 TC 29 Z9 29 U1 2 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0919-8172 EI 1442-2042 J9 INT J UROL JI Int. J. Urol. PD FEB PY 2014 VL 21 IS 2 BP 143 EP 149 DI 10.1111/iju.12232 PG 7 WC Urology & Nephrology SC Urology & Nephrology GA AQ1WF UT WOS:000342573800006 PM 23906282 ER PT J AU Charlton, BM Corliss, HL Missmer, SA Frazier, AL Rosario, M Kahn, JA Austin, SB AF Charlton, Brittany M. Corliss, Heather L. Missmer, Stacey A. Frazier, A. Lindsay Rosario, Margaret Kahn, Jessica A. Austin, S. Bryn TI Influence of Hormonal Contraceptive Use and Health Beliefs on Sexual Orientation Disparities in Papanicolaou Test Use SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Article ID CERVICAL-CANCER; LESBIANS; CARE; SERVICES; WOMEN; ADOLESCENTS; KNOWLEDGE; ATTITUDES; PROVIDERS; PROGRAM AB Objectives. Reproductive health screenings are a necessary part of quality health care. However, sexual minorities underutilize Papanicolaou (Pap) tests more than heterosexuals do, and the reasons are not known. Our objective was to examine if less hormonal contraceptive use or less positive health beliefs about Pap tests explain sexual orientation disparities in Pap test intention and utilization. Methods. We used multivariable regression with prospective data gathered from 3821 females aged 18 to 25 years in the Growing Up Today Study (GUTS). Results. Among lesbians, less hormonal contraceptive use explained 8.6% of the disparities in Pap test intention and 36.1% of the disparities in Pap test utilization. Less positive health beliefs associated with Pap testing explained 19.1% of the disparities in Pap test intention. Together, less hormonal contraceptive use and less positive health beliefs explained 29.3% of the disparities in Pap test intention and 42.2% of the disparities in Pap test utilization. Conclusions. Hormonal contraceptive use and health beliefs, to a lesser extent, help to explain sexual orientation disparities in intention and receipt of a Pap test, especially among lesbians. C1 [Charlton, Brittany M.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Corliss, Heather L.; Austin, S. Bryn] Harvard Univ, Sch Med, Div Adolescent & Young Adult Med, Boston Childrens Hosp, Boston, MA USA. [Missmer, Stacey A.] Brigham & Womens Hosp, Deparnnent Obstet Gynecol & Reprod Biol, Boston, MA 02115 USA. [Missmer, Stacey A.] Harvard Univ, Sch Med, Boston, MA USA. [Frazier, A. Lindsay] Dana Farber Canc Inst, Boston, MA 02115 USA. [Rosario, Margaret] CUNY, City Coll, New York, NY 10021 USA. [Rosario, Margaret] CUNY, Grad Ctr, New York, NY 10021 USA. [Kahn, Jessica A.] Cincinnati Childrens Hosp Med Ctr, Div Adolescent Med, Cincinnati, OH 45229 USA. RP Charlton, BM (reprint author), Harvard Univ, Sch Publ Hlth, Dept Epidemiol, 677 Huntington Ave,9th Floor, Boston, MA 02115 USA. EM bcharlton@mail.harvard.edu FU National Institutes of Health [R01HD057368]; Leadership Education in Adolescent Health Project from the Maternal and Child Health Bureau [T71 MC 00009]; National Institute on Drug Abuse [K01 DA023610]; Training Program in Cancer Epidemiology [T32 CA 09001] FX This study was supported by the National Institutes of Health (research grant R01HD057368). H. L. Corliss and S. B. Austin are supported by the Leadership Education in Adolescent Health Project (grant T71 MC 00009) from the Maternal and Child Health Bureau. H. L. Corliss is also supported by the National Institute on Drug Abuse (grant K01 DA023610). B. M. Charlton is supported by the Training Program in Cancer Epidemiology (grant T32 CA 09001). NR 29 TC 2 Z9 2 U1 1 U2 1 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 800 I STREET, NW, WASHINGTON, DC 20001-3710 USA SN 0090-0036 EI 1541-0048 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD FEB PY 2014 VL 104 IS 2 BP 319 EP 325 DI 10.2105/AJPH.2012.301114 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AP0KW UT WOS:000341751200046 PM 23763393 ER PT J AU Coulter, RWS Kenst, KS Bowen, DJ Scout AF Coulter, Robert W. S. Kenst, Karey S. Bowen, Deborah J. Scout TI Research Funded by the National Institutes of Health on the Health of Lesbian, Gay, Bisexual, and Transgender Populations SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Article ID HIV PREVALENCE; PUBLIC-HEALTH; LATINO MEN; SEX; RISK; CARE; BEHAVIORS; IDENTITY AB Objectives. We examined the proportion of studies funded by the National Institutes of Health (NIH) that focused on lesbian, gay, bisexual, and transgender (LGBT) populations, along with investigated health topics. Methods. We used the NIH RePORTER system to search for LGBT-related terms in NIH-funded research from 1989 through 2011. We coded abstracts for LGBT inclusion, subpopulations studied, health foci, and whether studies involved interventions. Results. NIH funded 628 studies concerning LGBT health. Excluding projects about HIV/AIDS and other sexual health matters, only 0.1% (n = 113) of all NIH-funded studies concerned LGBT health. Among the LGBT-related projects, 86.1% studied sexual minority men, 13.5% studied sexual minority women, and 6.8% studied transgender populations. Overall, 79.1% of LGBT-related projects focused on HIV/AIDS and substantially fewer on illicit drug use (30.9%), mental health (23.2%), other sexual health matters (16.4%), and alcohol use (12.9%). Only 202 studies examined LGBT health-related interventions. Over time, the number of LGBT-related projects per year increased. Conclusions. The lack of NIH-funded research about LGBT health contributes to the perpetuation of health inequities. Here we recommend ways for NIH to stimulate LGBT-related research. C1 [Coulter, Robert W. S.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Behav & Community Hlth Sci, Pittsburgh, PA 15261 USA. [Kenst, Karey S.] Massachusetts Gen Hosp, Mongan Inst Hlth Policy, Dispar Solut Ctr, Boston, MA 02114 USA. [Bowen, Deborah J.] Boston Univ, Sch Publ Hlth, Dept Community Hlth Sci, Boston, MA USA. [Scout] Fenway Hlth, Fenway Inst, Network LGBT Hlth Equ, Boston, MA USA. RP Coulter, RWS (reprint author), Univ Pittsburgh, Grad Sch Publ Hlth, Dept Behav & Community Hlth Sci, 130 DeSoto St, Pittsburgh, PA 15261 USA. EM robert.ws.coulter@gmail.com OI Coulter, Robert/0000-0001-8350-0075 FU Summer Institute in LGBT (lesbian, gay, bisexual, or transgender) Population Health; Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD) [R25HD064426]; National Institute of Mental Health (NIMH) [T32MH094174]; Network for LGBT Health Equity, Centers for Disease Control and Prevention (CDC) [U58DP001516]; Prevention Research Center, CDC [U48DP001922] FX This study was supported by the Summer Institute in LGBT (lesbian, gay, bisexual, or transgender) Population Health, the Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD; award R25HD064426); the Training Program to Address HIV-Related Health Disparities in MSM (men who have sex with men), National Institute of Mental Health (NIMH; award T32MH094174); the Network for LGBT Health Equity, Centers for Disease Control and Prevention (CDC; cooperative agreement U58DP001516); and the Prevention Research Center, CDC (cooperative agreement U48DP001922). NR 31 TC 35 Z9 36 U1 4 U2 12 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 800 I STREET, NW, WASHINGTON, DC 20001-3710 USA SN 0090-0036 EI 1541-0048 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD FEB PY 2014 VL 104 IS 2 BP E105 EP E112 DI 10.2105/AJPH.2013.301501 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AP0KW UT WOS:000341751200018 PM 24328665 ER PT J AU Papathanasiou, E Teles, F Griffin, T Arguello, E Finkelman, M Hanley, J Theoharides, TC AF Papathanasiou, E. Teles, F. Griffin, T. Arguello, E. Finkelman, M. Hanley, J. Theoharides, T. C. TI Gingival crevicular fluid levels of interferon-gamma, but not interleukin-4 or -33 or thymic stromal lymphopoietin, are increased in inflamed sites in patients with periodontal disease SO JOURNAL OF PERIODONTAL RESEARCH LA English DT Article DE cytokines; gingivitis; inflammatory mediator; inflammation; periodontal disease; periodontal immunology; periodontitis ID HUMAN EPITHELIAL-CELLS; AGGRESSIVE PERIODONTITIS; MAST-CELLS; CYTOKINES; INFLAMMATION; IL-33; MECHANISMS; SECRETION; PROFILES; THERAPY AB Objective: To investigate the hypothesis that levels of interferon (IFN)-gamma and interleukin (IL)-4, as well as the newer cytokines IL-33 and thymic stromal lymphopoietin (TSLP), in gingival crevicular fluid (GCF) samples differ from sites of patients at various clinical stages of periodontal disease and controls. Background: Periodontal diseases result from the complex interplay between pathogenic bacteria and the host's immune responses. Several inflammatory mediators, such as IFN-gamma and IL-4, have been detected in GCF samples in patients with periodontitis, but the results are mostly contradicting due to the lack of uniformity and collection of sites and methods of analysis. Material and Methods: GCF samples were collected from sites with different clinical characteristics (healthy, gingivitis and periodontitis sites) from periodontally healthy (n = 14), plaque-induced gingivitis (n = 17) and chronic periodontitis (n = 11) subjects. The GCF samples were analyzed for the frequency of detection and levels of IFN-c, IL-4, IL-33 and TSLP using a multiplex bead immunoassay. Results: Inflamed sites in both patients with plaque-induced gingivitis and chronic periodontitis showed statistically significantly higher volume of GCF compared to non-inflamed sites in all patients. IFN-gamma could be detected in about 50-70% of the samples analyzed and at significantly higher levels in sites with periodontitis compared to healthy sites in patients with chronic periodontitis (p = 0.035). We also show a statistically significant decrease of IFN- in healthy sites of patients with chronic periodontitis as compared to gingivitis sites in patients with plaque-induced gingivitis (p = 0.047). Only some of the GCF samples showed detectable levels for IL-4 and TSLP, while IL-33 was below the detection level in all samples collected. Conclusions: These results suggest that IFN-gamma levels in GCF depend on the clinical stage of the site and not on the disease stage of the patient, but need to be expanded to a greater number of subjects and additional analysis of corresponding gingival tissue biopsies for cytokine gene expression. C1 [Papathanasiou, E.; Griffin, T.; Arguello, E.; Hanley, J.] Tufts Univ, Sch Dent Med, Dept Periodontol, Boston, MA 02111 USA. [Teles, F.] Forsyth Inst, Dept Periodontol, Cambridge, MA USA. [Finkelman, M.] Tufts Univ, Sch Dent Med, Dept Res Adm, Boston, MA 02111 USA. [Theoharides, T. C.] Tufts Univ, Sch Med, Dept Mol Physiol & Pharmacol, Boston, MA 02111 USA. [Theoharides, T. C.] Tufts Univ, Sch Med, Dept Biochem, Boston, MA 02111 USA. [Theoharides, T. C.] Tufts Univ, Sch Med, Dept Internal Med, Boston, MA 02111 USA. [Theoharides, T. C.] Tufts Med Ctr, Boston, MA USA. RP Papathanasiou, E (reprint author), Tufts Univ, Sch Dent Med, Dept Periodontol, One Kneeland St, Boston, MA 02111 USA. EM Evangelos.Papathanasiou@tufts.edu FU Department of Periodontology; Graduate Research Program, Tufts University School of Dental Medicine; Theta Biomedical Consulting and Development Co., Inc. (Brookline, MA) FX This manuscript was supported in part by funds from the Department of Periodontology and the Graduate Research Program, Tufts University School of Dental Medicine, as well as Theta Biomedical Consulting and Development Co., Inc. (Brookline, MA). We thank Smaro Panagiotidou for her word processing skills. NR 27 TC 10 Z9 10 U1 2 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3484 EI 1600-0765 J9 J PERIODONTAL RES JI J. Periodont. Res. PD FEB PY 2014 VL 49 IS 1 BP 55 EP 61 DI 10.1111/jre.12078 PG 7 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA AP0KB UT WOS:000341749100007 PM 23550893 ER PT J AU Jia, TZ Hentrich, C Szostak, JW AF Jia, Tony Z. Hentrich, Christian Szostak, Jack W. TI Rapid RNA Exchange in Aqueous Two-Phase System and Coacervate Droplets SO ORIGINS OF LIFE AND EVOLUTION OF BIOSPHERES LA English DT Article DE Prebiotic chemistry; Phase separation; Compartmentalization; Aqueous two-phase systems; Coacervates; Origin of life ID VIRUS-DNA-POLYMERASE; INTERVENING SEQUENCE; MODEL PROTOCELLS; PHASE SEPARATION; COVALENT BONDS; GIANT VESICLES; PROTEIN; ORGANIZATION; CELLS; LIFE AB Compartmentalization in a prebiotic setting is an important aspect of early cell formation and is crucial for the development of an artificial protocell system that effectively couples genotype and phenotype. Aqueous two-phase systems (ATPSs) and complex coacervates are phase separation phenomena that lead to the selective partitioning of biomolecules and have recently been proposed as membrane-free protocell models. We show in this study through fluorescence recovery after photobleaching (FRAP) microscopy that despite the ability of such systems to effectively concentrate RNA, there is a high rate of RNA exchange between phases in dextran/polyethylene glycol ATPS and ATP/poly-L-lysine coacervate droplets. In contrast to fatty acid vesicles, these systems would not allow effective segregation and consequent evolution of RNA, thus rendering these systems ineffective as model protocells. C1 [Jia, Tony Z.; Hentrich, Christian; Szostak, Jack W.] Massachusetts Gen Hosp, Howard Hughes Med Inst, Dept Mol Biol, Boston, MA 02114 USA. [Jia, Tony Z.; Hentrich, Christian; Szostak, Jack W.] Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Boston, MA 02114 USA. [Jia, Tony Z.; Szostak, Jack W.] Harvard Univ, Dept Chem & Chem Biol, Cambridge, MA 02138 USA. RP Szostak, JW (reprint author), Massachusetts Gen Hosp, Howard Hughes Med Inst, Dept Mol Biol, 185 Cambridge St, Boston, MA 02114 USA. EM szostak@molbio.mgh.harvard.edu NR 51 TC 8 Z9 9 U1 4 U2 23 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0169-6149 EI 1573-0875 J9 ORIGINS LIFE EVOL B JI Orig. Life Evol. Biosph. PD FEB PY 2014 VL 44 IS 1 BP 1 EP 12 DI 10.1007/s11084-014-9355-8 PG 12 WC Biology SC Life Sciences & Biomedicine - Other Topics GA AN8XN UT WOS:000340889300001 PM 24577897 ER PT J AU Kim, HJ Cantor, H AF Kim, Hye-Jung Cantor, Harvey TI CD4 T-cell Subsets and Tumor Immunity: The Helpful and the Not-so-Helpful SO CANCER IMMUNOLOGY RESEARCH LA English DT Article ID PLASMACYTOID DENDRITIC CELLS; LARGE ESTABLISHED MELANOMA; REGULATORY T; IN-VIVO; B-CELLS; TH17 CELLS; TRANSPLANTATION IMMUNITY; CANCER-IMMUNOTHERAPY; MOLECULAR SIGNATURE; METASTATIC MELANOMA AB Research over the past decade has revealed the increasingly complex biologic features of the CD4(+) T-cell lineage. This T-cell subset, which was originally defined on the basis of helper activity in antibody responses, expresses receptors that recognize peptides that have been processed and presented by specialized antigen-presenting cells. At the core of the adaptive immune response, CD4 T cells display a large degree of plasticity and the ability to differentiate into multiple sublineages in response to developmental and environmental cues. These differentiated sublineages can orchestrate a broad range of effector activities during the initiation, expansion, and memory phase of an immune response. The contribution of CD4 cells to host defense against pathogenic invasion and regulation of autoimmunity is now well established. Emerging evidence suggests that CD4 cells also actively participate in shaping antitumor immunity. Here, we outline the biologic properties of CD4 T-cell subsets with an emphasis on their contribution to the antitumor response. (C) 2014 AACR. C1 [Kim, Hye-Jung; Cantor, Harvey] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. [Kim, Hye-Jung; Cantor, Harvey] Harvard Univ, Sch Med, Dept Microbiol & Immuno Biol, Div Immunol, Boston, MA 02115 USA. RP Cantor, H (reprint author), Dana Farber Canc Inst, 450 Brookline Ave,Smith 722, Boston, MA 02115 USA. EM Harvey_Cantor@dfci.harvard.edu FU National Institutes of Health [AI37562, AI48125]; LeRoy Schecter Research Foundation [CA70083]; Arthritis National Research Foundation FX This work was supported in part by the National Institutes of Health (AI37562, AI48125) and a gift from the LeRoy Schecter Research Foundation to H. Cantor; CA70083 and a Scholar Award from the Arthritis National Research Foundation to H-J Kim. NR 87 TC 40 Z9 41 U1 0 U2 8 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 2326-6066 EI 2326-6074 J9 CANCER IMMUNOL RES JI Cancer Immunol. Res. PD FEB PY 2014 VL 2 IS 2 BP 91 EP 98 DI 10.1158/2326-6066.CIR-13-0216 PG 8 WC Oncology; Immunology SC Oncology; Immunology GA AM7FU UT WOS:000340031200001 PM 24778273 ER PT J AU Yuan, JD Zhou, J Dong, ZW Tandon, S Kuk, D Panageas, KS Wong, P Wu, XQ Naidoo, J Page, DB Wolchok, JD Hodi, FS AF Yuan, Jianda Zhou, Jun Dong, Zhiwan Tandon, Sapna Kuk, Deborah Panageas, Katherine S. Wong, Philip Wu, Xinqi Naidoo, Jarushka Page, David B. Wolchok, Jedd D. Hodi, F. Stephen TI Pretreatment Serum VEGF Is Associated with Clinical Response and Overall Survival in Advanced Melanoma Patients Treated with Ipilimumab SO CANCER IMMUNOLOGY RESEARCH LA English DT Article ID LYMPHOCYTE-ASSOCIATED ANTIGEN-4; GROWTH-FACTOR RECEPTOR-1; T-CELL RESPONSES; METASTATIC MELANOMA; ANGIOGENIC FACTORS; ANTIBODY BLOCKADE; CTLA-4; CANCER; IMMUNOTHERAPY; BENEFIT AB Ipilimumab, an antibody that blocks CTL antigen 4 (CTLA-4), improves overall survival (OS) for patients with metastatic melanoma. Given its role in angiogenesis and immune evasion, serum VEGF levels were evaluated for association with clinical benefit in ipilimumab-treated patients. Sera were collected from 176 patients treated at 3 (n = 98) or 10 mg/kg (n = 68). The VEGF levels before treatment and at induction completion (week 12) were analyzed using the Meso Scale Discovery kit. The association of the levels of VEGF with clinical responses and OS were assessed using the Fisher exact and Kaplan-Meier log-rank tests. VEGF as a continuous variable was associated with OS (P = 0.002). Using 43 pg/mL as the cutoff pretreatment VEGF value defined by maximally selected log-rank statistics, pretreatment VEGF values correlated with clinical benefit at week 24 (P = 0.019; 159 patients evaluable). Pretreatment VEGF >= 43 pg/mL was associated with decreased OS (median OS 6.6 vs. 12.9 months, P = 0.006; 7.4 vs. 14.3 months, P = 0.037 for 3 mg/kg; and 6.2 vs. 10.9 months, P = 0.048 for 10 mg/kg). There was no correlation between VEGF changes and clinical outcome. Serum VEGF may be a predictive biomarker for ipilimumab treatment and is worthy of prospective investigation with various forms of immunologic checkpoint blockade. (C) 2014 AACR. C1 [Yuan, Jianda; Dong, Zhiwan; Tandon, Sapna; Wong, Philip; Wolchok, Jedd D.] Cornell Univ, Ludwig Ctr Canc Immunotherapy, Program Immunol, Immune Monitoring Core, New York, NY 10021 USA. [Wolchok, Jedd D.] Cornell Univ, Dept Med, New York, NY 10021 USA. [Kuk, Deborah; Panageas, Katherine S.; Wolchok, Jedd D.] Cornell Univ, Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10021 USA. [Wolchok, Jedd D.] Cornell Univ, Weill Cornell Med Coll, New York, NY 10021 USA. [Zhou, Jun; Wu, Xinqi; Hodi, F. Stephen] Harvard Univ, Sch Med, Dept Med Oncol, Boston, MA USA. [Zhou, Jun; Wu, Xinqi; Hodi, F. Stephen] Harvard Univ, Sch Med, Ctr Immunooncol, Boston, MA USA. [Zhou, Jun; Wu, Xinqi; Hodi, F. Stephen] Harvard Univ, Sch Med, Dana Farber Canc Inst, Melanoma Dis Ctr, Boston, MA USA. RP Hodi, FS (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. EM Stephen_hodi@dfci.harvard.edu OI Kuk, Deborah/0000-0003-1477-3170 FU NIH [RC2CA148868] FX Research reported in this publication was supported by the NIH under award number RC2CA148868. NR 25 TC 36 Z9 36 U1 0 U2 4 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 2326-6066 EI 2326-6074 J9 CANCER IMMUNOL RES JI Cancer Immunol. Res. PD FEB PY 2014 VL 2 IS 2 BP 127 EP 132 DI 10.1158/2326-6066.CIR-13-0163 PG 6 WC Oncology; Immunology SC Oncology; Immunology GA AM7FU UT WOS:000340031200006 PM 24778276 ER PT J AU Saleem, MM Stowkowy, J Cadenhead, KS Cannon, TD Cornblatt, BA McGlashan, TH Perkins, DO Seidman, LJ Tsuang, MT Walker, EF Woods, SW Addington, J AF Saleem, Majid M. Stowkowy, Jacqueline Cadenhead, Kristin S. Cannon, Tyrone D. Cornblatt, Barbara A. McGlashan, Thomas H. Perkins, Diana O. Seidman, Larry J. Tsuang, Ming T. Walker, Elaine F. Woods, Scott W. Addington, Jean TI Perceived discrimination in those at clinical high risk for psychosis SO EARLY INTERVENTION IN PSYCHIATRY LA English DT Article DE clinical high risk; perceived discrimination; prodrome; psychosis; risk ID INDIVIDUALS; SYMPTOMS; BELIEFS AB Aim: There is evidence to suggest that perceived discrimination may be associated with psychosis. Less is known about its potential impact on those at clinical high risk (CHR) for psychosis. The aim of this study was to determine the prevalence of perceived discrimination in a CHR sample and its possible relationship to attenuated positive symptoms and negative self-beliefs. Methods: Participants were 360 CHR individuals and 180 healthy controls. Assessments included a self-report measure of perceived discrimination, the Scale of Prodromal Symptoms and the Brief Core Schema Scale. Results: CHR participants reported significantly more perceived discrimination. Perceived discrimination was significantly associated with negative schemas, but not with attenuated positive symptoms. Conclusions: These results suggest that individuals at CHR for psychosis endorse a higher level of perceived discrimination, which is associated with increased negative schemas, but not attenuated positive symptoms. C1 [Saleem, Majid M.; Stowkowy, Jacqueline; Addington, Jean] Univ Calgary, Dept Psychiat, Calgary, AB T2N 4Z6, Canada. [Cadenhead, Kristin S.; Tsuang, Ming T.] Univ Calif San Diego, Dept Psychiat, San Diego, CA USA. [Cannon, Tyrone D.] Univ Calif Los Angeles, Dept Psychol, Los Angeles, CA 90024 USA. [Cannon, Tyrone D.] Univ Calif Los Angeles, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90024 USA. [Cornblatt, Barbara A.] Zucker Hillside Hosp, Dept Psychiat, Long Isl City, NY USA. [Cannon, Tyrone D.; McGlashan, Thomas H.; Woods, Scott W.] Yale Univ, Dept Psychol, New Haven, CT 06520 USA. [Perkins, Diana O.] Univ N Carolina, Dept Psychiat, Chapel Hill, NC USA. [Seidman, Larry J.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Dept Psychiat, Boston, MA 02215 USA. [Seidman, Larry J.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Walker, Elaine F.] Emory Univ, Dept Psychol, Atlanta, GA 30322 USA. [Walker, Elaine F.] Emory Univ, Dept Psychiat, Atlanta, GA 30322 USA. RP Addington, J (reprint author), Univ Calgary, Mathison Ctr Mental Hlth Res & Educ, 3280 Hosp Dr NW, Calgary, AB T2N 4Z6, Canada. EM jmadding@ucalgary.ca FU National Institute of Mental Health [U01MH081984]; Commonwealth of Massachusetts [SCDMH82101008006]; [U01 MH081928]; [P50 MH080272]; [R01 MH60720]; [U01 MH082022]; [K24 MH76191]; [U01MH082004-01A1]; [U01MH081988]; [U01MH082022]; [UO1MH081857] FX This study was supported by the National Institute of Mental Health (grant U01MH081984 to Dr Addington; grants U01 MH081928; P50 MH080272; Commonwealth of Massachusetts SCDMH82101008006; to Dr Seidman; grants R01 MH60720, U01 MH082022; and K24 MH76191 to Dr Cadenhead; grant to Dr Cannon; grant U01MH082004-01A1 to Dr Perkins; grant U01MH081988 to Dr Walker; grant U01MH082022 to Dr Woods; and UO1MH081857 grant to Dr Cornblatt. NR 17 TC 8 Z9 8 U1 1 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1751-7885 EI 1751-7893 J9 EARLY INTERV PSYCHIA JI Early Interv. Psychiatry PD FEB PY 2014 VL 8 IS 1 BP 77 EP 81 DI 10.1111/eip.12058 PG 5 WC Psychiatry SC Psychiatry GA AM4CD UT WOS:000339798600010 PM 23773288 ER PT J AU Tambouret, R Roberts, DJ AF Tambouret, Rosemary Roberts, Drucilla J. TI Screening for Cervical Cancer in Low-Resource Settings in 2011 Reply SO ARCHIVES OF PATHOLOGY & LABORATORY MEDICINE LA English DT Letter C1 [Tambouret, Rosemary; Roberts, Drucilla J.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. RP Tambouret, R (reprint author), Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU COLL AMER PATHOLOGISTS PI NORTHFIELD PA C/O KIMBERLY GACKI, 325 WAUKEGAN RD, NORTHFIELD, IL 60093-2750 USA SN 0003-9985 EI 1543-2165 J9 ARCH PATHOL LAB MED JI Arch. Pathol. Lab. Med. PD FEB PY 2014 VL 138 IS 2 BP 156 EP 156 DI 10.5858/arpa.2013-0627-LE PG 1 WC Medical Laboratory Technology; Medicine, Research & Experimental; Pathology SC Medical Laboratory Technology; Research & Experimental Medicine; Pathology GA AM0QF UT WOS:000339550000003 PM 24476513 ER PT J AU Kawano, T Hasegawa, K Watase, H Morita, H Yamamura, O AF Kawano, Takahisa Hasegawa, Kohei Watase, Hiroko Morita, Hiroshi Yamamura, Osamu TI Infectious Disease Frequency Among Evacuees at Shelters After the Great Eastern Japan Earthquake and Tsunami: A Retrospective Study SO DISASTER MEDICINE AND PUBLIC HEALTH PREPAREDNESS LA English DT Article DE Great Eastern Japan Earthquake; disaster; shelter; infectious disease; outbreak ID SURVEILLANCE; PREVENTION AB Objective: After the Great Eastern Japan Earthquake and tsunami, the World Health Organization cautioned that evacuees at shelters would be at increased risk of infectious disease transmission; however, the frequency that occurred in this population was not known. Methods: We reviewed medical charts of evacuees who visited medical clinics at 6 shelters from March 19, to April 8, 2011. Excluded were patients who did not reside within the shelters or whose medical records lacked a name or date. We investigated the frequency of and cumulative incidences of acute respiratory infection [ARI], acute gastroenteritis, acute jaundice syndrome, scabies, measles, pertussis, and tetanus. Results: Of 1364 patients who visited 6 shelter clinics, 1167 patients (86.1%) were eligible for the study. The median total number of evacuees was 2545 (interquartile range [IQR], 2277-3009). ARI was the most common infectious disease; the median number of patients with ARI was 168.8 per week per 1000 evacuees (IQR, 64.5-186.1). Acute gastroenteritis was the second most common; the median number of patients was 23.7 per week per 1000 evacuees (IQR, 5.1-24.3). No other infectious diseases were observed. The median cumulative incidence of ARI per 1000 evacuees in each shelter was 13.1 person-days (IQR, 8.5-18.8). The median cumulative incidence of gastroenteritis was 1.6 person-days (IQR, 0.3-3.4). Conclusion: After the Great Eastern Japan Earthquake and tsunami, outbreaks of ARI and acute gastroenteritis occurred in evacuation shelters. C1 [Kawano, Takahisa; Morita, Hiroshi] Univ Fukui Hosp, Dept Emergency Med, Fukui, Japan. [Yamamura, Osamu] Univ Fukui Hosp, Dept Community Hlth Care Promot, Fukui, Japan. [Watase, Hiroko] Japanese Emergency Med Network, Fukui, Japan. [Hasegawa, Kohei] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Emergency Med, Boston, MA USA. RP Kawano, T (reprint author), Univ Fukui Hosp, Dept Emergency Med, 23-3 Simoaigetsu, Fukui, Japan. EM maketenakunarakattenake@hotmail.com FU Daiwa Securities Health Foundation; Japan Society for the Promotion of Science (JSPS) FX Financial incentives were provided to the authors by Daiwa Securities Health Foundation and Grant-in-Aid for Young Scientists (B) of Japan Society for the Promotion of Science (JSPS). NR 27 TC 2 Z9 2 U1 0 U2 3 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 1935-7893 EI 1938-744X J9 DISASTER MED PUBLIC JI Dis. Med. Public Health Prep. PD FEB PY 2014 VL 8 IS 1 BP 58 EP 64 DI 10.1017/dmp.2014.15 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AL3XG UT WOS:000339064300009 PM 24606871 ER PT J AU Guichard, JL Benavides, G Ballinger, S Dell'Italia, L AF Guichard, J. L. Benavides, G. Ballinger, S. Dell'Italia, L. TI MITOCHONDRIAL DNA HAPLOTYPE CONTRIBUTES TO THE CYTOSKELETAL AND MITOCHONDRIAL RESPONSES TO CYCLICAL STRETCH IN ISOLATED CARDIOMYOCYTES SO JOURNAL OF INVESTIGATIVE MEDICINE LA English DT Meeting Abstract C1 [Guichard, J. L.; Benavides, G.; Ballinger, S.; Dell'Italia, L.] Univ Alabama Birmingham, Birmingham, AL USA. [Dell'Italia, L.] Birmingham Vet Affairs Med Ctr, Birmingham, AL USA. 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 1081-5589 EI 1708-8267 J9 J INVEST MED JI J. Invest. Med. PD FEB PY 2014 VL 62 IS 2 MA 358 BP 513 EP 513 PG 1 WC Medicine, General & Internal; Medicine, Research & Experimental SC General & Internal Medicine; Research & Experimental Medicine GA AL3SH UT WOS:000339048800367 ER PT J AU Musgrove, JL Estrada, C Morris, J Kraemer, R AF Musgrove, J. L. Estrada, C. Morris, J. Kraemer, R. TI PRIORITIZING DOMAINS OF CLINICAL REASONING TO INCLUDE IN A CURRICULUM SO JOURNAL OF INVESTIGATIVE MEDICINE LA English DT Meeting Abstract C1 [Musgrove, J. L.; Estrada, C.; Morris, J.; Kraemer, R.] Birmingham VAMC, Birmingham, AL USA. 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 1081-5589 EI 1708-8267 J9 J INVEST MED JI J. Invest. Med. PD FEB PY 2014 VL 62 IS 2 MA 585 BP 582 EP 583 PG 2 WC Medicine, General & Internal; Medicine, Research & Experimental SC General & Internal Medicine; Research & Experimental Medicine GA AL3SH UT WOS:000339048800594 ER PT J AU Kertesz, S Austin, E Holmes, S Lukas, CV Pollio, D White, B Schumacher, J AF Kertesz, S. Austin, E. Holmes, S. Lukas, Van Deusen C. Pollio, D. White, B. Schumacher, J. TI ENDING HOMELESSNESS FOR 48,000 VETERANS: ORGANIZATIONAL AND CLINICAL CHALLENGES FOR VA MEDICAL CENTERS SO JOURNAL OF INVESTIGATIVE MEDICINE LA English DT Meeting Abstract C1 [Kertesz, S.; Austin, E.] Birmingham VA Med Ctr, Birmingham, AL USA. [Kertesz, S.; Schumacher, J.] Univ Alabama Birmingham, Birmingham, AL USA. [Holmes, S.; Lukas, Van Deusen C.; White, B.] Boston VAMC, Boston, MA USA. [Pollio, D.] Univ Alabama, Tuscaloosa, AL USA. NR 0 TC 0 Z9 0 U1 1 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1081-5589 EI 1708-8267 J9 J INVEST MED JI J. Invest. Med. PD FEB PY 2014 VL 62 IS 2 MA 590 BP 584 EP 584 PG 1 WC Medicine, General & Internal; Medicine, Research & Experimental SC General & Internal Medicine; Research & Experimental Medicine GA AL3SH UT WOS:000339048800599 ER PT J AU Agarwalla, PK Stapleton, CJ Ogilvy, CS AF Agarwalla, Pankaj K. Stapleton, Christopher J. Ogilvy, Christopher S. TI Craniectomy in Acute Ischemic Stroke SO NEUROSURGERY LA English DT Article DE Decompressive craniectomy; Edema; Ischemic stroke; Suboccipital decompression ID MIDDLE CEREBRAL-ARTERY; AGGRESSIVE DECOMPRESSIVE SURGERY; OCCUPYING HEMISPHERIC INFARCTION; TRAUMATIC BRAIN-INJURY; OF-THE-LITERATURE; CEREBELLAR INFARCTION; SURGICAL DECOMPRESSION; MALIGNANT INFARCTION; INTRACRANIAL-PRESSURE; TERRITORY INFARCTION AB Anterior and posterior circulation acute ischemic stroke carries significant morbidity and mortality as a result of malignant cerebral edema. Decompressive craniectomy has evolved as a viable neurosurgical intervention in the armamentarium of treatment options for this life-threatening edema. In this review, we highlight the history of craniectomy for stroke and discuss recent data relevant to its efficacy in modern neurosurgical practice. C1 [Ogilvy, Christopher S.] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Ogilvy, CS (reprint author), Massachusetts Gen Hosp, Dept Neurosurg, 55 Fruit St,ACC 745, Boston, MA 02114 USA. EM cogilvy@partners.org NR 95 TC 5 Z9 5 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0148-396X EI 1524-4040 J9 NEUROSURGERY JI Neurosurgery PD FEB PY 2014 VL 74 SU 1 BP S151 EP S162 DI 10.1227/NEU.0000000000000226 PG 12 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA AL3VU UT WOS:000339059800018 PM 24402484 ER PT J AU Castillo, JJ Nadeem, O AF Castillo, Jorge J. Nadeem, Omar TI Improving the accuracy in prognosis for Burkitt lymphoma patients SO EXPERT REVIEW OF ANTICANCER THERAPY LA English DT Editorial Material DE Burkitt; disparities; elderly; epidemiology; lymphoma; prognosis ID B-CELL LYMPHOMA; ADULT BURKITT; UNITED-STATES; CHEMOIMMUNOTHERAPY; BLINATUMOMAB; DISPARITIES; SURVIVAL; OUTCOMES; THERAPY C1 [Castillo, Jorge J.] Dana Farber Canc Inst, Div Hematol Malignancies, Boston, MA 02215 USA. [Nadeem, Omar] Rhode Isl Hosp, Div Hematol & Oncol, Providence, RI 02903 USA. RP Castillo, JJ (reprint author), Dana Farber Canc Inst, Div Hematol Malignancies, M221,450 Brookline Ave, Boston, MA 02215 USA. EM jorgej_castillo@dfci.harvard.edu OI Castillo, Jorge/0000-0001-9490-7532 NR 15 TC 0 Z9 0 U1 0 U2 1 PU EXPERT REVIEWS PI LONDON PA UNITEC HOUSE, 3RD FL, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON N3 1QB, ENGLAND SN 1473-7140 EI 1744-8328 J9 EXPERT REV ANTICANC JI Expert Rev. Anticancer Ther PD FEB PY 2014 VL 14 IS 2 BP 125 EP 127 DI 10.1586/14737140.2014.866042 PG 3 WC Oncology SC Oncology GA AK2ZU UT WOS:000338291400002 PM 24329420 ER PT J AU Mack, JW Joffe, S AF Mack, Jennifer W. Joffe, Steven TI Communicating About Prognosis: Ethical Responsibilities of Pediatricians and Parents SO PEDIATRICS LA English DT Article DE communication; decision; end-of-life; hope; prognosis ID END-OF-LIFE; DOCTOR-PATIENT COMMUNICATION; ADVANCED CANCER-PATIENTS; PALLIATIVE CARE; CARDIOPULMONARY-RESUSCITATION; TREATMENT PREFERENCES; INFORMED-CONSENT; NEAR-DEATH; BAD-NEWS; HOPE AB Clinicians are sometimes reluctant to discuss prognosis with parents of children with life-threatening illness, usually because they worry about the emotional impact of this information. However, parents often want this prognostic information because it underpins informed decision-making, especially near the end of life. In addition, despite understandable clinician concerns about its emotional impact, prognostic disclosure can actually support hope and peace of mind among parents struggling to live with a child's illness. Children, too, may need to understand what is ahead to manage uncertainty and make plans for the ways their remaining life will be lived. In this article, we describe the ethical issues involved in disclosure of prognostic information to parents and children with life-threatening illness and offer practical guidance for these conversations. C1 [Mack, Jennifer W.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02215 USA. [Mack, Jennifer W.] Dana Farber Canc Inst, Ctr Populat Sci, Boston, MA 02215 USA. [Mack, Jennifer W.] Boston Childrens Hosp, Div Pediat Hematol Oncol, Boston, MA USA. [Joffe, Steven] Univ Penn, Perelman Sch Med, Dept Med Eth & Hlth Policy, Philadelphia, PA 19104 USA. RP Mack, JW (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. EM jennifer_mack@dfci.harvard.edu OI Joffe, Steven/0000-0002-0667-7384 FU American Cancer Society Mentored Research Scholar grant FX Dr Mack was funded by an American Cancer Society Mentored Research Scholar grant. NR 48 TC 22 Z9 22 U1 2 U2 6 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 EI 1098-4275 J9 PEDIATRICS JI Pediatrics PD FEB PY 2014 VL 133 SU 1 BP S24 EP S30 DI 10.1542/peds.2013-3608E PG 7 WC Pediatrics SC Pediatrics GA AK3RH UT WOS:000338341900004 PM 24488537 ER PT J AU Verrier, RL AF Verrier, Richard L. TI Is there a role of MMA T wave alternans test for risk assessment in Brugada syndrome? SO ANADOLU KARDIYOLOJI DERGISI-THE ANATOLIAN JOURNAL OF CARDIOLOGY LA English DT Letter ID SODIUM-CHANNEL BLOCKER C1 [Verrier, Richard L.] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Div Cardiovasc Med,Harvard Thorndike Electrophysi, Boston, MA 02215 USA. RP Verrier, RL (reprint author), Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, 99 Brookline Ave,RN-301B, Boston, MA 02215 USA. EM rverrier@bidmc.harvard.edu NR 10 TC 0 Z9 0 U1 0 U2 0 PU AVES PI FINDIKZADE PA IBRAHIM KARA, KIZILELMA CAD 5-3, FINDIKZADE, ISTANBUL 34096, TURKEY SN 1302-8723 EI 1308-0032 J9 ANADOLU KARDIYOL DER JI Anadolu Kardiyol. Derg. PD FEB PY 2014 VL 14 IS 1 BP 96 EP 96 DI 10.5152/akd.2013.201315 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AK0LU UT WOS:000338105200025 PM 24382500 ER PT J AU Johansen, KL Dalrymple, LS Delgado, C Kaysen, GA Kornak, J Grimes, B Chertow, GM AF Johansen, Kirsten L. Dalrymple, Lorien S. Delgado, Cynthia Kaysen, George A. Kornak, John Grimes, Barbara Chertow, Glenn M. TI Association between Body Composition and Frailty among Prevalent Hemodialysis Patients: A US Renal Data System Special Study SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID CHRONIC KIDNEY-DISEASE; DIALYSIS PATIENTS; FLUID VOLUME; MORTALITY; HEALTH; OLDER; CONSEQUENCES; PREDICTOR; OUTCOMES; OBESITY AB Studies of frailty among patients on hemodialysis have relied on definitions that substitute self-reported functioning for measures of physical performance and omit weight loss or substitute alternate criteria. We examined the association between body composition and a definition of frailty that includes measured physical performance and weight loss in a cross-sectional analysis of 638 adult patients receiving maintenance hemodialysis at 14 centers. Frailty was defined as having three of following characteristics: weight loss, weakness, exhaustion, low physical activity, and slow gait speed. We performed logistic regression with body mass index (BMI) and bioelectrical impedance spectroscopy (BIS)-derived estimates of intracellular water (ICW), fat mass, and extracellular water (ECW) as the main predictors, and age, sex, race, and comorbidity as covariates. Overall, 30% of participants were frail. Older age (odds ratio [OR], 1.31 per 10 years; 95% confidence interval [95% CI], 1.14 to 1.50), diabetes (OR, 1.65; 95% CI, 1.13 to 2.40), higher fat mass (OR, 1.18; 95% CI, 1.02 to 1.37), and higher ECW(OR, 1.33; 95% CI, 1.20 to 1.47) associated with higher odds of frailty. Higher ICW associated with lower odds of frailty (OR, 0.80 per kg; 95% CI, 0.73 to 0.87). The addition of BMI data did not change the area under the receiver operating characteristics curve (AUC; AUC=0.66 versus 0.66; P=0.71), but the addition of BIS data did change the AUC (AUC=0.72; P < 0.001). Thus, individual components of body composition but not BMI associate strongly with frailty in this cohort of patients receiving hemodialysis. C1 [Johansen, Kirsten L.; Delgado, Cynthia] Univ Calif San Francisco, Dept Med, Div Nephrol, San Francisco, CA USA. [Johansen, Kirsten L.; Kornak, John; Grimes, Barbara] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Johansen, Kirsten L.; Delgado, Cynthia] San Francisco VA Med Ctr, Nephrol Sect, San Francisco, CA 94121 USA. [Dalrymple, Lorien S.; Kaysen, George A.] Univ Calif Davis, Div Nephrol, Davis, CA 95616 USA. [Chertow, Glenn M.] Stanford Univ, Dept Med, Sch Med, Div Nephrol, Stanford, CA 94305 USA. RP Johansen, KL (reprint author), San Francisco VA Med Ctr, Nephrol Sect, 111J,4150 Clement St, San Francisco, CA 94121 USA. EM Kirsten.Johansen@ucsf.edu FU National Institutes of Health [N01-DK-0005, N01-DK-2450] FX This work was supported by National Institutes of Health Grants N01-DK-0005 (to K.L.J.) and N01-DK-2450 (to G.M.C.). NR 28 TC 32 Z9 32 U1 2 U2 5 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 FEB 1 PY 2014 VL 25 IS 2 BP 381 EP 389 DI 10.1681/ASN.2013040431 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA AJ8QM UT WOS:000337971700020 PM 24158987 ER PT J AU Robinson-Cohen, C Littman, AJ Duncan, GE Weiss, NS Sachs, MC Ruzinski, J Kundzins, J Rock, D de Boer, IH Ikizler, TA Himmelfarb, J Kestenbaum, BR AF Robinson-Cohen, Cassianne Littman, Alyson J. Duncan, Glen E. Weiss, Noel S. Sachs, Michael C. Ruzinski, John Kundzins, John Rock, Denise de Boer, Ian H. Ikizler, T. Alp Himmelfarb, Jonathan Kestenbaum, Bryan R. TI Physical Activity and Change in Estimated GFR among Persons with CKD SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID CHRONIC KIDNEY-DISEASE; CORONARY-HEART-DISEASE; ALL-CAUSE MORTALITY; CARDIOVASCULAR-DISEASE; BLOOD-PRESSURE; RISK-FACTOR; RENAL-INSUFFICIENCY; INSULIN-RESISTANCE; OLDER-ADULTS; CYSTATIN-C AB Physical activity may counteract metabolic disturbances that promote the progression of CKD. To address this concept, we performed a longitudinal cohort study of 256 participants in the Seattle Kidney Study, a clinic-based study of CKD. Participants with an estimated GFR (eGFR) of 15-59 ml/min per 1.73 m(2) at baseline were eligible for the study. Physical activity was quantified using the Four-Week Physical Activity History Questionnaire. We used generalized estimating equations to test associations of physical activity with change in eGFR determined by longitudinal measurements of serum cystatin C. Mean baseline eGFR was 42 ml/min per 1.73 m(2). During a median 3.7 years of follow-up, the mean change in eGFR(cystatin) (C) was -7.6% per year (interquartile range, -16.8%, 4.9% per year). Participants who reported >150 minutes of physical activity per week had the lowest rate of eGFR(cystatin C) loss (mean -6.2% per year compared with -9.6% per year among inactive participants). In adjusted analyses, each 60-minute increment in weekly physical activity duration associated with a 0.5% slower decline per year in eGFR (95% confidence interval, 0.02 to 0.98; P=0.04). Results were similar in sensitivity analyses restricted to participants without cardiovascular disease or diabetes, or to participants with moderate/high physical function. After adjustment for eGFR at the time of questionnaire completion, physical activity did not associate with the incidence of ESRD(n=34 events). In summary, higher physical activity levels associated with slower rates of eGFR loss in persons with established CKD. C1 [Robinson-Cohen, Cassianne; Sachs, Michael C.; Ruzinski, John; Kundzins, John; Rock, Denise; de Boer, Ian H.; Himmelfarb, Jonathan; Kestenbaum, Bryan R.] Univ Washington, Kidney Res Inst, Seattle, WA 98104 USA. [Robinson-Cohen, Cassianne; Littman, Alyson J.; Duncan, Glen E.; Weiss, Noel S.; de Boer, Ian H.; Kestenbaum, Bryan R.] Univ Washington, Dept Epidemiol, Seattle, WA 98104 USA. [Littman, Alyson J.] Vet Affairs Puget Sound Hlth Care Syst, Seattle Epidemiol Res & Informat Ctr, Seattle, WA USA. [Duncan, Glen E.] Univ Washington, Nutr Sci Program, Seattle, WA 98104 USA. [de Boer, Ian H.; Kestenbaum, Bryan R.] Univ Washington, Dept Med, Div Nephrol, Seattle, WA 98104 USA. [Ikizler, T. Alp; Himmelfarb, Jonathan] Vet Affairs Tennessee Valley Healthcare Syst Nash, Nashville, TN USA. [Ikizler, T. Alp] Vanderbilt Univ, Div Nephrol, Nashville, TN 37235 USA. RP Robinson-Cohen, C (reprint author), Univ Washington, Kidney Res Inst, 325 Ninth Ave,Box 359606, Seattle, WA 98104 USA. EM cassyrc@uw.edu RI Duncan, Glen/A-3771-2008; OI Duncan, Glen/0000-0001-6909-1869; Robinson-Cohen, Cassianne/0000-0003-4783-7046 FU Kidney Research Institute (Seattle, WA); National Institutes of Health National Heart, Lung, and Blood Institute [2R01HL070938]; Department of Veterans Affairs (Rehabilitation Research & Development Career Development Award) [6982] FX This article is the result of work supported by the Kidney Research Institute (Seattle, WA). This research was also supported by the National Institutes of Health National Heart, Lung, and Blood Institute (Grant 2R01HL070938 to J.H.) and the Department of Veterans Affairs (Rehabilitation Research & Development Career Development Award 6982 to A.J.L.). NR 53 TC 22 Z9 22 U1 2 U2 9 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 FEB 1 PY 2014 VL 25 IS 2 BP 399 EP 406 DI 10.1681/ASN.2013040392 PG 8 WC Urology & Nephrology SC Urology & Nephrology GA AJ8QM UT WOS:000337971700022 PM 24335971 ER PT J AU Whyte, J Rajan, R Rosenbaum, A Katz, D Kalmar, K Seel, R Greenwald, B Zafonte, R Demarest, D Brunner, R Kaelin, D AF Whyte, John Rajan, Riya Rosenbaum, Amy Katz, Douglas Kalmar, Kathleen Seel, Ron Greenwald, Brian Zafonte, Ross Demarest, David Brunner, Robert Kaelin, Darryl TI Zolpidem and Restoration of Consciousness SO AMERICAN JOURNAL OF PHYSICAL MEDICINE & REHABILITATION LA English DT Article DE Brain Injuries; Consciousness Disorders; Vegetative State; Minimally Conscious State; Zolpidem ID PERSISTENT VEGETATIVE STATE; PLACEBO-CONTROLLED TRIAL; TRAUMATIC BRAIN-INJURY; COMA; AROUSAL; DISORDERS; EEG; SCALE AB Objective: Zolpidem has been reported to cause temporary recovery of consciousness in vegetative and minimally conscious patients, but how often and why this occurs are unknown. The authors aimed to determine the frequency of this phenomenon and whether it can be predicted from demographic and clinical variables. Design: This is a placebo-controlled, double-blind, single-dose, crossover study performed by caregivers and replicated by trained professionals, for naive participants. Four previously identified responders were also studied to further characterize the clinical drug response. Results: Eighty-four participants with traumatic and nontraumatic disorders of consciousness of at least 4 mos' duration were studied. Four "definite responders" were identified, but no demographic or clinical features were predictive of the response. Indicators of a drug response included increased movement, social interaction, command following, attempts at communication, and functional object use; typically lasted 1-2 hrs; and sometimes ended with increased somnolence. Adverse events were more common on zolpidem than placebo, but most were rated as mild. Conclusions: Approximately 5% (4.8%) of the participants responded to zolpidem, but the responders could not be distinguished in advance from the non-responders. Future research is needed to understand the mechanism of zolpidem in enhancing consciousness and its potential role in treatment and research. C1 [Whyte, John; Rajan, Riya] Moss Rehabil Res Inst, Elkins Pk, PA 19027 USA. [Rosenbaum, Amy] Pk Terrace Care Ctr, Rego Pk Queens, NY USA. [Katz, Douglas] Boston Univ, Dept Neurol, Sch Med, Boston, MA 02215 USA. [Katz, Douglas] Braintree Rehabil Hosp, Brain Injury Program, Braintree, MA USA. [Kalmar, Kathleen] Johnson Rehabil Inst Ctr Head Injuries, Edison, NJ USA. [Seel, Ron] Shepherd Ctr, Crawford Res Inst, Atlanta, GA USA. [Seel, Ron] Shepherd Ctr, Brain Injury Program, Atlanta, GA USA. [Greenwald, Brian] Icahn Sch Med Mt Sinai, Dept Rehabil Med, New York, NY 10029 USA. [Zafonte, Ross] Harvard Univ, Brigham & Womens Hosp, Dept Phys Med & Rehabil, Spaulding Rehabil Hosp,Massachusetts Gen Hosp,Med, Boston, MA 02115 USA. [Demarest, David] On With Life, Ankeny, IA USA. [Brunner, Robert] Univ Alabama Birmingham, Dept Phys Med & Rehabil, Birmingham, AL USA. [Kaelin, Darryl] Univ Louisville, Div Phys Med & Rehabil, Louisville, KY 40292 USA. RP Whyte, J (reprint author), Moss Rehabil Res Inst, 50 Township Line Rd, Elkins Pk, PA 19027 USA. FU National Institute on Disability and Rehabilitation Research (NIDRR), United States Department of Education [H133G080066] FX Supported, in part, by grant no. H133G080066 from the National Institute on Disability and Rehabilitation Research (NIDRR), United States Department of Education (J.W., principal investigator). Financial disclosure statements have been obtained, and no conflicts of interest have been reported by the authors or by any individuals in control of the content of this article. NR 30 TC 11 Z9 11 U1 1 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0894-9115 EI 1537-7385 J9 AM J PHYS MED REHAB JI Am. J. Phys. Med. Rehabil. PD FEB PY 2014 VL 93 IS 2 BP 101 EP 113 DI 10.1097/PHM.0000000000000069 PG 13 WC Rehabilitation; Sport Sciences SC Rehabilitation; Sport Sciences GA AJ5PD UT WOS:000337736200001 PM 24434886 ER PT J AU Carter, SA Hicks, SC Brahmbhatt, R Liang, MK AF Carter, Stacey A. Hicks, Stephanie C. Brahmbhatt, Reshma Liang, Mike K. TI Recurrence and Pseudorecurrence after Laparoscopic Ventral Hernia Repair: Predictors and Patient-focused Outcomes SO AMERICAN SURGEON LA English DT Article ID INCISIONAL HERNIA; EXPERIENCE; CLOSURE; MESH; TRIAL AB Laparoscopic ventral hernia repair (LVHR) is gaining popularity as an option to repair abdominal wall hernias. Bulging after repair remains common after this technique. This study evaluates the incidence and factors associated with bulging after LVHR. Between 2000 and 2010, 201 patients underwent LVHR at two affiliated institutions. Patients who developed recurrence or pseudorecurrence (seroma or eventration) were analyzed with univariate and multivariate analyses to identify predictors of these complications. Of the 201 patients who underwent LVHR, 40 (19.9%) patients developed a seroma, 63 (31.3%) patients had radiographically proven eventration, and 25 (12.4%) patients had a hernia recurrence. On multivariate analysis, seromas were associated with number of prior ventral hernia repairs, surgical site infections, and prostate disease. Mesh eventration was associated with hernia size and surgical technique. Tissue eventration was associated with primary hernias and surgical technique. Hernia recurrence was associated with incisional hernias and mesh type used. Recurrence and pseudorecurrence are important complications after LVHR. Large hernia size, infections, and surgical technique are important clinical factors that affect outcomes after LVHR. C1 [Carter, Stacey A.; Brahmbhatt, Reshma; Liang, Mike K.] Baylor Coll Med, Michael E DeBakey Dept Surg, Houston, TX 77030 USA. [Hicks, Stephanie C.] Dana Farber Canc Inst, Dept Stat, Cambridge, MA USA. [Liang, Mike K.] Univ Texas Hlth Sci Ctr Houston, Dept Surg, Houston, TX 77023 USA. RP Liang, MK (reprint author), Univ Texas Hlth Sci Ctr Houston, Dept Surg, 5656 Kelley St, Houston, TX 77023 USA. EM mike.liang@uth.tmc.edu RI Liang, Mike/L-8493-2015 OI Liang, Mike/0000-0001-7063-7291 NR 31 TC 12 Z9 12 U1 0 U2 2 PU SOUTHEASTERN SURGICAL CONGRESS PI CUMMING PA 115 SAMARITAN DR, #200, CUMMING, GA 30040-2354 USA SN 0003-1348 EI 1555-9823 J9 AM SURGEON JI Am. Surg. PD FEB PY 2014 VL 80 IS 2 BP 138 EP 148 PG 11 WC Surgery SC Surgery GA AJ5QO UT WOS:000337740800021 PM 24480213 ER PT J AU Eberlin, KR Nguyen, B Karia, PS Carter, JB Liang, CA Schmults, CD AF Eberlin, Kyle R. Bichchau Nguyen Karia, Pritesh S. Carter, Joi B. Liang, Christine A. Schmults, Chrysalyne D. TI The Z-Advancement Flap for Reconstruction of Lateral Nasal Tip and Medial Alar Defects SO DERMATOLOGIC SURGERY LA English DT Article ID ALGORITHM; SUPRATIP AB BACKGROUND Reconstruction of lateral nasal tip and medial alar defects is challenging. Contour, symmetry, and skin texture of the nose, along with adequate nasal airway patency, should be preserved. The Z-advancement flap is a novel reconstruction technique designed for optimal cosmesis and function. OBJECTIVE To evaluate the aesthetic and functional outcomes of Z-advancement flap nasal reconstruction. MATERIALS AND METHODS Twenty-nine consecutive patients with defects 1 cm or less in diameter on the lateral nasal tip or medial ala underwent Z-advancement flap repair. Patients completed a survey assessing cosmesis and airway patency. Three physicians evaluated standardized photographs on visibility of scar lines, erythema and telangiectasia, and contour and symmetry of the ala and nostril opening. RESULTS Twenty-eight (96%) patients completed survey questionnaires. All patients were satisfied with the look and feel of their reconstructed nose. Twenty-four (86%) saw no visible scar or abnormality. Postoperative photographs were available for review in 19 (66%) patients. In 95% to 96% of physician ratings, scars were invisible or visible only on close inspection, and alar symmetry was unchanged or only slightly altered. In 88%, nostril opening symmetry was unchanged or slightly altered. CONCLUSIONS The Z-advancement flap preserves aesthetic subunits of the nose to produce excellent cosmesis and patient satisfaction for defects of the lateral nasal tip or medial ala 1 cm or less in diameter. C1 [Eberlin, Kyle R.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Plast Surg, Boston, MA USA. [Bichchau Nguyen; Karia, Pritesh S.; Liang, Christine A.; Schmults, Chrysalyne D.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Dermatol, Boston, MA 02115 USA. [Carter, Joi B.] Harvard Univ, Sch Med, Dept Dermatol, Massachusetts Gen Hosp, Boston, MA 02115 USA. RP Schmults, CD (reprint author), Harvard Univ, Sch Med, Dept Dermatol, Brigham & Womens Hosp, 1153 Ctr St,Suite 4349, Jamaica Plain, MA 02130 USA. EM cschmults@partners.org NR 15 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1076-0512 EI 1524-4725 J9 DERMATOL SURG JI Dermatol. Surg. PD FEB PY 2014 VL 40 IS 2 BP 101 EP 109 DI 10.1111/dsu.12409 PG 9 WC Dermatology; Surgery SC Dermatology; Surgery GA AJ4FI UT WOS:000337627200002 PM 24373101 ER PT J AU Brink, JA AF Brink, James A. TI DOSE TRACKING AND RATIONAL EXAMINATION SELECTION FOR THE MEDICALLY-EXPOSED POPULATION SO HEALTH PHYSICS LA English DT Article DE dose assessment; imaging; medical radiation; National Council on Radiation Protection and Measurements ID RADIATION-EXPOSURE; DECISION-SUPPORT; CANCER-RISKS; CT AB Tracking the radiation dose to medically-exposed populations can promote adoption of best practices among medical facilities that use ionizing radiation. Dose index registries provide an important tool for practices to benchmark their radiation doses for medical imaging and highlight areas where improvements may be made. However, individual patient dose tracking has many confounding variables to consider. It is not clear which dose measures should be tracked, and the variation among these dose measures must be understood relative to the variations in body habitus that are encountered in clinical practice. In addition, there are many uncertainties associated with risk estimation from low-dose radiation that relate to the age, gender, and life expectancy of the exposed individual. Other sources of variation in the use of ionizing radiation for medical imaging are of concern. Specifically, deviation from best practice in the use of medical imaging should be reduced, if not eliminated. Several tools exist to help reduce variation among practices when it comes to rational examination selection. Computerized order entry with decision support offers the promise to introduce these tools at the point of care, which should increase their use and adoption in the medical community at large. C1 [Brink, James A.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Brink, James A.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. RP Brink, JA (reprint author), Harvard Univ, Sch Med, 175 Cambridge St,2nd Floor, Boston, MA 02114 USA. EM jabrink@partners.org NR 15 TC 3 Z9 3 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0017-9078 EI 1538-5159 J9 HEALTH PHYS JI Health Phys. PD FEB PY 2014 VL 106 IS 2 BP 225 EP 228 DI 10.1097/HP.0000000000000022 PG 4 WC Environmental Sciences; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging GA AJ2SO UT WOS:000337512400012 PM 24378497 ER PT J AU Travis, LB Ng, AK Allan, JM Pui, CH Kennedy, AR Xu, XG Purdy, JA Applegate, K Yahalom, J Constine, LS Gilbert, ES Boice, JD AF Travis, Lois B. Ng, Andrea K. Allan, James M. Pui, Ching-Hon Kennedy, Ann R. Xu, X. George Purdy, James A. Applegate, Kimberly Yahalom, Joachim Constine, Louis S. Gilbert, Ethel S. Boice, John D., Jr. TI SECOND MALIGNANT NEOPLASMS AND CARDIOVASCULAR DISEASE FOLLOWING RADIOTHERAPY SO HEALTH PHYSICS LA English DT Article DE cancer; health effects; medical radiation; National Council on Radiation Protection and Measurements ID RADIATION-THERAPY; TESTICULAR CANCER; BREAST-CANCER; HODGKINS-DISEASE; RISK; CHEMOTHERAPY; CARCINOMA; SURVIVORS; ROLES; SUSCEPTIBILITY AB Second malignant neoplasms (SMNs) and cardiovascular disease (CVD) are among the most serious and life-threatening late adverse effects experienced by the growing number of cancer survivors worldwide and are due in part to radiotherapy. The National Council on Radiation Protection and Measurements (NCRP) convened an expert scientific committee to critically and comprehensively review associations between radiotherapy and SMNs and CVD, taking into account radiobiology; genomics; treatment (i.e., radiotherapy with or without chemotherapy and other therapies); type of radiation; and quantitative considerations (i.e., dose-response relationships). Major conclusions of the NCRP include: (1) the relevance of older technologies for current risk assessment when organ-specific absorbed dose and the appropriate relative biological effectiveness are taken into account and (2) the identification of critical research needs with regard to newer radiation modalities, dose-response relationships, and genetic susceptibility. Recommendation for research priorities and infrastructural requirements include (1) long-term large-scale follow-up of extant cancer survivors and prospectively treated patients to characterize risks of SMNs and CVD in terms of radiation dose and type; (2) biological sample collection to integrate epidemiological studies with molecular and genetic evaluations; (3) investigation of interactions between radiotherapy and other potential confounding factors, such as age, sex, race, tobacco and alcohol use, dietary intake, energy balance, and other cofactors, as well as genetic susceptibility; (4) focusing on adolescent and young adult cancer survivors, given the sparse research in this population; and (5) construction of comprehensive risk prediction models for SMNs and CVD to permit the development of follow-up guidelines and prevention and intervention strategies. C1 [Travis, Lois B.; Constine, Louis S.] Univ Rochester, Med Ctr, Rubin Ctr Canc Survivorship, Rochester, NY 14642 USA. [Travis, Lois B.; Constine, Louis S.] Univ Rochester, Med Ctr, James P Wilmot Canc Ctr, Dept Radiat Oncol, Rochester, NY 14642 USA. [Ng, Andrea K.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Radiat Oncol, Boston, MA 02115 USA. [Ng, Andrea K.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Allan, James M.] Newcastle Univ, Northern Inst Canc Res, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. [Pui, Ching-Hon] St Jude Childrens Res Hosp, Dept Oncol, Memphis, TN 38105 USA. [Pui, Ching-Hon] Univ Tennessee, Ctr Hlth Sci, Memphis, TN 38163 USA. [Kennedy, Ann R.] Univ Penn, Sch Med, Dept Radiat Oncol, Philadelphia, PA 19104 USA. [Xu, X. George] Rensselaer Polytech Inst, Nucl Engn & Engn Phys Program, Troy, NY USA. [Purdy, James A.] Univ Calif Davis, Dept Radiat Oncol, Davis, CA 95616 USA. [Applegate, Kimberly] Emory Univ, Dept Radiol, Atlanta, GA 30322 USA. [Yahalom, Joachim] Mem Sloan Kettering Canc Ctr, Dept Radiat Oncol, New York, NY 10021 USA. [Gilbert, Ethel S.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Boice, John D., Jr.] Natl Council Radiat Protect & Measurements, Bethesda, MD USA. [Boice, John D., Jr.] Vanderbilt Univ, Dept Med, Nashville, TN USA. RP Travis, LB (reprint author), Univ Rochester, Med Ctr, Rubin Ctr Canc Survivorship, 265 Crittenden Blvd,CU 420318, Rochester, NY 14642 USA. EM Lois_Travis@URMC.Rochester.edu FU National Institutes of Health [CA21765]; American Lebanese Syrian Associated Charities; University of Rochester Medical Center FX Supported in part by grant CA21765 from the National Institutes of Health, the American Lebanese Syrian Associated Charities (Ching-Hon Pui), and the University of Rochester Medical Center (Lois B. Travis). NR 26 TC 9 Z9 10 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0017-9078 EI 1538-5159 J9 HEALTH PHYS JI Health Phys. PD FEB PY 2014 VL 106 IS 2 BP 229 EP 246 DI 10.1097/HP.0000000000000013 PG 18 WC Environmental Sciences; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging GA AJ2SO UT WOS:000337512400013 PM 24378498 ER PT J AU Heyworth, L Paquin, AM Clark, J Kamenker, V Stewart, M Martin, T Simon, SR AF Heyworth, Leonie Paquin, Allison M. Clark, Justice Kamenker, Victor Stewart, Max Martin, Tracey Simon, Steven R. TI Engaging patients in medication reconciliation via a patient portal following hospital discharge SO JOURNAL OF THE AMERICAN MEDICAL INFORMATICS ASSOCIATION LA English DT Article ID ADVERSE DRUG EVENTS; RANDOMIZED-CONTROLLED-TRIAL; PHARMACIST INTERVENTION; ADMISSION; ERRORS; CARE; IMPLEMENTATION; COMMUNICATION; PROGRAM; RECORD AB Few ambulatory medication reconciliation tools exist. Transitions between inpatient and outpatient care can result in medication discrepancies. An interdisciplinary team designed a new 'Secure Messaging for Medication Reconciliation Tool' (SMMRT) within a patient web portal and piloted it among 60 patients at a Veterans Affairs hospital, an integrated system with a shared electronic health record. Recently discharged patients used SMMRT to view their medications in a secure email message and replied using SMMRT's interactive form, verifying their medication regimens and clarifying any inaccuracies. In total, 108 medication discrepancies and 23 potential adverse drug events (ADEs) were seen. Nearly 50% of the potential ADEs were classified as serious. Overall, participants were enthusiastic about SMMRT; 90% said they would use SMMRT again. Enabling patients to conduct medication reconciliation through a web portal is feasible in the transition from inpatient to outpatient care and may improve medication safety. C1 [Heyworth, Leonie; Clark, Justice; Kamenker, Victor; Stewart, Max; Martin, Tracey; Simon, Steven R.] VA Boston Healthcare Syst, Gen Internal Med Sect, Boston, MA 02130 USA. [Heyworth, Leonie; Simon, Steven R.] Brigham & Womens Hosp, Div Gen Med, Boston, MA 02115 USA. [Paquin, Allison M.] VA Boston Healthcare Syst, Dept Pharm, Boston, MA 02130 USA. RP Heyworth, L (reprint author), VA Boston Healthcare Syst, Gen Internal Med Sect, 150 South Huntington Ave, Boston, MA 02130 USA. EM lheyworth@gmail.com FU Center for Medicine and Innovative Technology (CIMIT) [1183]; Veterans Engineering Resource Center (VERC) [1395]; HRSA [T32 HP10251]; Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development FX This study was funded by the Center for Medicine and Innovative Technology (CIMIT) grant 1183 and the Veterans Engineering Resource Center (VERC) grant 1395. Neither funding source played a role in the study concept or design, in the data analysis or interpretation, or in the drafting of the manuscript. LH was supported by HRSA grant T32 HP10251 and by the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development. NR 29 TC 13 Z9 13 U1 5 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 FEB PY 2014 VL 21 IS E1 BP E157 EP E162 DI 10.1136/amiajnl-2013-001995 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 AJ4UM UT WOS:000337672800025 PM 24036155 ER PT J AU Meeks, DW Takian, A Sittig, DF Singh, H Barber, N AF Meeks, Derek W. Takian, Amirhossein Sittig, Dean F. Singh, Hardeep Barber, Nick TI Exploring the sociotechnical intersection of patient safety and electronic health record implementation SO JOURNAL OF THE AMERICAN MEDICAL INFORMATICS ASSOCIATION LA English DT Article ID ORDER ENTRY SYSTEMS; INFORMATION-TECHNOLOGY; FOLLOW-UP; MEDICAL-RECORD; UNINTENDED CONSEQUENCES; CARE; ERRORS; MANAGEMENT; ADOPTION; CLASSIFICATION AB Objective The intersection of electronic health records (EHR) and patient safety is complex. To examine the applicability of two previously developed conceptual models comprehensively to understand safety implications of EHR implementation in the English National Health Service (NHS). Methods We conducted a secondary analysis of interview data from a 30-month longitudinal, prospective, case study-based evaluation of EHR implementation in 12 NHS hospitals. We used a framework analysis approach to apply conceptual models developed by Sittig and Singh to understand better EHR implementation and use: an eight-dimension sociotechnical model and a three-phase patient safety model (safe technology, safe use of technology, and use of technology to improve safety). Results The intersection of patient safety and EHR implementation and use was characterized by risks involving technology (hardware and software, clinical content, and human-computer interfaces), the interaction of technology with non-technological factors, and improper or unsafe use of technology. Our data support that patient safety improvement activities as well as patient safety hazards change as an organization evolves from concerns about safe EHR functionality, ensuring safe and appropriate EHR use, to using the EHR itself to provide ongoing surveillance and monitoring of patient safety. Discussion We demonstrate the face validity of two models for understanding the sociotechnical aspects of safe EHR implementation and the complex interactions of technology within a healthcare system evolving from paper to integrated EHR. Conclusions Using sociotechnical models, including those presented in this paper, may be beneficial to help stakeholders understand, synthesize, and anticipate risks at the intersection of patient safety and health information technology. C1 [Meeks, Derek W.] Baylor Coll Med, Michael E DeBakey Vet Affairs Med Ctr, VA HSR&D Ctr Excellence, Dept Family & Community Med, Houston, TX 77030 USA. [Takian, Amirhossein] Brunel Univ, Sch Hlth Sci & Social Care, Div Hlth Studies, Uxbridge UB8 3PH, Middx, England. [Sittig, Dean F.] Univ Texas Sch Biomed Informat, Houston, TX USA. [Sittig, Dean F.] UT Mem Hermann Ctr Healthcare Qual & Safety, Houston, TX USA. [Singh, Hardeep] Baylor Coll Med, Dept Med, Michael E DeBakey Vet Affairs Med Ctr, Houston VA HSR&D Ctr Excellence,Sect Hlth Serv Re, Houston, TX 77030 USA. [Barber, Nick] UCL Sch Pharm, Dept Practice & Policy, London, England. RP Meeks, DW (reprint author), Houston VA HSR&D Ctr Excellence 152, 2002 Holcombe Blvd, Houston, TX 77030 USA. EM derek.meeks@bcm.edu FU NHS Connecting for Health Evaluation Programme [005 08/S0709/97]; VA National Center of Patient Safety, Agency for Health Care Research and Quality; Houston VA HSR&D Center of Excellence [HFP90-020]; Baylor College of Medicine Department of Family and Community Medicine; Ruth L. Kirschstein national research service award [T32HP10031] FX This paper is independent research commissioned by the NHS Connecting for Health Evaluation Programme (005 08/S0709/97) led by Professor Richard Lilford. The views expressed in this publication are those of the authors and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health. HS is supported by the VA National Center of Patient Safety, Agency for Health Care Research and Quality, and in part by the Houston VA HSR&D Center of Excellence (HFP90-020). DWM is supported by the Baylor College of Medicine Department of Family and Community Medicine post-doctoral fellowship program and the Ruth L. Kirschstein national research service award (T32HP10031). These sources had no role in the preparation, review, or approval of the manuscript. NR 51 TC 12 Z9 12 U1 2 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 FEB PY 2014 VL 21 IS E1 BP E28 EP E34 DI 10.1136/amiajnl-2013-001762 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 AJ4UM UT WOS:000337672800006 PM 24052536 ER PT J AU Phillips, AB Wilson, RV Kaushal, R Merrill, JA AF Phillips, Andrew B. Wilson, Rosalind V. Kaushal, Rainu Merrill, Jacqueline A. CA HITEC Investigators TI Implementing health information exchange for public health reporting: a comparison of decision and risk management of three regional health information organizations in New York state SO JOURNAL OF THE AMERICAN MEDICAL INFORMATICS ASSOCIATION LA English DT Article AB Health information exchange (HIE) is a significant component of healthcare transformation strategies at both the state and national levels. HIE is expected to improve care coordination, and advance public health, but implementation is massively complex and involves significant risk. In New York, three regional health information organizations (RHIOs) implemented an HIE use case for public health reporting by demonstrating capability to deliver accurate responses to electronic queries via a set of services called the Universal Public Health Node. We investigated process and outcomes of the implementation with a comparative case study. Qualitative analysis was structured around a decision and risk matrix. Although each RHIO had a unique operational model, two common factors influenced risk management and implementation success: leadership capable of agile decision-making and commitment to a strong organizational vision. While all three RHIOs achieved certification for the public health reporting, only one has elected to deploy a production version. C1 [Phillips, Andrew B.] Massachusetts Gen Hosp East, Inst Hlth Profess, Sch Nursing, Charlestown Navy Yard, Boston, MA 02129 USA. [Wilson, Rosalind V.] Columbia Univ, Sch Nursing, New York, NY USA. [Kaushal, Rainu] Weill Cornell Med Coll, Dept Pediat, New York, NY USA. [Merrill, Jacqueline A.] Columbia Univ, Dept Biomed Informat, Sch Nursing, New York, NY USA. RP Phillips, AB (reprint author), Massachusetts Gen Hosp East, Inst Hlth Profess, Sch Nursing, Charlestown Navy Yard, 36 1st Ave, Boston, MA 02129 USA. EM aphillips@mghihp.edu OI Merrill, Jacqueline A./0000-0001-5425-1663 FU New York State Department of Health (NYS) [C023699]; National Institute of Nursing Research [T32NR007969] FX This study was supported by the New York State Department of Health (NYS contract number C023699). ABP received support from an institutional training grant to Columbia University from the National Institute of Nursing Research (T32NR007969). NR 24 TC 2 Z9 2 U1 1 U2 15 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 FEB PY 2014 VL 21 IS E1 BP E173 EP E177 DI 10.1136/amiajnl-2013-001716 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 AJ4UM UT WOS:000337672800028 PM 23975626 ER PT J AU Zai, AH Kim, S Kamis, A Hung, K Ronquillo, JG Chueh, HC Atlas, SJ AF Zai, Adrian H. Kim, Seokjin Kamis, Arnold Hung, Ken Ronquillo, Jeremiah G. Chueh, Henry C. Atlas, Steven J. TI Applying operations research to optimize a novel population management system for cancer screening SO JOURNAL OF THE AMERICAN MEDICAL INFORMATICS ASSOCIATION LA English DT Article ID DISCRETE-EVENT SIMULATION; RANDOMIZED-CONTROLLED-TRIAL; BREAST-CANCER; HEALTH-CARE; QUEUING THEORY; WOMEN; MODEL; RECOMMENDATIONS; METAANALYSIS; DIAGNOSIS AB Objective To optimize a new visit-independent, population-based cancer screening system (TopCare) by using operations research techniques to simulate changes in patient outreach staffing levels (delegates, navigators), modifications to user workflow within the information technology (IT) system, and changes in cancer screening recommendations. Materials and methods TopCare was modeled as a multiserver, multiphase queueing system. Simulation experiments implemented the queueing network model following a next-event time-advance mechanism, in which systematic adjustments were made to staffing levels, IT workflow settings, and cancer screening frequency in order to assess their impact on overdue screenings per patient. Results TopCare reduced the average number of overdue screenings per patient from 1.17 at inception to 0.86 during simulation to 0.23 at steady state. Increases in the workforce improved the effectiveness of TopCare. In particular, increasing the delegate or navigator staff level by one person improved screening completion rates by 1.3% or 12.2%, respectively. In contrast, changes in the amount of time a patient entry stays on delegate and navigator lists had little impact on overdue screenings. Finally, lengthening the screening interval increased efficiency within TopCare by decreasing overdue screenings at the patient level, resulting in a smaller number of overdue patients needing delegates for screening and a higher fraction of screenings completed by delegates. Conclusions Simulating the impact of changes in staffing, system parameters, and clinical inputs on the effectiveness and efficiency of care can inform the allocation of limited resources in population management. C1 [Zai, Adrian H.; Ronquillo, Jeremiah G.; Chueh, Henry C.] Massachusetts Gen Hosp, Comp Sci Lab, Boston, MA 02114 USA. [Zai, Adrian H.; Ronquillo, Jeremiah G.; Chueh, Henry C.; Atlas, Steven J.] Harvard Univ, Sch Med, Boston, MA USA. [Kim, Seokjin; Kamis, Arnold; Hung, Ken] Suffolk Univ, Sawyer Business Sch, Boston, MA 02114 USA. [Atlas, Steven J.] Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. RP Zai, AH (reprint author), Massachusetts Gen Hosp, Comp Sci Lab, 50 Staniford St,7th Floor, Boston, MA 02114 USA. EM azai@partners.org FU Agency for Healthcare Research and Quality (AHRQ) [R18-HS018161]; CRICO/RMF FX This research was supported in part by grant R18-HS018161 from the Agency for Healthcare Research and Quality (AHRQ), and by CRICO/RMF. NR 46 TC 11 Z9 11 U1 2 U2 6 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 FEB PY 2014 VL 21 IS E1 BP E129 EP E135 DI 10.1136/amiajnl-2013-001681 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 AJ4UM UT WOS:000337672800020 PM 24043318 ER PT J AU Peter, I Papandonatos, GD Belalcazar, LM Yang, Y Erar, B Jakicic, JM Unick, JL Balasubramanyam, A Lipkin, EW Delahanty, LM Wagenknecht, LE Wing, RR Mccaffery, JM Huggins, GS AF Peter, Inga Papandonatos, George D. Belalcazar, L. Maria Yang, Yao Erar, Bahar Jakicic, John M. Unick, Jessica L. Balasubramanyam, Ashok Lipkin, Edward W. Delahanty, Linda M. Wagenknecht, Lynne E. Wing, Rena R. Mccaffery, Jeanne M. Huggins, Gordon S. CA Look AHEAD Res Grp TI Genetic Modifiers of Cardiorespiratory Fitness Response to Lifestyle Intervention SO MEDICINE AND SCIENCE IN SPORTS AND EXERCISE LA English DT Article DE METABOLIC EQUIVALENT; CLINICAL TRIAL; CARE ISELECT IBC CHIP; GENOTYPE-TREATMENT INTERACTION ID TYPE-2 DIABETES-MELLITUS; GENOME-WIDE ASSOCIATION; LOOK-AHEAD TRIAL; WEIGHT-LOSS; CARDIOVASCULAR-DISEASE; PHYSICAL-ACTIVITY; CLINICAL-TRIAL; RISK-FACTORS; EXERCISE; INDIVIDUALS AB Purpose: Numerous prospective studies indicate that improved cardiorespiratory fitness reduces type 2 diabetes risk and delays disease progression. We hypothesized that genetic variants modify fitness response to an intensive lifestyle intervention (ILI) in the Action for Health in Diabetes (Look AHEAD) randomized clinical trial, aimed to detect whether ILI will reduce cardiovascular events in overweight/obese subjects with type 2 diabetes compared with a standard of care. Methods: Polymorphisms in established fitness genes and in all loci assayed on the Illumina CARe iSelect chip were examined as predictors of change in MET level, estimated using a treadmill test, in response to a 1-yr intervention in 3899 participants. Results: We identified a significant signal in previously reported fitness-related gene RUNX1 that was associated with 1-yr METs response in ILI (0.19 +/- 0.04 MET less improvement per minor allele copy; P = 1.9 x 10(-5)) and genotype-intervention interaction (P = 4.8 x 10(-3)). In the chipwide analysis, FKBP7 rs17225700 showed a significant association with ILI response among subjects not receiving beta-blocker medications (0.47 +/- 0.09 METs less improvement; P = 5.3 x 10(-7)) and genotype-treatment interaction (P = 5.3 x 10(-5)). The Gene Relationships Among Implicated Loci pathway-based analysis identified connections between associated genes, including those influencing vascular tone, muscle contraction, cardiac energy substrate dynamics, and muscle protein synthesis. Conclusions: This is the first study to identify genetic variants associated with fitness responses to a randomized lifestyle intervention in overweight/obese diabetic individuals. RUNX1 and FKBP7, involved in erythropoesis and muscle protein synthesis, respectively, are related to change in cardiorespiratory fitness in response to exercise. C1 [Peter, Inga; Yang, Yao] Mt Sinai Sch Med, Dept Genet & Genom Sci, New York, NY 10029 USA. [Papandonatos, George D.; Erar, Bahar] Brown Univ, Ctr Stat Sci, Providence, RI 02912 USA. [Belalcazar, L. Maria] Univ Texas Med Branch, Dept Med, Galveston, TX 77555 USA. [Jakicic, John M.] Univ Pittsburgh, Phys Act & Weight Management Res Ctr, Dept Hlth & Phys Act, Pittsburgh, PA USA. [Unick, Jessica L.; Wing, Rena R.; Mccaffery, Jeanne M.] Miriam Hosp, Dept Psychiat & Human Behav, Weight Control & Diabet Res Ctr, Providence, RI 02906 USA. [Unick, Jessica L.; Wing, Rena R.; Mccaffery, Jeanne M.] Brown Med Sch, Providence, RI USA. [Balasubramanyam, Ashok] Baylor Coll Med, Div Diabet Endocrinol & Metab, Diabet Res Ctr, Translat Metab Unit, Houston, TX 77030 USA. [Lipkin, Edward W.] Univ Washington, Div Metab Endocrinol & Nutr, Seattle, WA 98195 USA. [Delahanty, Linda M.] Massachusetts Gen Hosp, Diabet Res Ctr, Boston, MA 02114 USA. [Delahanty, Linda M.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Wagenknecht, Lynne E.] Wake Forest Sch Med, Div Publ Hlth Sci, Winston Salem, NC USA. [Huggins, Gordon S.] Tufts Med Ctr, Ctr Translat Genom, Mol Cardiol Res Inst, Boston, MA USA. [Huggins, Gordon S.] Tufts Univ, Boston, MA 02111 USA. RP Peter, I (reprint author), Mt Sinai Sch Med, Dept Genet & Genom Sci, 1425 Madison Ave,Box 1498, New York, NY 10029 USA. EM inga.peter@mssm.edu RI Papandonatos, George/J-2328-2014; Yang, Yao/M-7425-2014; OI Yang, Yao/0000-0003-0366-6943; Papandonatos, George/0000-0001-6770-932X FU Department of Health and Human Services through from the National Institutes of Health [DK57136, DK57149, DK56990, DK57177, DK57171, DK57151, DK57182, DK57131, DK57002, DK57078, DK57154, DK57178, DK57219, DK57008, DK57135, DK56992]; National Institute of Diabetes and Digestive and Kidney Diseases; National Heart, Lung, and Blood Institute; National Institute of Nursing Research; National Center on Minority Health and Health Disparities; NIH Office of Research on Women's Health; Centers for Disease Control and Prevention; Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases; Johns Hopkins Medical Institutions Bayview General Clinical Research Center [M01RR02719]; Massachusetts General Hospital Mallinckrodt General Clinical Research Center [M01RR01066]; University of Colorado Health Sciences Center General Clinical Research Center [M01RR00051]; Clinical Nutrition Research Unit [P30 DK48520]; University of Tennessee at Memphis General Clinical Research Center [M01RR0021140]; University of Pittsburgh General Clinical Research Center [M01RR000056 44]; NIH [DK 046204]; VA Puget Sound Health Care System Medical Research Service, Department of Veterans Affairs; Frederic C. Bartter General Clinical Research Center [M01RR01346, DK090043] FX This study is supported by the Department of Health and Human Services through the following cooperative agreements from the National Institutes of Health: DK57136, DK57149, DK56990, DK57177, DK57171, DK57151, DK57182, DK57131, DK57002, DK57078, DK57154, DK57178, DK57219, DK57008, DK57135, and DK56992. The following federal agencies have contributed support: National Institute of Diabetes and Digestive and Kidney Diseases; National Heart, Lung, and Blood Institute; National Institute of Nursing Research; National Center on Minority Health and Health Disparities; NIH Office of Research on Women's Health; and Centers for Disease Control and Prevention. This research was supported in part by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases. The Indian Health Service (I. H. S.) provided personnel, medical oversight, and use of facilities. The opinions expressed in this paper are those of the authors and do not necessarily reflect the views of the I. H. S. or other funding sources.; Additional support was received from The Johns Hopkins Medical Institutions Bayview General Clinical Research Center (M01RR02719); the Massachusetts General Hospital Mallinckrodt General Clinical Research Center (M01RR01066); the University of Colorado Health Sciences Center General Clinical Research Center (M01RR00051) and Clinical Nutrition Research Unit (P30 DK48520); the University of Tennessee at Memphis General Clinical Research Center (M01RR0021140); the University of Pittsburgh General Clinical Research Center (M01RR000056 44) and NIH grant (DK 046204); the VA Puget Sound Health Care System Medical Research Service, Department of Veterans Affairs; and the Frederic C. Bartter General Clinical Research Center (M01RR01346), and DK090043 to J.M.M. NR 41 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 0195-9131 EI 1530-0315 J9 MED SCI SPORT EXER JI Med. Sci. Sports Exerc. PD FEB PY 2014 VL 46 IS 2 BP 302 EP 311 DI 10.1249/MSS.0b013e3182a66155 PG 10 WC Sport Sciences SC Sport Sciences GA AJ4ZB UT WOS:000337688000012 PM 23899896 ER PT J AU Kandathil, CK Dilwali, S Wu, CC Ibrahimov, M McKenna, MJ Lee, H Stankovic, KM AF Kandathil, Cherian K. Dilwali, Sonam Wu, Chen-Chi Ibrahimov, Metin McKenna, Michael J. Lee, Hang Stankovic, Konstantina M. TI Aspirin Intake Correlates With Halted Growth of Sporadic Vestibular Schwannoma In Vivo SO OTOLOGY & NEUROTOLOGY LA English DT Article DE Aspirin intake; Decreased tumor growth; In vivo; Retrospective case review; Sporadic vestibular schwannoma ID CORONARY-HEART-DISEASE; NF-KAPPA-B; ACOUSTIC NEUROMAS; GENDER; RISK; METAANALYSIS; CANCER; NERVE AB Objective: Given the presence of a pathological immune response in sporadic vestibular schwannoma (sVS), this study aims to explore the roles of aspirin in minimizing sVS growth in vivo. Study Design: Retrospective case review. Setting: Tertiary care hospital. Patients: People diagnosed with sVS and followed at a tertiary referral center by serial magnetic resonance imaging (MRI) for at least 4 months within the period of January 1980 through April 2012. Main Outcome Measures: Patient use of aspirin and sVS growth rate measured by changes in the largest tumor dimension as noted on serial MRIs Results: Within a set of 689 cases, 347 were followed by serial MRI scans (50.3%); of the latter, 81 took aspirin, of which, 33 demonstrated sVS growth, and 48 did not. Of the 266 nonaspirin users, 154 demonstrated sVS growth, and 112 did not. A significant inverse association was found among aspirin users and sVS growth (odds ratio [OR]: 0.50, 95% confidence interval [CI]: 0.29-0.85), which was not confounded by age or sex. Conclusion: Our results suggest a potential therapeutic role of aspirin in inhibiting sVS growth. C1 [Kandathil, Cherian K.; Dilwali, Sonam; Wu, Chen-Chi; Ibrahimov, Metin; McKenna, Michael J.; Stankovic, Konstantina M.] Massachusetts Eye & Ear Infirm, Dept Otolaryngol, Boston, MA 02114 USA. [Dilwali, Sonam; Stankovic, Konstantina M.] Harvard Univ, Sch Med, Program Speech & Hearing Biosci & Technol, Cambridge, MA 02138 USA. [Dilwali, Sonam; Stankovic, Konstantina M.] MIT, Cambridge, MA 02139 USA. [Lee, Hang] Massachusetts Gen Hosp, Ctr Biostat, Boston, MA 02114 USA. [Lee, Hang] Harvard Univ, Sch Med, Boston, MA USA. RP Stankovic, KM (reprint author), Massachusetts Eye & Ear Infirm, Dept Otolaryngol, 243 Charles St, Boston, MA 02114 USA. EM konstantina_stankovic@meei.harvard.edu OI WU, CHEN-CHI/0000-0002-5047-2204 FU National Institute on Deafness and Other Communication Disorders [T32 DC00038, K08DC010419]; Bertarelli Foundation FX This study was supported by the National Institute on Deafness and Other Communication Disorders Grant Nos. T32 DC00038 (to S. D.) and K08DC010419 (to K. M. S.) and the Bertarelli Foundation (to K. M. S.). NR 23 TC 9 Z9 9 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1531-7129 EI 1537-4505 J9 OTOL NEUROTOL JI Otol. Neurotol. PD FEB PY 2014 VL 35 IS 2 BP 353 EP 357 PG 5 WC Clinical Neurology; Otorhinolaryngology SC Neurosciences & Neurology; Otorhinolaryngology GA AJ5BZ UT WOS:000337697100033 PM 24448296 ER PT J AU Singh, JA AF Singh, Jasvinder A. TI Arthroplasty Outcomes Are Improving, but Why Isn't My Patient With Rheumatoid Arthritis Doing as Well? SO ARTHRITIS & RHEUMATOLOGY LA English DT Editorial Material ID TOTAL KNEE ARTHROPLASTY; TOTAL HIP-ARTHROPLASTY; RISK-FACTORS; MEDICARE PATIENTS; INFECTION; MORTALITY C1 [Singh, Jasvinder A.] Birmingham VA Med Ctr, Rochester, MN USA. [Singh, Jasvinder A.] Univ Alabama Birmingham, Rochester, MN USA. [Singh, Jasvinder A.] Mayo Clin, Rochester, MN USA. RP Singh, JA (reprint author), Univ Alabama Birmingham, Fac Off Tower 805B,510 20th St South, Birmingham, AL 35294 USA. EM Jasvinder.md@gmail.com FU NIA NIH HHS [U01 AG018947] NR 14 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2326-5191 EI 2326-5205 J9 ARTHRITIS RHEUMATOL JI Arthritis Rheumatol. PD FEB PY 2014 VL 66 IS 2 BP 250 EP 253 DI 10.1002/art.38236 PG 4 WC Rheumatology SC Rheumatology GA AJ0PQ UT WOS:000337357900004 PM 24504796 ER PT J AU Tomasson, G Davis, JC Hoffman, GS McCune, WJ Specks, U Spiera, R St Clair, EW Stone, JH Merkel, PA AF Tomasson, Gunnar Davis, John C. Hoffman, Gary S. McCune, W. Joseph Specks, Ulrich Spiera, Robert St Clair, E. William Stone, John H. Merkel, Peter A. TI The Value of a Patient Global Assessment of Disease Activity in Granulomatosis With Polyangiitis (Wegener's) SO ARTHRITIS & RHEUMATOLOGY LA English DT Article ID VASCULITIS ACTIVITY SCORE; HEALTH SURVEY SF-36; RHEUMATOID-ARTHRITIS; PERSPECTIVE; CYCLOPHOSPHAMIDE; RITUXIMAB; THERAPY AB Objective. To 1) describe the distribution of patient global assessment (PtGA) scores of disease activity in patients with granulomatosis with polyangiitis (GPA; Wegener's), 2) explore the discordance between PtGA scores and physician global assessment (PhGA) scores of disease activity, and 3) explore whether PtGA scores during disease remission are associated with future disease relapse. Methods. Data from the Wegener's Granulomatosis Etanercept Trial (WGET) were used. PtGA and PhGA scores were assessed on 100-mm visual analog scales (VAS). Presence of active disease was determined using the Birmingham Vasculitis Activity Score for WG (BVAS/WG), and remission was defined as a BVAS/WG score of 0. Disease relapse was defined as a BVAS/WG score of >0 after remission had been achieved. Discordance between PtGA and PhGA scores was defined as a difference of >= 20 points between the two measures. Mixed linear models were used in longitudinal analysis of PtGA scores. Results. Data were obtained from 180 patients in the WGET cohort, seen at a total of 1,719 study visits. The mean +/- SD PtGA and PhGA disease activity scores (on 100-mm VAS) at baseline were 64.2 +/- 27.4 and 55.5 +/- 23.4, respectively. PtGA-PhGA discordance occurred in 53% of patients at baseline, and this was inversely associated with newly diagnosed disease (as opposed to relapsing disease) at baseline (odds ratio 0.37, 95% confidence interval [95% CI] 0.20-0.68) but not with age, sex, or presence of renal or pulmonary disease. Patients were in disease remission during 62% of the study visits. The mean PtGA score during visits immediately prior to relapse was 4.52 points higher (95% CI 0.66-8.4) than that at other remission visits (P = 0.03). Conclusion. PtGA-PhGA discordance is common in GPA. A rise in the PtGA disease activity score during times defined by physicians as periods of remission is associated with subsequent occurrence of disease relapse. These findings support the addition of PtGA as an outcome measure for GPA. C1 [Tomasson, Gunnar] Univ Iceland, IS-101 Reykjavik, Iceland. [Davis, John C.] Genentech Inc, San Francisco, CA 94080 USA. [Hoffman, Gary S.] Cleveland Clin, Cleveland, OH 44106 USA. [McCune, W. Joseph] Univ Michigan, Ann Arbor, MI 48109 USA. [Specks, Ulrich] Mayo Clin, Rochester, MN USA. [Spiera, Robert] Hosp Special Surg, New York, NY 10021 USA. [St Clair, E. William] Duke Univ, Durham, NC USA. [St Clair, E. William] Duke Univ, Med Ctr, Durham, NC USA. [Stone, John H.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Merkel, Peter A.] Univ Penn, Philadelphia, PA 19104 USA. [Merkel, Peter A.] Boston Univ, Boston, MA 02215 USA. RP Tomasson, G (reprint author), Univ Iceland, Stapi Hringbraut, IS-101 Reykjavik, Iceland. EM gunnar.tomasson@gmail.com FU NIH (National Institute of Arthritis and Musculoskeletal and Skin Diseases [NIAMS]) [N01-AR-92240]; NIH (National Center for Research Resources, General Clinical Research Center) [M01-RRO-00533, M01-RRO-0042, M01-RR-30, M01-RRO-2719]; FDA, Office of Orphan Products [FD-R-001652]; NIH (NIAMS) [K24-AR-02126-04, K24-AR-049185-01, K24-AR-2224-01A1] FX The Wegener's Granulomatosis Etanercept Trial was supported by the NIH (National Institute of Arthritis and Musculoskeletal and Skin Diseases [NIAMS] grant N01-AR-92240 and National Center for Research Resources, General Clinical Research Center grants M01-RRO-00533 to Boston University, M01-RRO-0042 to University of Michigan, M01-RR-30 to Duke University, and M01-RRO-2719 to Johns Hopkins University School of Medicine) and by the FDA, Office of Orphan Products (grant FD-R-001652). Drs. St. Clair, Stone, and Merkel's work was supported by the NIH (NIAMS grants K24-AR-02126-04, K24-AR-049185-01, and K24-AR-2224-01A1). NR 14 TC 9 Z9 10 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2326-5191 EI 2326-5205 J9 ARTHRITIS RHEUMATOL JI Arthritis Rheumatol. PD FEB PY 2014 VL 66 IS 2 BP 428 EP 432 DI 10.1002/art.38248 PG 5 WC Rheumatology SC Rheumatology GA AJ0PQ UT WOS:000337357900025 PM 24504815 ER PT J AU Mohan, D Fischhoff, B Farris, C Switzer, GE Rosengart, MR Yealy, DM Saul, M Angus, DC Barnato, AE AF Mohan, Deepika Fischhoff, Baruch Farris, Coreen Switzer, Galen E. Rosengart, Matthew R. Yealy, Donald M. Saul, Melissa Angus, Derek C. Barnato, Amber E. TI Validating a Vignette-Based Instrument to Study Physician Decision Making in Trauma Triage SO MEDICAL DECISION MAKING LA English DT Article DE survey methods; psychometric/scaling; performance measures ID SIGNAL-DETECTION ANALYSIS; PRIMARY-CARE PHYSICIANS; STANDARDIZED PATIENTS; CLINICAL VIGNETTES; UNITED-STATES; QUALITY; SYSTEM; ABSTRACTION; MORTALITY; CASELOAD AB Background. The evidence supporting the use of vignettes to study physician decision making comes primarily from the study of low-risk decisions and the demonstration of good agreement at the group level between vignettes and actual practice. The validity of using vignettes to predict decision making in more complex, high-risk contexts and at the individual level remains unknown. Methods. We had previously developed a vignette-based instrument to study physician decision making in trauma triage. Here, we measured the retest reliability, internal consistency, known-groups performance, and criterion validity of the instrument. Thirty-two emergency physicians, recruited at a national academic meeting, participated in reliability testing. Twenty-eight trauma surgeons, recruited using personal contacts, participated in known-groups testing. Twenty-eight emergency physicians, recruited from physicians working at hospitals for which we had access to medical records, participated in criterion validity testing. We measured rates of undertriage (the proportion of severely injured patients not transferred to trauma centers) and overtriage (the proportion of patients transferred with minor injuries) on the instrument. For physicians participating in criterion validity testing, we compared rates of triage on the instrument with rates in practice, based on chart review. Results. Physicians made similar transfer decisions for cases (k = 0.42, P < 0.01) on 2 administrations of the instrument. Responses were internally consistent (Kuder-Richardson, 0.71-0.91). Surgeons had lower rates of undertriage than emergency physicians (13% v. 70%, P < 0.01). No correlation existed between individual rates of under-or overtriage on the vignettes and in practice (r = -0.17, P = 0.4; r = -0.03, P = 0.85). Conclusions. The instrument developed to assess trauma triage decision making performed reliably and detected known group differences. However, it did not predict individual physician performance. C1 [Mohan, Deepika; Rosengart, Matthew R.; Angus, Derek C.] Univ Pittsburgh, CRISMA Clin Res Invest & Syst Modeling Acute Illn, Dept Crit Care Med, Sch Med, Pittsburgh, PA 15261 USA. [Mohan, Deepika; Rosengart, Matthew R.] Univ Pittsburgh, Sch Med, Dept Surg, Pittsburgh, PA 15261 USA. [Fischhoff, Baruch] Carnegie Mellon Univ, Dept Social & Decis Sci, Pittsburgh, PA 15213 USA. [Switzer, Galen E.] Univ Pittsburgh, VA Pittsburgh Healthcare Syst, VA Ctr Hlth Equity Res & Promot, Pittsburgh, PA 15261 USA. [Switzer, Galen E.; Barnato, Amber E.] Univ Pittsburgh, Sch Med, Dept Med, Pittsburgh, PA 15261 USA. [Switzer, Galen E.] Univ Pittsburgh, Clin & Translat Sci Inst, Pittsburgh, PA 15261 USA. [Farris, Coreen] RAND Corp, Pittsburgh, PA USA. [Yealy, Donald M.] Univ Pittsburgh, Sch Med, Dept Emergency Med, Pittsburgh, PA 15261 USA. [Switzer, Galen E.] Univ Pittsburgh, Dept Psychiat, Sch Med, Pittsburgh, PA 15261 USA. [Saul, Melissa] Univ Pittsburgh, Dept Biomed Informat, Sch Med, Pittsburgh, PA 15261 USA. RP Mohan, D (reprint author), Univ Pittsburgh, CRISMA Lab, Room 637 Scaife Hall,3550 Terrace St, Pittsburgh, PA 15261 USA. EM mohand@upmc.edu RI Angus, Derek/E-9671-2012 FU NIGMS NIH HHS [1K23 GM101292-01, K23 GM101292] NR 38 TC 10 Z9 10 U1 0 U2 8 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 FEB PY 2014 VL 34 IS 2 BP 242 EP 252 PG 11 WC Health Care Sciences & Services; Medical Informatics SC Health Care Sciences & Services; Medical Informatics GA AI8QH UT WOS:000337185600011 PM 24125789 ER PT J AU Parker, MA Cheng, YF Kinouchi, H Bieber, R Edge, ASB AF Parker, Mark A. Cheng, Yen-fu Kinouchi, Hikaru Bieber, Rebecca Edge, Albert S. B. TI An Independent Construct for Conditional Expression of Atonal Homolog-1 SO HUMAN GENE THERAPY METHODS LA English DT Article ID DEVELOPING NERVOUS-SYSTEM; HAIR-CELLS; MAMMALIAN COCHLEA; INNER-EAR; IN-VIVO; ECTOPIC EXPRESSION; ESTROGEN-RECEPTOR; GENE-TRANSFER; MATH1; GENERATION AB The mammalian homolog of the basic helix-loop-helix transcription factor atonal-1 (Atoh1 or Math1) is required for development of cochlear hair cells that function as the mechanosensory cells required for audition. Forced expression of Atoh1 in cochlear-supporting cells may provide a way to regenerate hair cells and provide for a therapy for hearing loss. Additionally, Atoh1 is an inhibitor of proliferation and has further clinical applications in anticancer therapies. The goal of these experiments was to improve the method for Atoh1 expression by engineering a genetic construct that may be used in future translational applications. To address the poor control of Atoh1 expression in standard gene expression systems where Atoh1 is expressed constitutively at abnormally elevated levels, our aim was to engineer an inducible system whereby Atoh1 was upregulated by an inducer and downregulated once the inducer was removed. A further aim was to engineer a single genetic construct that allowed for conditional expression of Atoh1 independent of secondary regulatory elements. Here we describe a stand-alone genetic construct that utilizes the tamoxifen sensitivity of a mutated estrogen receptor (ER) ligand-binding domain for the conditional expression of Atoh1. The Atoh1-ER-DsRed construct is translated into an ATOH1-ER-DSRED fusion protein that remains sequestered in the cytoplasm and therefore rendered inactive because it cannot enter the nucleus to activate Atoh1 signaling pathways. However, application of 4-hydroxytamoxifen results in translocation of the fusion protein to the nucleus, where it binds to the Atoh1 enhancer, upregulates transcription and translation of endogenous ATOH1 and activates downstream Atoh1 signaling such as upregulation of the hair cell protein MYOSIN 7A. Removal of tamoxifen reverses the upregulation of endogenous Atoh1 signaling. This construct serves as an independent genetic construct that allows for the conditional upregulation and downregulation of Atoh1, and may prove useful for manipulating Atoh1 expression in vivo. C1 [Parker, Mark A.; Kinouchi, Hikaru; Bieber, Rebecca] Tufts Univ, Dept Otolaryngol Head & Neck Surg, Sch Med, Boston, MA 02111 USA. [Parker, Mark A.; Cheng, Yen-fu; Edge, Albert S. B.] Harvard Univ, Dept Otol & Laryngol, Sch Med, Boston, MA 02115 USA. [Parker, Mark A.; Cheng, Yen-fu; Edge, Albert S. B.] Harvard Univ, Program Speech & Hearing Biosci & Technol, Sch Med, Boston, MA 02115 USA. [Parker, Mark A.; Cheng, Yen-fu; Edge, Albert S. B.] Massachusetts Eye & Ear Infirm, Eaton Peabody Lab, Boston, MA 02114 USA. [Parker, Mark A.; Cheng, Yen-fu; Edge, Albert S. B.] Steward St Elizabeths Med Ctr, Boston, MA 02135 USA. RP Parker, MA (reprint author), St Elizabeths Med Ctr, Dept Otolaryngol Head & Neck Surg, 736 Cambridge St,SMC 8, Boston, MA 02135 USA. EM mark.parker@steward.org FU National Institute of Deafness and Other Communicative Disorders [R03DC010065, RO1DC007174, P30DC05209] FX The authors would like to thank their research team, including Kevin Jiang at the Massachusetts Eye and Ear Infirmary and Ashley Galetta, and Caitlin Simmons of Emerson College for their dedication. This work was supported by the National Institute of Deafness and Other Communicative Disorders (R03DC010065 [M.A.P.]; RO1DC007174 [A.E.]; P30DC05209 [Massachusetts Eye and Ear Infirmary Core Support for Hearing Research]). NR 25 TC 3 Z9 3 U1 0 U2 4 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1946-6536 EI 1946-6544 J9 HUM GENE THER METHOD JI Hum. Gene Ther. Methods PD FEB PY 2014 VL 25 IS 1 BP 1 EP 13 DI 10.1089/hgtb.2013.014 PG 13 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA AI5MN UT WOS:000336911600001 PM 24066662 ER PT J AU Chatterjee, P Joynt, KE AF Chatterjee, Paula Joynt, Karen E. TI Do Cardiology Quality Measures Actually Improve Patient Outcomes? SO JOURNAL OF THE AMERICAN HEART ASSOCIATION LA English DT Review DE cardiovascular outcomes; health policy and outcomes research; hospital performance; pay for performance; quality ID ACUTE MYOCARDIAL-INFARCTION; PERCUTANEOUS CORONARY INTERVENTION; PAY-FOR-PERFORMANCE; COOPERATIVE CARDIOVASCULAR PROJECT; 30-DAY READMISSION RATES; BYPASS GRAFT-SURGERY; HEALTH-CARE QUALITY; NEW-YORK-STATE; HOSPITAL QUALITY; HEART-FAILURE C1 [Chatterjee, Paula; Joynt, Karen E.] Harvard Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA 02115 USA. [Joynt, Karen E.] Brigham & Womens Hosp, Div Cardiovasc, Boston, MA 02115 USA. [Chatterjee, Paula; Joynt, Karen E.] Harvard Univ, Sch Med, Boston, MA USA. [Joynt, Karen E.] VA Boston Healthcare Syst, Serv Cardiol, Boston, MA USA. RP Joynt, KE (reprint author), 75 Francis St, Boston, MA 02115 USA. EM kjoynt@partners.org FU NIH from the National Heart, Lung, and Blood Institute [1K23HL109177-01] FX Dr Joynt was supported by NIH grant 1K23HL109177-01 from the National Heart, Lung, and Blood Institute. The funder 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 68 TC 16 Z9 16 U1 2 U2 12 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2047-9980 J9 J AM HEART ASSOC JI J. Am. Heart Assoc. PD FEB PY 2014 VL 3 IS 1 AR e000404 DI 10.1161/JAHA.113.000404 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AI3VZ UT WOS:000336794500007 PM 24510114 ER PT J AU Chen, C Feng, Y Zou, L Wang, L Chen, HH Cai, JY Xu, JM Sosnovik, DE Chao, W AF Chen, Chan Feng, Yan Zou, Lin Wang, Larry Chen, Howard H. Cai, Jia-Yan Xu, Jun-Mei Sosnovik, David E. Chao, Wei TI Role of Extracellular RNA and TLR3-Trif Signaling in Myocardial Ischemia-Reperfusion Injury SO JOURNAL OF THE AMERICAN HEART ASSOCIATION LA English DT Article DE apoptosis; inflammation; ischemia; myocardial infarction; reperfusion; RNA; TLR ID TOLL-LIKE RECEPTOR-3; MODULATES NEUTROPHIL FUNCTION; DOUBLE-STRANDED-RNA; NF-KAPPA-B; CIRCULATING MICRORNAS; INNATE IMMUNITY; IN-VIVO; CARDIOVASCULAR-DISEASES; WOUND INFLAMMATION; ENDOGENOUS LIGAND AB Background-Toll-like receptor 3 (TLR3) was originally identified as the receptor for viral RNA and represents a major host antiviral defense mechanism. TLR3 may also recognize extracellular RNA (exRNA) released from injured tissues under certain stress conditions. However, a role for exRNA and TLR3 in the pathogenesis of myocardial ischemic injury has not been tested. This study examined the role of exRNA and TLR3 signaling in myocardial infarction (MI), apoptosis, inflammation, and cardiac dysfunction during ischemia-reperfusion (I/R) injury. Methods and Results-Wild-type (WT), TLR3(-/-), Trif(-/-), and interferon (IFN) alpha/beta receptor-1 deficient (IFNAR1(-/-)) mice were subjected to 45 minutes of coronary artery occlusion and 24 hours of reperfusion. Compared with WT, TLR3(-/-) or Trif(-/-) mice had smaller MI and better preserved cardiac function. Surprisingly, unlike TLR(2/4)-MyD88 signaling, lack of TLR3-Trif signaling had no impact on myocardial cytokines or neutrophil recruitment after I/R, but myocardial apoptosis was significantly attenuated in Trif(-/-) mice. Deletion of the downstream IFNAR1 had no effect on infarct size. Importantly, hypoxia and I/R led to release of RNA including microRNA from injured cardiomyocytes and ischemic heart, respectively. Necrotic cardiomyocytes induced a robust and dose-dependent cytokine response in cultured cardiomyocytes, which was markedly reduced by RNase but not DNase, and partially blocked in TLR3-deficient cardiomyocytes. In vivo, RNase administration reduced serum RNA level, attenuated myocardial cytokine production, leukocytes infiltration and apoptosis, and conferred cardiac protection against I/R injury. Conclusion-TLR3-Trif signaling represents an injurious pathway during I/R. Extracellular RNA released during I/R may contribute to myocardial inflammation and infarction. C1 [Chen, Chan; Feng, Yan; Zou, Lin; Cai, Jia-Yan; Chao, Wei] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Anesthesia Crit Care & Pain Med, Boston, MA USA. [Chen, Howard H.; Sosnovik, David E.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Martinos Ctr Biomed Imaging,Dept Radiol, Boston, MA USA. [Chen, Chan; Xu, Jun-Mei] Cent S Univ, Xiangya Hosp 2, Dept Anesthesiol, Changsha, Hunan, Peoples R China. [Wang, Larry] Childrens Hosp Los Angeles, Dept Pathol & Lab Med, Los Angeles, CA 90027 USA. RP Chao, W (reprint author), Massachusetts Gen Hosp, Room 4-212,149 13th St, Charlestown, MA 02129 USA. EM wchao@mgh.harvard.edu FU National Institutes of Health [R01GM-080906, R01GM-097259]; International Anesthesia Research Society; Chinese Scholar Council FX This work was supported in part by the National Institutes of Health grants R01GM-080906 and R01GM-097259 (to Dr Chao) and a mentored research award from International Anesthesia Research Society (to Dr Zou). Dr Chen was supported by a scholarship from Chinese Scholar Council. NR 54 TC 32 Z9 32 U1 3 U2 21 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2047-9980 J9 J AM HEART ASSOC JI J. Am. Heart Assoc. PD FEB PY 2014 VL 3 IS 1 AR e000683 DI 10.1161/JAHA.113.000683 PG 23 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AI3VZ UT WOS:000336794500008 PM 24390148 ER PT J AU Francis, SA Cheng, S Arteaga, CL Moslehi, J AF Francis, Sanjeev A. Cheng, Susan Arteaga, Carlos L. Moslehi, Javid TI Heart Failure and Breast Cancer Therapies: Moving Towards Personalized Risk Assessment SO JOURNAL OF THE AMERICAN HEART ASSOCIATION LA English DT Editorial Material DE Editorials; breast cancer; cardio-oncology; cardiotoxicity; trastuzumab ID ADJUVANT CHEMOTHERAPY; PLUS TRASTUZUMAB; TRIAL; CARDIOTOXICITY; ANTHRACYCLINES C1 [Francis, Sanjeev A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiooncol Program, Boston, MA 02138 USA. [Cheng, Susan; Moslehi, Javid] Brigham & Womens Hosp, Div Cardiovasc, Boston, MA 02115 USA. [Arteaga, Carlos L.] Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Dept Med, Nashville, TN 37212 USA. [Arteaga, Carlos L.] Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Dept Canc Biol, Nashville, TN 37212 USA. [Arteaga, Carlos L.] Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Breast Canc Res Program, Nashville, TN 37212 USA. [Moslehi, Javid] Harvard Univ, Sch Med, Dana Farber Canc Inst, Cardiooncol Program, Boston, MA 02115 USA. RP Francis, SA (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiooncol Program, 55 Fruit St, Boston, MA 02138 USA. EM safrancis@partners.org NR 16 TC 11 Z9 11 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2047-9980 J9 J AM HEART ASSOC JI J. Am. Heart Assoc. PD FEB PY 2014 VL 3 IS 1 AR e000780 DI 10.1161/JAHA.113.000780 PG 4 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AI3VZ UT WOS:000336794500011 PM 24584746 ER PT J AU Gottlieb, DJ AF Gottlieb, Daniel J. TI Sleep Apnea and the Risk of Atrial Fibrillation Recurrence: Structural or Functional Effects? SO JOURNAL OF THE AMERICAN HEART ASSOCIATION LA English DT Editorial Material DE Editorials; atrial fibrillation; obstructive sleep apnea; cardiac magnetic resonance imaging ID POSITIVE AIRWAY PRESSURE; CATHETER ABLATION; ADULTS; IMPACT C1 [Gottlieb, Daniel J.] Brigham & Womens Hosp, VA Boston Healthcare Syst, Boston, MA 02115 USA. [Gottlieb, Daniel J.] Harvard Univ, Sch Med, Boston, MA USA. RP Gottlieb, DJ (reprint author), VA Boston Healthcare Syst 111PI, 1400 VFW Pkwy, West Roxbury, MA 02132 USA. EM djgottlieb@partners.org NR 14 TC 3 Z9 3 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2047-9980 J9 J AM HEART ASSOC JI J. Am. Heart Assoc. PD FEB PY 2014 VL 3 IS 1 AR e000654 DI 10.1161/JAHA.113.000654 PG 3 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AI3VZ UT WOS:000336794500013 PM 24390147 ER PT J AU Lindvall, C Hultman, TD Jackson, VA AF Lindvall, Charlotta Hultman, Todd D. Jackson, Vicki A. TI Overcoming the Barriers to Palliative Care Referral for Patients With Advanced Heart Failure SO JOURNAL OF THE AMERICAN HEART ASSOCIATION LA English DT Editorial Material DE Editorials; health-related quality of life; heart failure; palliative care ID QUALITY-OF-LIFE; CONSULTATION; CANCER C1 [Lindvall, Charlotta; Hultman, Todd D.; Jackson, Vicki A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Lindvall, Charlotta; Jackson, Vicki A.] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. RP Jackson, VA (reprint author), Massachusetts Gen Hosp, 55 Fruit St,Founders 600, Boston, MA 02114 USA. EM vjackson@partners.org NR 10 TC 5 Z9 5 U1 1 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2047-9980 J9 J AM HEART ASSOC JI J. Am. Heart Assoc. PD FEB PY 2014 VL 3 IS 1 AR e000742 DI 10.1161/JAHA.113.000742 PG 3 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AI3VZ UT WOS:000336794500032 PM 24584742 ER PT J AU Nohria, A Kinlay, S Buck, JS Redline, W Copeland-Halperin, R Kim, S Beckman, JA AF Nohria, Anju Kinlay, Scott Buck, J. Stewart Redline, Whitney Copeland-Halperin, Robert Kim, Sora Beckman, Joshua A. TI The Effect of Salsalate Therapy on Endothelial Function in a Broad Range of Subjects SO JOURNAL OF THE AMERICAN HEART ASSOCIATION LA English DT Article DE atherosclerosis; endothelium; glucose; inflammation; vasodilation ID FREE FATTY-ACID; NF-KAPPA-B; CORONARY-ARTERY-DISEASE; NITRIC-OXIDE PRODUCTION; C-REACTIVE PROTEIN; INSULIN-RESISTANCE; SODIUM-SALICYLATE; RANDOMIZED-TRIAL; IKK-BETA; CYCLOOXYGENASE-2 INHIBITION AB Background-Inflammation is fundamental to the development of atherosclerosis. We examined the effect of anti-inflammatory doses of salicylate on endothelium-dependent vasodilation, a biomarker of cardiovascular risk, in a broad range of subjects. Methods and Results-We performed a randomized, double-blind, placebo-controlled crossover trial evaluating the effects of 4 weeks of high-dose salsalate (disalicylate) therapy on endothelium-dependent flow-mediated and endothelium-independent vasodilation. Fifty-eight subjects, including 17 with metabolic syndrome, 13 with atherosclerosis, and 28 healthy controls, were studied. Among all subjects, endothelium-dependent flow-mediated vasodilation decreased after salsalate compared with placebo therapy (P=0.01), whereas nitroglycerin-mediated, endothelium-independent vasodilation was unchanged (P=0.97). Endothelium-dependent flow-mediated vasodilation after salsalate therapy was impaired compared with placebo therapy in subjects with therapeutic salicylate levels (n=31, P<0.02) but not in subjects with subtherapeutic levels (P>0.2). Conclusions-Salsalate therapy, particularly when therapeutic salicylate levels are achieved, impairs endothelium-dependent vasodilation in a broad range of subjects. These data raise concern about the possible deleterious effects of anti-inflammatory doses of salsalate on cardiovascular risk. C1 [Nohria, Anju; Kinlay, Scott; Buck, J. Stewart; Redline, Whitney; Copeland-Halperin, Robert; Kim, Sora; Beckman, Joshua A.] Brigham & Womens Hosp, Dept Internal Med, Boston, MA 02115 USA. [Nohria, Anju; Kinlay, Scott; Buck, J. Stewart; Redline, Whitney; Copeland-Halperin, Robert; Kim, Sora; Beckman, Joshua A.] Harvard Univ, Sch Med, Boston, MA USA. [Kinlay, Scott] VA Boston Healthcare Syst, Div Cardiovasc, West Roxbury, MA USA. RP Beckman, JA (reprint author), Brigham & Womens Hosp, Div Cardiovasc, 75 Francis St, Boston, MA 02115 USA. EM jbeckman@partners.org OI Beckman, Joshua/0000-0001-8332-8439 FU American Diabetes Association [ADA 1-06-CD-01]; Doris Duke Charitable Foundation FX This research was supported by the American Diabetes Association (ADA 1-06-CD-01). Dr Nohria was supported by a Clinical Scientist Development Award from the Doris Duke Charitable Foundation. NR 52 TC 8 Z9 8 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2047-9980 J9 J AM HEART ASSOC JI J. Am. Heart Assoc. PD FEB PY 2014 VL 3 IS 1 AR e000609 DI 10.1161/JAHA.113.000609 PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AI3VZ UT WOS:000336794500036 PM 24390146 ER PT J AU Li, J Zhu, S Kozono, D Ng, K Futalan, D Shen, Y Akers, JC Steed, T Kushwaha, D Schlabach, M Carter, BS Kwon, CH Furnari, F Cavenee, W Elledge, S Chen, CC AF Li, Jie Zhu, Shan Kozono, David Ng, Kimberly Futalan, Diahnn Shen, Ying Akers, Johnny C. Steed, Tyler Kushwaha, Deepa Schlabach, Michael Carter, Bob S. Kwon, Chang-Hyuk Furnari, Frank Cavenee, Webster Elledge, Stephen Chen, Clark C. TI Genome-wide shRNA screen revealed integrated mitogenic signaling between dopamine receptor D2 (DRD2) and epidermal growth factor receptor (EGFR) in glioblastoma SO ONCOTARGET LA English DT Article DE Glioblastoma; DRD2; EGFR; mitogenic signaling ID PROTEIN-COUPLED RECEPTORS; KINASE INHIBITORS; TUMOR-SUPPRESSOR; STEM-CELLS; GLIOMA; ACTIVATION; RESISTANCE; RNAI; PHOSPHORYLATION; THERAPY AB Glioblastoma remains one of the deadliest of human cancers, with most patients succumbing to the disease within two years of diagnosis. The available data suggest that simultaneous inactivation of critical nodes within the glioblastoma molecular circuitry will be required for meaningful clinical efficacy. We conducted parallel genome-wide shRNA screens to identify such nodes and uncovered a number of G-Protein Coupled Receptor (GPCR) neurotransmitter pathways, including the Dopamine Receptor D2 (DRD2) signaling pathway. Supporting the importance of DRD2 in glioblastoma, DRD2 mRNA and protein expression were elevated in clinical glioblastoma specimens relative to matched non-neoplastic cerebrum. Treatment with independent si-/shRNAs against DRD2 or with DRD2 antagonists suppressed the growth of patient-derived glioblastoma lines both in vitro and in vivo. Importantly, glioblastoma lines derived from independent genetically engineered mouse models (GEMMs) were more sensitive to haloperidol, an FDA approved DRD2 antagonist, than the premalignant astrocyte lines by approximately an order of magnitude. The pro-proliferative effect of DRD2 was, in part, mediated through a GNAI2/Rap1/Ras/ERK signaling axis. Combined inhibition of DRD2 and Epidermal Growth Factor Receptor (EGFR) led to synergistic tumoricidal activity as well as ERK suppression in independent in vivo and in vitro glioblastoma models. Our results suggest combined EGFR and DRD2 inhibition as a promising strategy for glioblastoma treatment. C1 [Li, Jie; Ng, Kimberly; Futalan, Diahnn; Shen, Ying; Akers, Johnny C.; Steed, Tyler; Carter, Bob S.; Chen, Clark C.] Univ Calif San Diego, Div Neurosurg, Ctr Translat & Appl Neurooncol, San Diego, CA 92103 USA. [Zhu, Shan; Kozono, David; Kushwaha, Deepa] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA USA. [Schlabach, Michael] Novartis Inst BioMed Res, Cambridge, MA USA. [Kwon, Chang-Hyuk] Ohio State Univ, Med Ctr, Dept Neurol Surg, Columbus, OH 43210 USA. [Kwon, Chang-Hyuk] Ohio State Univ, Med Ctr, Solid Tumor Program, Columbus, OH 43210 USA. [Furnari, Frank; Cavenee, Webster] Ludwig Inst Canc Res, La Jolla, CA USA. [Elledge, Stephen] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA. RP Chen, CC (reprint author), Univ Calif San Diego, Div Neurosurg, Ctr Translat & Appl Neurooncol, San Diego, CA 92103 USA. EM clarkchen@ucsd.edu RI Kwon, Chang-hyuk/E-3450-2011; Li, Jie/L-1737-2015 OI Li, Jie/0000-0002-0590-9817 FU NIGMS NIH HHS [T32 GM007198]; NINDS NIH HHS [R01 NS080939] NR 49 TC 18 Z9 19 U1 0 U2 5 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD FEB PY 2014 VL 5 IS 4 BP 882 EP 893 PG 12 WC Oncology; Cell Biology SC Oncology; Cell Biology GA AI6EA UT WOS:000336962300003 PM 24658464 ER PT J AU Lunardi, A Webster, KA Papa, A Padmani, B Clohessy, JG Bronson, RT Pandolfi, PP AF Lunardi, Andrea Webster, Kaitlyn A. Papa, Antonella Padmani, Bhavik Clohessy, John G. Bronson, Roderick T. Pandolfi, Pier Paolo TI Role of aberrant PI3K pathway activation in gallbladder tumorigenesis SO ONCOTARGET LA English DT Article DE PI3K; PTEN; gallbladder tumorigenesis; mouse model ID TUMOR SUPPRESSION; BILIARY-TRACT; PTEN; CANCER; MUTATIONS; CARCINOMAS; EXPRESSION AB The PI3K/AKT pathway governs a plethora of cellular processes, including cell growth, proliferation, and metabolism, in response to growth factors and cytokines. By acting as a unique lipid phosphatase converting phosphatidylinositol-3,4,5,-trisphosphate (PIP3) to phosphatidylinositol-4,5,-bisphosphate (PIP2), phosphatase and tensin homolog (PTEN) acts as the major cellular suppressor of PI3K signaling and AKT activation. Recently, PI3K mutations and loss/mutation of PTEN have been characterized in human gallbladder tumors; whether aberrant PTEN/PI3K pathway plays a causal role in gallbladder carcinogenesis, however, remains unknown. Herein we show that in mice, deregulation of PI3K/AKT signaling is sufficient to transform gallbladder epithelial cells and trigger fully penetrant, highly proliferative gallbladder tumors characterized by high levels of phospho-AKT. Histopathologically, these mouse tumors faithfully resemble human adenomatous gallbladder lesions. The identification of PI3K pathway deregulation as both an early event in the neoplastic transformation of the gallbladder epithelium and a main mechanism of tumor growth in Pten heterozygous and Pten mutant mouse models provides a new framework for studying in vivo the efficacy of target therapies directed against the PI3K pathway, as advanced metastatic tumors are often addicted to "trunkular" mutations. C1 [Lunardi, Andrea; Webster, Kaitlyn A.; Papa, Antonella; Pandolfi, Pier Paolo] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Canc Res Inst,Beth Israel Deaconess Canc Ctr,Dept, Boston, MA 02215 USA. [Padmani, Bhavik; Clohessy, John G.] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Preclin Murine Pharmacogenet Facil, Boston, MA 02215 USA. [Bronson, Roderick T.] Dana Farber Harvard Comprehens Canc Ctr, Boston, MA USA. RP Pandolfi, PP (reprint author), Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Canc Res Inst,Beth Israel Deaconess Canc Ctr,Dept, Boston, MA 02215 USA. EM ppandolf@bidmc.harvard.edu OI Papa, Antonella/0000-0001-8653-7121 FU Istituto Toscano Tumori (ITT, Italy); NIH [R01 CA082328] FX AL has been supported in part by a fellowship from the Istituto Toscano Tumori (ITT, Italy). This work was supported by the NIH grant R01 CA082328 to P.P.P. NR 29 TC 12 Z9 13 U1 0 U2 2 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD FEB PY 2014 VL 5 IS 4 BP 894 EP 900 PG 7 WC Oncology; Cell Biology SC Oncology; Cell Biology GA AI6EA UT WOS:000336962300004 PM 24658595 ER PT J AU Cheng, G Alavi, A Werner, TJ Del Bello, CV Akers, SR AF Cheng, Gang Alavi, Abass Werner, Thomas J. Del Bello, Catherine V. Akers, Scott R. TI Serial Changes of FDG Uptake and Diagnosis of Suspected Lung Malignancy A Lesion-Based Analysis SO CLINICAL NUCLEAR MEDICINE LA English DT Article DE FDG PET; delayed imaging; lung cancer; diagnosis ID DUAL-TIME-POINT; POSITRON-EMISSION-TOMOGRAPHY; TUBERCULOSIS-ENDEMIC COUNTRY; SOLITARY PULMONARY NODULES; PHASE F-18-FDG PET; LYMPH-NODES; CANCER; BENIGN; DIFFERENTIATION; IMPACT AB Objective: This study prospectively evaluates the serial change of FDG uptake and its diagnostic value in malignant versus benign lung lesions in patients with suspected lung cancer. Patients and Methods: Patients with suspected lung malignancy underwent whole-body FDG PET/CT at 1, 2, and 3 hours after an IV injection of F-18-FDG. The SUVs of FDG in lung nodules and hilar/mediastinal nodes at each time point were correlated with biopsy/surgical pathologic findings. Results: There were a total of 45 malignant lesions and 80 benign lesions from 43 patients with pathologic diagnosis that were included for analysis. The SUVmax had an average of 25.5% increase in all tumor-positive lesions from 1 to 2 hours (vs 1.6% decrease in all tumor-negative lesions, P < 0.0001) and an average of 39.1% increase from 1 to 3 hours (vs 4.5% increase in all tumor-negative lesions, P G 0.0001). The receiver operating characteristic analysis showed that the 2-hour and 3-hour SUVmax had similar area under the curve and outperformed the SUVmax on the 1-hour initial imaging or retention index (RI). The optimal cutoff values to differentiate malignancy from benign lesions were 3.24 for 1-hour SUVmax, 3.67 for 2-hour SUVmax, and 4.21 for 3-hour SUVmax, with 11.6% for 1- to 2-hour RI and 23.9% for 1-to 3-hour RI. The 3-hour delayed SUVmax of 4.21 provided the best overall performance (accuracy of 88.8%). The analysis of the lesion-to-background ratio revealed that delayed imaging improved the image quality significantly, leading to much easier detection of either malignant or benign lesions. Conclusions: Multiple time point FDG PET/CT imaging moderately improves the diagnostic accuracy of lung cancer and significantly improves the image quality. C1 [Cheng, Gang; Del Bello, Catherine V.; Akers, Scott R.] Philadelphia VA Med Ctr, Dept Radiol, Philadelphia, PA 19104 USA. [Cheng, Gang; Alavi, Abass; Werner, Thomas J.] Hosp Univ Penn, Dept Radiol, Philadelphia, PA 19104 USA. RP Akers, SR (reprint author), Philadelphia VA Med Ctr, Dept Radiol, 3900 Woodland Ave, Philadelphia, PA 19104 USA. EM gangcheng99@yahoo.com; akerssco@me.com FU Department of Veterans Affairs FX Supported in part by a pilot grant from the Department of Veterans Affairs (VISN 4 CPPF grant). NR 28 TC 5 Z9 5 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0363-9762 EI 1536-0229 J9 CLIN NUCL MED JI Clin. Nucl. Med. PD FEB PY 2014 VL 39 IS 2 BP 147 EP 155 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AI3DB UT WOS:000336738100022 PM 24368534 ER PT J AU Cheng, G Morley, JF AF Cheng, Gang Morley, James F. TI Complete and Readily Reversible Blocking of Striatal DaTscan Binding by Methylphenidate SO CLINICAL NUCLEAR MEDICINE LA English DT Editorial Material DE DaTscan; I-123 ioflupane; SPECT; methylphenidate; parkinsonian syndrome; striatum; blocking effect ID DOPAMINE TRANSPORTERS; SPECT; ABSTINENCE C1 [Cheng, Gang] Philadelphia VA Med Ctr, Dept Radiol, Philadelphia, PA 19104 USA. [Morley, James F.] Philadelphia VA Med Ctr, Parkinsons Dis Res Educ & Clin Ctr, Philadelphia, PA 19104 USA. [Morley, James F.] Univ Penn, Dept Neurol, Perelman Sch Med, Philadelphia, PA 19104 USA. RP Cheng, G (reprint author), Philadelphia VA Med Ctr, Dept Radiol, 3900 Woodland Ave, Philadelphia, PA 19104 USA. EM gangcheng99@yahoo.com NR 11 TC 2 Z9 2 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0363-9762 EI 1536-0229 J9 CLIN NUCL MED JI Clin. Nucl. Med. PD FEB PY 2014 VL 39 IS 2 BP 211 EP 213 PG 3 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AI3DB UT WOS:000336738100041 PM 24300364 ER PT J AU Pajic, M Mangharam, R Sokolsky, O Arney, D Goldman, J Lee, I AF Pajic, Miroslav Mangharam, Rahul Sokolsky, Oleg Arney, David Goldman, Julian Lee, Insup TI Model-Driven Safety Analysis of Closed-Loop Medical Systems SO IEEE TRANSACTIONS ON INDUSTRIAL INFORMATICS LA English DT Article DE Closed-loop medical systems; high-confidence medical systems; model-based development; safety analysis ID FORMAL METHODS; VERIFICATION AB In modern hospitals, patients are treated using a wide array of medical devices that are increasingly interacting with each other over the network, thus offering a perfect example of a cyber-physical system. We study the safety of a medical device system for the physiologic closed-loop control of drug infusion. The main contribution of the paper is the verification approach for the safety properties of closed-loop medical device systems. We demonstrate, using a case study, that the approach can be applied to a system of clinical importance. Our method combines simulation-based analysis of a detailed model of the system that contains continuous patient dynamics with model checking of a more abstract timed automata model. We show that the relationship between the two models preserves the crucial aspect of the timing behavior that ensures the conservativeness of the safety analysis. We also describe system design that can provide open-loop safety under network failure. C1 [Pajic, Miroslav; Mangharam, Rahul] Univ Penn, Dept Elect & Syst Engn, Philadelphia, PA 19104 USA. [Sokolsky, Oleg; Arney, David; Lee, Insup] Univ Penn, Dept Comp & Informat Sci, Philadelphia, PA 19104 USA. [Goldman, Julian] Massachusetts Gen Hosp, Boston, MA 02139 USA. [Goldman, Julian] CIMIT, Boston, MA 02139 USA. RP Pajic, M (reprint author), Univ Penn, Dept Elect & Syst Engn, Philadelphia, PA 19104 USA. EM pajic@seas.upenn.edu; rahulm@seas.upenn.edu; sokolsky@seas.upenn.edu; arney@seas.upenn.edu; jmgoldman@partners.org; lee@seas.upenn.edu FU National Science Foundation [CNS-0834524, CNS-0930647] FX Research has been supported in part by the National Science Foundation grants CNS-0834524 and CNS-0930647. Some initial results from this work were presented in [1]. Paper no. TII-10-10-0275. NR 28 TC 16 Z9 16 U1 4 U2 16 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 1551-3203 EI 1941-0050 J9 IEEE T IND INFORM JI IEEE Trans. Ind. Inform. PD FEB PY 2014 VL 10 IS 1 BP 3 EP 16 DI 10.1109/TII.2012.2226594 PG 14 WC Automation & Control Systems; Computer Science, Interdisciplinary Applications; Engineering, Industrial SC Automation & Control Systems; Computer Science; Engineering GA AI2DW UT WOS:000336668600001 ER PT J AU Cummings, DE Cohen, RV AF Cummings, David E. Cohen, Ricardo V. TI Beyond BMI: the need for new guidelines governing the use of bariatric and metabolic surgery SO LANCET DIABETES & ENDOCRINOLOGY LA English DT Article ID TYPE-2 DIABETES-MELLITUS; SWEDISH OBESE SUBJECTS; VERTICAL BANDED GASTROPLASTY; GASTRIC BYPASS-SURGERY; LAPAROSCOPIC SLEEVE GASTRECTOMY; RANDOMIZED-CONTROLLED-TRIAL; CARDIOVASCULAR RISK-FACTORS; LIFE-STYLE INTERVENTION; LONG-TERM MORTALITY; BODY-MASS INDEX AB Bariatric surgery use is largely governed worldwide by a 1991 National Institutes of Health consensus statement that advocates BMI as the primary operative criterion and restricts surgery to severely obese patients. These guidelines have been enormously valuable in standardising practice, thereby facilitating accumulation of a copious database of information regarding long-term surgical benefits and risks, from vast clinical experience and research. However, the National Institutes of Health recommendations had important limitations from the outset and are now gravely outdated. They do not account for remarkable advances in minimally invasive surgical techniques or the development of entirely new procedures. In the two decades since they were crafted, we have gained far greater understanding of the dramatic, weight-independent benefits of some operations on metabolic diseases, especially type 2 diabetes, and of the inadequacy of BMI as a primary criterion for surgical selection. Furthermore, there is now a substantial and rapidly burgeoning body of level-1 evidence from randomised trials comparing surgical versus non-surgical approaches to obesity, type 2 diabetes, and other metabolic diseases, including among only mildly obese or merely overweight patients. Herein, we present arguments to impel the development of new guidelines for the use of bariatric and so-called metabolic surgery to inform clinical practice and insurance compensation. C1 [Cummings, David E.] Univ Washington, Sch Med, Diabet & Obes Ctr Excellence, Seattle, WA 98195 USA. [Cummings, David E.] Univ Washington, Sch Med, Vet Affairs Puget Sound Hlth Care Syst, Seattle, WA 98195 USA. [Cohen, Ricardo V.] Oswaldo Cruz Hosp, Ctr Excellence Bariatr & Metab Surg, Sao Paulo, Brazil. RP Cummings, DE (reprint author), Univ Washington, Diabet & Obes Ctr Excellence, Box 358280 Mail Stop 111, Seattle, WA 98195 USA. EM davidec@u.washington.edu FU Johnson Johnson; Johnson & Johnson Medical Brasil; Oswaldo Cruz Hospital; NIH [RO1 DK517498, RO1 DK61516, RO1 DK089528, UO1 DK66568, P30 DK17047] FX DEC is a principal investigator on the COSMID trial, which is funded by Johnson & Johnson. RVC is a principal investigator for the MOMS trial, which is funded by Johnson & Johnson Medical Brasil and Oswaldo Cruz Hospital. DEC is supported by NIH grants RO1 DK517498, RO1 DK61516, RO1 DK089528, UO1 DK66568, and P30 DK17047. NR 76 TC 26 Z9 30 U1 1 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 2213-8587 J9 LANCET DIABETES ENDO JI Lancet Diabetes Endocrinol. PD FEB PY 2014 VL 2 IS 2 BP 175 EP 181 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AI2XQ UT WOS:000336722900025 PM 24622721 ER PT J AU Tessler, O Reish, RG Maman, DY Smith, BL Austen, WG AF Tessler, Oren Reish, Richard G. Maman, Daniel Y. Smith, Barbara L. Austen, William G., Jr. TI Beyond Biologics: Absorbable Mesh as a Low-Cost, Low-Complication Sling for Implant-Based Breast Reconstruction SO PLASTIC AND RECONSTRUCTIVE SURGERY LA English DT Article ID ACELLULAR DERMAL MATRIX; SKIN-SPARING MASTECTOMY; CAPSULE FORMATION; IMMEDIATE RECONSTRUCTION; SUBCUTANEOUS MASTECTOMY; ALLODERM; NIPPLE; SURGERY; CORE; CONSERVATION AB Background: There is an intense push to decrease overall healthcare costs in the United States. Although the use of acellular dermal matrix in implant-based reconstruction has grown significantly over the past decade, potential drawbacks remain a source of debate. Matrices are costly and not universally available across institutions, whereas Vicryl mesh is widely available, relatively inexpensive, and resistant to bacteria biofilm formation. With the intent of maximizing the reconstructive and economic advantages of direct-to-implant breast reconstruction, the authors report the first experience in the literature using an absorbable mesh as an inferolateral sling. Methods: A retrospective review was performed of the first 50 consecutive patients (76 reconstructions) who underwent implant-based breast reconstruction with Vicryl mesh from August of 2011 until June of 2012. Results: Fifty patients underwent 76 direct-to-implant reconstructions with Vicryl mesh between August of 2011 and June of 2012 (mean follow-up, 1.2 years). Five breasts (6.6 percent) had complications, with only one complication resulting in implant loss (1.3 percent). Implant positioning and contour were excellent, with only two patients [three breasts (3.9 percent)] undergoing revision procedures, for size enlargement. Using costs available at the authors' institution, use of Vicryl mesh instead of acellular dermal matrix resulted in a direct material cost savings of $172,112 in 10 months. Conclusions: Results to date have been encouraging, with a low complication rate (6.6 percent) and excellent aesthetic results. The technique has resulted in $172,112 in direct material cost savings over 10 months. Continued follow-up is planned to evaluate long-term results. C1 [Tessler, Oren; Reish, Richard G.; Maman, Daniel Y.; Smith, Barbara L.; Austen, William G., Jr.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Plast Surg, Boston, MA USA. RP Austen, WG (reprint author), Massachusetts Gen Hosp, Div Plast Surg, Boston, MA 02114 USA. EM wausten@partners.org NR 47 TC 14 Z9 14 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0032-1052 EI 1529-4242 J9 PLAST RECONSTR SURG JI Plast. Reconstr. Surg. PD FEB PY 2014 VL 133 IS 2 BP 90E EP 99E DI 10.1097/01.prs.0000437253.55457.63 PG 10 WC Surgery SC Surgery GA AI0AB UT WOS:000336507000001 PM 24469217 ER PT J AU Lee, JH McCormack, MC Austen, WG AF Lee, Jeffrey H. McCormack, Michael C. Austen, William Gerald, Jr. TI Reply: The Effect of Pressure and Shear on Autologous Fat Grafting SO PLASTIC AND RECONSTRUCTIVE SURGERY LA English DT Letter C1 [Lee, Jeffrey H.; McCormack, Michael C.; Austen, William Gerald, Jr.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Austen, WG (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 4 TC 2 Z9 2 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0032-1052 EI 1529-4242 J9 PLAST RECONSTR SURG JI Plast. Reconstr. Surg. PD FEB PY 2014 VL 133 IS 2 BP 223E EP 224E DI 10.1097/01.prs.0000437250.70704.04 PG 2 WC Surgery SC Surgery GA AI0AB UT WOS:000336507000021 PM 24469198 ER PT J AU Ferrone, CR AF Ferrone, Cristina R. TI Lymphadenectomy for Pancreatic Neuroendocrine Tumors: Is That the Relevant Debate? SO ANNALS OF SURGERY LA English DT Editorial Material ID ENDOCRINE TUMORS; SURVIVAL; RESECTION; OUTCOMES C1 Massachusetts Gen Hosp, Div Gen Surg, Boston, MA 02114 USA. RP Ferrone, CR (reprint author), Massachusetts Gen Hosp, Div Gen Surg, 15 Parkman St,WANG 460, Boston, MA 02114 USA. EM cferrone@partners.org NR 16 TC 5 Z9 7 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-4932 EI 1528-1140 J9 ANN SURG JI Ann. Surg. PD FEB PY 2014 VL 259 IS 2 BP 213 EP 214 DI 10.1097/SLA.0000000000000533 PG 2 WC Surgery SC Surgery GA AH6NM UT WOS:000336247600023 PM 24398923 ER PT J AU Heneghan, AF Pierre, JF Gosain, A Kudsk, KA AF Heneghan, Aaron F. Pierre, Joseph F. Gosain, Ankush Kudsk, Kenneth A. TI IL-25 Improves Luminal Innate Immunity and Barrier Function During Parenteral Nutrition SO ANNALS OF SURGERY LA English DT Article DE innate immunity; parenteral nutrition; Paneth cells; goblet cells; secretory phospholipase A(2); small intestine ID UPPER RESPIRATORY-TRACT; MAJOR ABDOMINAL-TRAUMA; IIA PHOSPHOLIPASE A(2); LYMPHOID-TISSUE; MUCOSAL IMMUNITY; STAPHYLOCOCCUS-AUREUS; INFLAMMATORY FLUID; SEPTIC MORBIDITY; MESSENGER-RNA; CELL-WALL AB Background: Parenteral nutrition (PN) increases risks of infections in critically injured patients. Recently, PN was shown to reduce intestine luminal levels of the Paneth cell antimicrobial molecule secretory phospholipase A(2) (sPLA(2)) and the goblet cell glycoprotein mucin2 (MUC2). These molecules are critical factors for innate mucosal immunity and provide barrier protection. Interleukin-4 (IL-4) and IL-13 regulate sPLA(2) and MUC2 production through the IL-13 receptor. Because IL-25 stimulates IL-4 and IL-13 release and PN reduces luminal sPLA(2) and MUC2, we hypothesized that adding IL-25 to PN would restore these innate immune factors and maintain barrier function. Methods: Two days after venous cannulation, male ICR (Institute of Cancer Research) mice were randomized to receive chow (n = 12), PN (n = 9), or PN + 0.7 g of exogenous IL-25 (n = 11) daily for 5 days. Small-intestine wash fluid (SIWF) was collected for analysis of sPLA(2) activity, MUC2 density, and luminal levels of IL-4 and IL-13. Small-intestinal tissue was harvested for analysis of tissue sPLA(2) activity or immediate use in an ex-vivo intestinal segment culture (EVISC) to assess susceptibility of the tissue segments to enteroinvasive Escherichia coli. Results: PN reduced luminal sPLA(2) (P < 0.0001) and MUC2 (P <0.002) compared with chow, whereas the addition of IL-25 to PN increased luminal sPLA(2) (P < 0.0001) and MUC2 (P < 0.02) compared with PN. Tissue IL-4 and IL-13 decreased with PN compared with chow (IL-4: P < 0.0001, IL-13: P < 0.002), whereas IL-25 increased both cytokines compared with PN (IL-4: P < 0.03, IL-13: P < 0.02). Tissue levels of sPLA(2) were significantly decreased with PN compared with chow, whereas IL-25 significantly increased tissue sPLA(2) levels compared with PN alone. Functionally, more bacteria invaded the PN-treated tissue compared with chow (P < 0.01), and the addition of IL-25 to PN decreased enteroinvasion to chow levels (P < 0.01). Conclusions: PN impairs innate mucosal immunity by suppressing luminal sPLA(2) activity and MUC2 density compared with chow. PN also increases bacterial invasion in ex-vivo tissue. Administration of exogenous IL-25 reverses this dysfunction and increases luminal sPLA(2) and MUC2. PN tissue treated with IL-25 was significantly more resistant to bacterial invasion than with PN alone, suggesting that IL-25-induced effects augment the barrier defense mechanisms. C1 [Heneghan, Aaron F.; Pierre, Joseph F.; Gosain, Ankush; Kudsk, Kenneth A.] Univ Wisconsin, Dept Surg, Sch Med & Publ Hlth, Madison, WI USA. [Kudsk, Kenneth A.] William S Middleton Mem Vet Adm Med Ctr, Vet Adm Surg Serv, Madison, WI USA. RP Kudsk, KA (reprint author), 600 Highland Ave H4-736, Madison, WI 53792 USA. EM kudsk@surgery.wisc.edu OI Gosain, Ankush/0000-0002-0428-1503 FU National Institutes of Health (NIH) [R01 GM 53439]; Biomedical Laboratory Research & Development Service of the VA Office of Research and Development, Washington, DC [I01BX001672] FX Supported by the National Institutes of Health (NIH) grant R01 GM 53439 and Award number I01BX001672 from the Biomedical Laboratory Research & Development Service of the VA Office of Research and Development, Washington, DC. NR 54 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 0003-4932 EI 1528-1140 J9 ANN SURG JI Ann. Surg. PD FEB PY 2014 VL 259 IS 2 BP 394 EP 400 DI 10.1097/SLA.0b013e318284f510 PG 7 WC Surgery SC Surgery GA AH6NM UT WOS:000336247600049 PM 23426341 ER PT J AU Shahian, DM AF Shahian, David M. TI Reply to Letter: "Surgical Statistics: Let's Act Fast and Grasp the Opportunity" SO ANNALS OF SURGERY LA English DT Letter ID BYPASS-GRAFTING SURGERY; ADULT CARDIAC-SURGERY; QUALITY MEASUREMENT; SOCIETY C1 [Shahian, David M.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Surg, Boston, MA 02163 USA. [Shahian, David M.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Qual & Safety, Boston, MA USA. RP Shahian, DM (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Surg, Boston, MA 02163 USA. NR 12 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-4932 EI 1528-1140 J9 ANN SURG JI Ann. Surg. PD FEB PY 2014 VL 259 IS 2 BP E14 EP E15 DI 10.1097/SLA.0000000000000282 PG 2 WC Surgery SC Surgery GA AH6NM UT WOS:000336247600002 PM 24169171 ER PT J AU Villar, J Sulemanji, D Kacmarek, RM AF Villar, Jesus Sulemanji, Demet Kacmarek, Robert M. TI The acute respiratory distress syndrome: incidence and mortality, has it changed? SO CURRENT OPINION IN CRITICAL CARE LA English DT Review DE acute lung injury; acute respiratory distress syndrome; incidence; mortality; outcome ID ACUTE LUNG INJURY; RANDOMIZED CONTROLLED-TRIAL; PEDIATRIC INTENSIVE-CARE; LOWER TIDAL VOLUMES; CIRCULATING HISTONES; VENTILATION; PRESSURE; ARDS; METAANALYSIS; MULTICENTER AB Purpose of reviewThe purpose of this review is to examine and discuss the incidence and outcome of patients with the acute respiratory distress syndrome (ARDS). This is a challenging task, as there is no specific clinical sign or diagnostic test that accurately identifies and adequately defines this syndrome.Recent findingsThis review will focus on published epidemiological studies reporting population-based incidence of ARDS, as defined by the American-European Consensus Conference criteria. In addition, the current outcome figures for ARDS patients reported in observational and randomized controlled trials will be reviewed. The focus will be on studies published since 2000, when the ARDSnet study on protective mechanical ventilation was published, although particular emphasis will be on those articles published in the last 24 months.SummaryOn the basis of current evidence, and despite the order of magnitude of reported European and USA incidence figures, it seems that the incidence and overall mortality of ARDS has not changed substantially since the original ARDSnet study. The current mortality of adult ARDS is still greater than 40%. C1 [Villar, Jesus] Inst Salud Carlos III, CIBER Enfermedades Resp, Madrid, Spain. [Villar, Jesus] Hosp Univ Dr Negrin, Res Unit, Las Palmas Gran Canaria, Spain. [Villar, Jesus] St Michaels Hosp, Li Ka Shing Knowledge Inst, Keenan Res Ctr, Toronto, ON M5B 1W8, Canada. [Sulemanji, Demet; Kacmarek, Robert M.] Massachusetts Gen Hosp, Dept Resp Care, Boston, MA 02114 USA. [Sulemanji, Demet; Kacmarek, Robert M.] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. [Sulemanji, Demet; Kacmarek, Robert M.] Harvard Univ, Sch Med, Boston, MA USA. RP Kacmarek, RM (reprint author), Massachusetts Gen Hosp, Dept Resp Care, 55 Fruit St,Warren 1225, Boston, MA 02114 USA. EM rkacmarek@partners.org FU Instituto de Salud Carlos III, Spain [10/0393, CB06/06/1088] FX This study is supported in part by Instituto de Salud Carlos III, Spain (#10/0393 and CB06/06/1088). NR 38 TC 44 Z9 64 U1 4 U2 13 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1070-5295 EI 1531-7072 J9 CURR OPIN CRIT CARE JI Curr. Opin. Crit. Care PD FEB PY 2014 VL 20 IS 1 BP 3 EP 9 DI 10.1097/MCC.0000000000000057 PG 7 WC Critical Care Medicine SC General & Internal Medicine GA AF7UP UT WOS:000334920600002 PM 24309954 ER PT J AU Richardson, PG Blade, J AF Richardson, Paul G. Blade, Joan TI The comprehensive clinical management of multiple myeloma and related-plasma cell disorders SO EXPERT REVIEW OF HEMATOLOGY LA English DT Editorial Material DE amyloidosis; clinical management; myeloma; new directions; novel therapies; Waldenstrom's macroglobulinemia AB Whilst we think of multiple myeloma and related plasma cell disorders as incurable to date, never before has there been such hope and enthusiasm about advances in the research and treatment of these various diseases. Translational research is very much at the forefront of progress for further refining targeted therapies and continuing to improve clinical efficacy. Whilst some of these advances in the last decade have been truly dramatic in their scope and timing, it is also worth noting that relatively incremental changes have favorably impacted on patient outcome, and this comprehensive clinical management review captures these accordingly. We hope therefore that this concise overview will give readers, be they specialist hemato-oncologists, or other providers and researchers in the field, an enlightening insight into the exciting future of therapeutic opportunities, as well as a practical hands on' approach. C1 [Richardson, Paul G.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol,Jerome Lipper Multiple Myeloma Ctr, Boston, MA 02115 USA. [Blade, Joan] Hosp Clin Barcelona, Dept Hematol, Amyloidosis & Myeloma Unit, Barcelona, Spain. [Blade, Joan] IDIBAPS, Barcelona, Spain. [Blade, Joan] Univ Barcelona, Barcelona, Spain. RP Richardson, PG (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol,Jerome Lipper Multiple Myeloma Ctr, 44 Binney St, Boston, MA 02115 USA. EM Paul_Richardson@dfci.harvard.edu NR 16 TC 3 Z9 3 U1 0 U2 0 PU EXPERT REVIEWS PI LONDON PA UNITEC HOUSE, 3RD FL, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON N3 1QB, ENGLAND SN 1747-4086 EI 1747-4094 J9 EXPERT REV HEMATOL JI Expert Rev. Hematol. PD FEB PY 2014 VL 7 IS 1 BP 1 EP 3 DI 10.1586/17474086.2014.882763 PG 3 WC Hematology SC Hematology GA AG8CQ UT WOS:000335646800001 PM 24483345 ER PT J AU Rosenblatt, J Bar-Natan, M Munshi, NC Avigan, DE AF Rosenblatt, Jacalyn Bar-Natan, Michal Munshi, Nikhil C. Avigan, David E. TI Immunotherapy for multiple myeloma SO EXPERT REVIEW OF HEMATOLOGY LA English DT Review DE cellular immunotherapy; dendritic cell vaccines; NK cells ID CYTOTOXIC T-LYMPHOCYTES; STEM-CELL TRANSPLANTATION; NATURAL-KILLER-CELLS; WT1 PEPTIDE VACCINATION; PULSED DENDRITIC CELLS; IDIOTYPE VACCINATION; PERIPHERAL-BLOOD; IMMUNE-RESPONSES; BONE-MARROW; THERAPEUTIC ANTIBODY AB The potential potency of the immune system in targeting malignant plasma cells in multiple myeloma is best demonstrated in the allogeneic transplant setting, where durable responses can be achieved. However, allogeneic transplantation is associated with significant morbidity and mortality related to graft versus host disease, due to the non-specific nature of allo-reactive T cell responses mediated by donor lymphocytes. Immunotherapeutic approaches that more specifically target the malignant plasma cells have the potential to improve outcomes in multiple myeloma. The development of clinically efficacious immunotherapy in multiple myeloma is dependent on achieving a greater understanding of the complex interactions between the immunologic milieu and the growth of the malignant plasma cell clone. A number of antigens have been identified on malignant plasma cells that may be targeted by both humoral and cell mediated immunotherapeutic strategies. Encouraging results have been demonstrated both pre-clinically and in clinical trials. In this review, we summarize the clinical data evaluating immunotherapeutic approaches for the treatment of multiple myeloma. C1 [Rosenblatt, Jacalyn; Bar-Natan, Michal] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Boston, MA 02215 USA. [Munshi, Nikhil C.] Dana Farber Canc Inst, Boston, MA 02215 USA. [Munshi, Nikhil C.] VA Boston Healthcare Syst, Boston, MA 02215 USA. RP Rosenblatt, J (reprint author), Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, 330 Brookline Ave, Boston, MA 02215 USA. EM jrosenb1@bidmc.harvard.edu NR 80 TC 5 Z9 6 U1 1 U2 15 PU EXPERT REVIEWS PI LONDON PA UNITEC HOUSE, 3RD FL, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON N3 1QB, ENGLAND SN 1747-4086 EI 1747-4094 J9 EXPERT REV HEMATOL JI Expert Rev. Hematol. PD FEB PY 2014 VL 7 IS 1 BP 91 EP 96 DI 10.1586/17474086.2014.878226 PG 6 WC Hematology SC Hematology GA AG8CQ UT WOS:000335646800012 PM 24417573 ER PT J AU Laubach, JP Voorhees, PM Hassoun, H Jakubowiak, A Lonial, S Richardson, PG AF Laubach, Jacob P. Voorhees, Peter M. Hassoun, Hani Jakubowiak, Andrzej Lonial, Sagar Richardson, Paul G. TI Current strategies for treatment of relapsed/refractory multiple myeloma SO EXPERT REVIEW OF HEMATOLOGY LA English DT Review DE autologous stem cell transplantation; bortezomib; carfilzomib; clonal evolution; elotuzumab; lenalidomide; multiple myeloma; pomalidomide ID STEM-CELL TRANSPLANTATION; LOW-DOSE DEXAMETHASONE; IMPAIRED RENAL-FUNCTION; LENALIDOMIDE PLUS DEXAMETHASONE; PROTEASOME INHIBITOR BORTEZOMIB; RANDOMIZED PHASE-III; PEGYLATED LIPOSOMAL DOXORUBICIN; HIGH-RISK PATIENTS; PERIPHERAL NEUROPATHY; COMBINATION THERAPY AB In spite of significant advances in the management of multiple myeloma (MM), the disease remains incurable and nearly all patients ultimately relapse and require salvage chemotherapy. As such, relapsed and relapsed-refractory MM remains a critical area of research pertaining to biological mechanisms of progression and chemotherapy resistance, as well as to the development of new pharmacologic agents and immunologic approaches for the disease. The immunomodulatory agents and proteasome inhibitors represent the cornerstone of treatment in this setting, with combination regimens incorporating these drugs demonstrating encouraging rates and duration of response, including the newer agents, pomalidomide and carfilzomib. In addition, novel drug classes have shown promising activity in RR MM, including the orally-administered proteasome inhibitors ixazomib and oprozomib; monoclonal antibodies such as the anti-CS1 monoclonal antibody elotuzumab and anti-CD38 monoclonal antibody daratumumab; and histone deacetylase inhibitors such as panobinostat and rocilinostat. C1 [Laubach, Jacob P.; Richardson, Paul G.] Dana Farber Canc Inst, Jerome Lipper Multiple Myeloma Ctr, Dept Med Oncol, Boston, MA 02115 USA. [Voorhees, Peter M.] Univ N Carolina, Lineberger Comprehens Canc Ctr, Div Hematol Oncol, Chapel Hill, NC 27599 USA. [Hassoun, Hani] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10021 USA. [Jakubowiak, Andrzej] Univ Chicago, Dept Med, Chicago, IL 60637 USA. [Jakubowiak, Andrzej] Univ Chicago, Ctr Comprehens Canc, Chicago, IL 60637 USA. [Lonial, Sagar] Emory Univ, Sch Med, Dept Hematol & Med Oncol, Atlanta, GA USA. RP Laubach, JP (reprint author), Dana Farber Canc Inst, Jerome Lipper Multiple Myeloma Ctr, Dept Med Oncol, Boston, MA 02115 USA. EM Jacobp_laubach@dfci.harvard.edu NR 128 TC 30 Z9 32 U1 1 U2 12 PU EXPERT REVIEWS PI LONDON PA UNITEC HOUSE, 3RD FL, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON N3 1QB, ENGLAND SN 1747-4086 EI 1747-4094 J9 EXPERT REV HEMATOL JI Expert Rev. Hematol. PD FEB PY 2014 VL 7 IS 1 BP 97 EP 111 DI 10.1586/17474086.2014.882764 PG 15 WC Hematology SC Hematology GA AG8CQ UT WOS:000335646800013 PM 24471924 ER PT J AU Terpos, E Berenson, J Raje, N Roodman, GD AF Terpos, Evangelos Berenson, James Raje, Noopur Roodman, G. David TI Management of bone disease in multiple myeloma SO EXPERT REVIEW OF HEMATOLOGY LA English DT Review DE activin-A; bisphosphonates; bone disease; denosumab; RANKL; sclerostin; sotatercept; Wnt pathway ID SKELETAL-RELATED EVENTS; ZOLEDRONIC ACID; DOUBLE-BLIND; ACTIVIN-A; KAPPA-B; RECEPTOR ACTIVATOR; BREAST-CANCER; INHIBITS OSTEOCLASTOGENESIS; ALKALINE-PHOSPHATASE; RESORPTION MARKERS AB Osteolytic bone disease is the most common complication of multiple myeloma, resulting in skeletal complications that cause significant morbidity and mortality. Currently, bisphosphonates (BPs) are the mainstay for the treatment of myeloma bone disease. Zoledronic acid which has been found to be superior to clodronate, both in terms of reduction of skeletal-related events (SREs) and survival, and pamidronate are used for the management of myeloma-related bone disease. Patients with active disease (not in CR or VGPR) should receive BPs (especially zoledronic acid) even after two years of administration. Radiotherapy and surgical interventions can also be used for specific conditions, such as pathological fractures, spinal cord compression or uncontrolled pain. The better understanding of the biology of myeloma bone disease has led to the production of several novel agents, such as denosumab (targeting RANKL), sotatercept (activin-A antagonist) and romosozumab (targeting sclerostin) that appear very promising and have entered to clinical development. C1 [Terpos, Evangelos] Univ Athens, Dept Clin Therapeut, Sch Med, Alexandra Gen Hosp, Athens 11528, Greece. [Berenson, James] Inst Myeloma & Bone Res, West Hollywood, CA USA. [Raje, Noopur] Massachusetts Gen Hosp, Ctr Canc, Ctr Multiple Myeloma, Boston, MA USA. [Roodman, G. David] Indiana Univ Sch Med, Indianapolis, IN 46202 USA. RP Terpos, E (reprint author), Univ Athens, Dept Clin Therapeut, Sch Med, Alexandra Gen Hosp, 80 Vas Sofias Ave, Athens 11528, Greece. EM eterpos@med.uoa.gr FU Novartis; Millenium; Celgene; Onyx; Medtronics; Acetylon; Eli Lilly; Lilly FX E Terpos has received honoraria from Novartis, Amgen, Janssen-Cilag and Celgene, and is on the advisory board for Amgen. J Berenson has received honoraria and research funding from Novartis, Millenium, Celgene, Onyx and Medtronics and is a Consultant for Onyx. N Raje is a consultant for Celgene, Millenium, Onyx and Amgen and has received research funding from Acetylon and Eli Lilly. GD Roodman is on the advisory board for Amgen and has received research funds from Lilly. 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 99 TC 25 Z9 26 U1 0 U2 8 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND SN 1747-4086 EI 1747-4094 J9 EXPERT REV HEMATOL JI Expert Rev. Hematol. PD FEB PY 2014 VL 7 IS 1 BP 113 EP 125 DI 10.1586/17474086.2013.874943 PG 13 WC Hematology SC Hematology GA AG8CQ UT WOS:000335646800014 PM 24433088 ER PT J AU Ocio, EM Mitsiades, CS Orlowski, RZ Anderson, KC AF Ocio, Enrique M. Mitsiades, Constantine S. Orlowski, Robert Z. Anderson, Kenneth C. TI Future agents and treatment directions in multiple myeloma SO EXPERT REVIEW OF HEMATOLOGY LA English DT Review DE immunomodulatory agents; monoclonal antibodies; multiple myeloma; proteasome inhibitors; targeted agents; targeted drugs ID LENALIDOMIDE PLUS DEXAMETHASONE; PROTEASOME INHIBITOR PS-341; LOW-DOSE DEXAMETHASONE; PHASE I/II TRIAL; NF-KAPPA-B; SINGLE-AGENT; OPEN-LABEL; SUPPRESSOR-CELLS; IN-VIVO; COMBINED BENDAMUSTINE AB The development of bortezomib and immunomodulatory agents resulted in a revolution in the treatment of multiple myeloma (MM). Moreover, second-generation proteasome inhibitors (carfilzomib) and immunomodulatory agents (pomalidomide) have recently been approved. Nevertheless, the incurability of this disease requires other drugs with different mechanisms of action to either prolong the survival of patients refractory to current therapies, or achieve cure. Active research has been done exploring the pathogenesis of MM and searching for novel, druggable targets. In this regard, some of these novel agents seem promising, such as monoclonal antibodies (anti-CD38 - daratumumab or anti-CS1 - elotuzumab) or the kinesin protein inhibitor Arry-520. Other agents under investigation are kinase inhibitors, signaling pathways inhibitors or deacetylase inhibitors. With so many novel agents under investigation, future therapy in MM will probably involve the combined use of the already approved drugs with some of those newly discovered. C1 [Ocio, Enrique M.] Univ Hosp & Canc Res Ctr, IBMCC USAL CSIC, Univ Hosp Salamanca IBSAL, Dept Hematol, Salamanca 37007, Spain. [Mitsiades, Constantine S.] Harvard Univ, Dana Farber Canc Inst, Sch Med, Dept Med Oncol,Dept Med, Boston, MA 02115 USA. [Orlowski, Robert Z.] Univ Texas MD Anderson Canc Ctr, Dept Lymphoma Myeloma, Houston, TX 77030 USA. [Anderson, Kenneth C.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Jerome Lipper Multiple Myeloma Ctr, Boston, MA 02115 USA. [Anderson, Kenneth C.] Harvard Univ, Sch Med, Dana Farber Canc Inst, LeBow Inst Myeloma Therapeut, Boston, MA 02115 USA. RP Ocio, EM (reprint author), Univ Hosp & Canc Res Ctr, IBMCC USAL CSIC, Univ Hosp Salamanca IBSAL, Dept Hematol, P San Vicente 58-182, Salamanca 37007, Spain. EM emocio@usal.es FU Celgene; Onyx; Pharmamar; Array Pharmaceuticals; Amgen; AVEO Pharma; OSI; EMD Serono; Sunesis; Gloucester Pharmaceuticals; Genzyme; Johnson Johnson; Millennium FX EM Ocio: Consultancy: Onyx; Bristol Myers Squibb; Array Pharmaceuticals. Research Funding: Celgene; Onyx; Pharmamar; Array Pharmaceuticals. C Mitsiades: Consultancy: Millennium Pharmaceuticals, Celgene, Novartis Pharmaceuticals, Bristol-Myers Squibb, Merck & Co., Kosan Pharmaceuticals, Pharmion, Centocor, Arno Therapeutics. Curis & Axios Biosciences (pro bono); Licensing royalties from PharmaMar; Research support from Amgen, AVEO Pharma, OSI, EMD Serono, Sunesis, Gloucester Pharmaceuticals, Genzyme and Johnson & Johnson. RZ Orlowski: Consultancy: Abbott Laboratories; Centocor Ortho Biotech; Cephalon; Millennium; Novartis; Onyx. Research Funding: Celgene; Johnson and Johnson; Millennium; Onyx. KC Anderson: Consultancy: Gilead; Sanofi-Aventis; Onyx; Celgene. Stock Ownership; Acetylon; Oncoprep. 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 162 TC 14 Z9 15 U1 0 U2 10 PU EXPERT REVIEWS PI LONDON PA UNITEC HOUSE, 3RD FL, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON N3 1QB, ENGLAND SN 1747-4086 EI 1747-4094 J9 EXPERT REV HEMATOL JI Expert Rev. Hematol. PD FEB PY 2014 VL 7 IS 1 BP 127 EP 141 DI 10.1586/17474086.2014.858595 PG 15 WC Hematology SC Hematology GA AG8CQ UT WOS:000335646800015 PM 24350987 ER PT J AU Sahin, I Leblebjian, H Treon, SP Ghobrial, IM AF Sahin, Ilyas Leblebjian, Houry Treon, Steven P. Ghobrial, Irene M. TI Waldenstrom macroglobulinemia: from biology to treatment SO EXPERT REVIEW OF HEMATOLOGY LA English DT Review DE biology; Bruton's tyrosine; kinase; MYD88; treatment; Waldenstrom macroglobulinemia ID IGM MONOCLONAL GAMMOPATHY; L265P SOMATIC MUTATION; PHASE-II TRIAL; CHRONIC LYMPHOCYTIC-LEUKEMIA; MARGINAL ZONE LYMPHOMA; CELL LYMPHOPROLIFERATIVE DISORDERS; CONSENSUS PANEL RECOMMENDATIONS; 2ND INTERNATIONAL WORKSHOP; INDEPENDENT RISK-FACTOR; BRUTON TYROSINE KINASE AB Waldenstrom macroglobulinemia (WM) is distinct B-cell lymphoproliferative disorder primarily characterized by bone marrow infiltration of lymphoplasmacytic cells along with production of a serum monoclonal (IgM). In this review, we describe the biology of WM, the diagnostic evaluation for WM with a discussion of other conditions that are in the differential diagnosis and clinical manifestations of the disease as well as current treatment options. Within the novel agents discussed are everolimus, perifosine, enzastaurin, panobinostat, bortezomib and carfilzomib, pomalidomide and ibrutinib. Many of the novel agents have shown good responses and have a better toxicity profile compared to traditional chemotherapeutic agents, which makes them good candidates to be used as primary therapies for WM in the future. C1 [Sahin, Ilyas; Treon, Steven P.; Ghobrial, Irene M.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Leblebjian, Houry] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pharm, Boston, MA 02115 USA. RP Ghobrial, IM (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, 44 Binney St, Boston, MA 02115 USA. EM Ireneghobrial@dfci.harvard.edu FU Genzyme; BMS; Pharmacyclics; Janssen Pharmacuticals; Onyx Pharmaceuticals FX IM Ghobrial is on the advisory board for Onyx, BMS and Celgene and receives research lab support from Genzyme and BMS. SP Treon receives research support from honoraria, and consulting fees from Pharmacyclics, Janssen Pharmacuticals and Onyx Pharmaceuticals. 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 114 TC 11 Z9 11 U1 0 U2 8 PU EXPERT REVIEWS PI LONDON PA UNITEC HOUSE, 3RD FL, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON N3 1QB, ENGLAND SN 1747-4086 EI 1747-4094 J9 EXPERT REV HEMATOL JI Expert Rev. Hematol. PD FEB PY 2014 VL 7 IS 1 BP 157 EP 168 DI 10.1586/17474086.2014.871494 PG 12 WC Hematology SC Hematology GA AG8CQ UT WOS:000335646800017 PM 24405328 ER PT J AU Borghi, E Romagnoli, S Fuchs, BB Cirasola, D Perdoni, F Tosi, D Braidotti, P Bulfamante, G Morace, G Mylonakis, E AF Borghi, Elisa Romagnoli, Solange Fuchs, Beth Burgwyn Cirasola, Daniela Perdoni, Federica Tosi, Delfina Braidotti, Paola Bulfamante, Gaetano Morace, Giulia Mylonakis, Eleftherios TI Correlation between Candida albicans biofilm formation and invasion of the invertebrate host Galleria mellonella SO FUTURE MICROBIOLOGY LA English DT Article DE biofilm; Candida albicans; Galleria mellonella; histology; virulence ID ANTIFUNGAL SUSCEPTIBILITY; FUNGAL PATHOGENESIS; MODEL HOSTS; INFECTIONS; INSECTS; VIRULENCE; MACROPHAGES; DROSOPHILA AB Aim: The aim of our study was to investigate whether biofilm production by Candida albicans clinical isolates could be a hallmark of virulence in vivo. Materials & methods: Twenty clinical isolates of C. albicans were examined via histological studies on larvae infected with various fungal doses (from 10(3) to 10(5) CFU/larva) of biofilm producer and nonproducer strains. Results: The poor prognostic role of infection due to a biofilm-producing isolate was confirmed by the Wald test (hazard ratio: 2.63; 95% CI: 2.03-3.41). Histological examinations at 24 h showed a strong innate immune response, with evidence of melanization for both infection groups. However, at 48 h, we found huge differences in filamentation and tissue invasion capability between biofilm nonproducing and producing isolates, the latter being highly organized into biofilm and invading the larval intestinal tract. Invasion corroborated survival data. Conclusion: The histological results demonstrate that the production of biofilm could enhance the invasiveness of C. albicans. C1 [Borghi, Elisa; Romagnoli, Solange; Cirasola, Daniela; Perdoni, Federica; Tosi, Delfina; Bulfamante, Gaetano; Morace, Giulia] Univ Milan, Dept Hlth Sci, I-20142 Milan, Italy. [Borghi, Elisa; Fuchs, Beth Burgwyn; Mylonakis, Eleftherios] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Romagnoli, Solange; Tosi, Delfina; Bulfamante, Gaetano] AO San Paolo, UOC Anat Patol Citogenet & Patol Mol, I-20142 Milan, Italy. [Fuchs, Beth Burgwyn; Mylonakis, Eleftherios] Brown Univ, Rhode Isl Hosp, Div Infect Dis, Warren Alpert Med Sch, Providence, RI 02903 USA. [Cirasola, Daniela] Univ Milan, Specializat Sch Microbiol & Virol, I-20133 Milan, Italy. [Braidotti, Paola] AO San Paolo, Electron Microscopy Unit, I-20142 Milan, Italy. RP Borghi, E (reprint author), Univ Milan, Dept Hlth Sci, Via Rudini 8, I-20142 Milan, Italy. EM elisa.borghi@unimi.it RI Borghi, Elisa/I-8811-2012 OI Borghi, Elisa/0000-0002-1893-0455 NR 33 TC 10 Z9 11 U1 0 U2 5 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1746-0913 EI 1746-0921 J9 FUTURE MICROBIOL JI Future Microbiol. PD FEB PY 2014 VL 9 IS 2 BP 163 EP 173 DI 10.2217/fmb.13.159 PG 11 WC Microbiology SC Microbiology GA AB6CJ UT WOS:000331874900010 PM 24571071 ER PT J AU Nadal, R Taplin, ME Bellmunt, J AF Nadal, Rosa Taplin, Mary-Ellen Bellmunt, Joaquim TI Enzalutamide for the treatment of prostate cancer: results and implications of the AFFIRM trial SO FUTURE ONCOLOGY LA English DT Article DE AFFIRM study; androgen receptor F876L mutations; castration-resistant prostate cancer; enzalutamide; MDV3100 ID MITOXANTRONE PLUS PREDNISONE; ANDROGEN RECEPTOR GENE; INCREASED SURVIVAL; DOCETAXEL; PROGRESSION; RESISTANCE; ABIRATERONE; EXPRESSION; VARIANTS; THERAPY AB Enzalutamide is a second-generation androgen receptor signaling inhibitor that was approved by the US FDA in 2012 for the treatment of metastatic docetaxel-pretreated castrate-resistant prostate cancer. In preclinical studies, enzalutamide demonstrated higher affinity to the androgen receptor compared with the first-generation androgen receptor inhibitors. In the well-designed Phase III AFFIRM study, enzalutamide treatment showed improved overall survival compared with placebo in addition to improvement of all preplanned secondary parameters. Overall, enzalutamide seemed to be very well tolerated with a favorable side-effect profile, with a lower incidence of grade 3-4 adverse events. A potentially concerning adverse effect was the occurrence of seizures that were reported in approximately 1% of the patients receiving enzalutamide (compared with 0% in the placebo arm). This review will summarize the mechanism of action of enzalutamide, the preclinical and clinical development that led to its approval focusing on the AFFIRM trial results, its safety and efficacy and the ongoing trials, as well as patterns of resistance to this drug in the context of five new drugs approved for the treatment of metastatic castration-resistant prostate cancer. With a changing landscape for these patients, treatment sequencing and best treatment for individual patients remains challenging. C1 [Nadal, Rosa] Johns Hopkins Univ, Sindey Kimmel Comprehens Canc Ctr, Baltimore, MD 21231 USA. [Taplin, Mary-Ellen] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Bellmunt, Joaquim] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02215 USA. RP Bellmunt, J (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. EM joaquim_bellmunt@dfci.harvard.edu FU Astellas; Medivation FX J Bellmunt has received consultancy and lecture fees from Astellas. M-E Taplin has received research funding from Medivation and has served in a consulting or advisory role for Medivation. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflicts with the subject matter or materials discussed in the manuscript apart from those disclosed. NR 53 TC 4 Z9 4 U1 0 U2 3 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1479-6694 EI 1744-8301 J9 FUTURE ONCOL JI Future Oncol. PD FEB PY 2014 VL 10 IS 3 BP 351 EP 362 DI 10.2217/FON.13.275 PG 12 WC Oncology SC Oncology GA AB3NX UT WOS:000331698600009 PM 24559444 ER PT J AU Ramsey, H Zhang, Q Brown, DE Steensma, DP Lin, CP Wu, MX AF Ramsey, Haley Zhang, Qi Brown, Diane E. Steensma, David P. Lin, Charles P. Wu, Mei X. TI Stress-induced hematopoietic failure in the absence of immediate early response gene X-1 (IEX-1, IER3) SO HAEMATOLOGICA LA English DT Article ID BERNARD-SOULIER-SYNDROME; MYELODYSPLASTIC SYNDROMES; BONE-MARROW; F1FO-ATPASE INHIBITOR; PROPLATELET FORMATION; STEM-CELL; APOPTOSIS; EXPRESSION; MOUSE; MICE AB Expression of the immediate early response gene X-1 (IEX-1, IER3) is diminished significantly in hematopoietic stem cells in a subgroup of patients with early stage myelodysplastic syndromes, but it is not clear whether the deregulation contributes to the disease. The current study demonstrates increased apoptosis and a concomitant decrease in the number of hematopoietic stem cells lacking this early response gene. Null mutation of the gene also impeded platelet differentiation and shortened a lifespan of red blood cells. When bone marrow cells deficient in the gene were transplanted into wild-type mice, the deficient stem cells produced significantly fewer circulating platelets and red blood cells, despite their enhanced repopulation capability. Moreover, after exposure to a non-myeloablative dose of radiation, absence of the gene predisposed to thrombocytopenia, a significant decline in red blood cells, and dysplastic bone marrow morphology, typical characteristics of myelodysplastic syndromes. These findings highlight a previously unappreciated role for this early response gene in multiple differentiation steps within hematopoiesis, including thrombopoiesis, erythropoiesis and in the regulation of hematopoietic stem cell quiescence. The deficient mice offer a novel model for studying the initiation and progression of myelodysplastic syndromes as well as strategies to prevent this disorder. C1 [Ramsey, Haley; Zhang, Qi; Lin, Charles P.; Wu, Mei X.] Harvard Univ, Sch Med, Dept Dermatol, Wellman Ctr Photomed,Massachusetts Gen Hosp, Boston, MA 02115 USA. [Brown, Diane E.] Harvard Univ, Sch Med, Dept Pathol, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Brown, Diane E.] Massachusetts Gen Hosp, Ctr Comparat Med, Boston, MA 02114 USA. [Steensma, David P.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Lin, Charles P.; Wu, Mei X.] Harvard MIT Div Hlth Sci & Technol, Cambridge, MA USA. RP Wu, MX (reprint author), Harvard Univ, Sch Med, Dept Dermatol, Wellman Ctr Photomed,Massachusetts Gen Hosp, Boston, MA 02115 USA. EM mwu2@partners.org OI Steensma, David/0000-0001-5130-9284 FU National Institutes of Health [CA158756, AI089779, DA028378, HL097748] FX This work is supported by the National Institutes of Health Grants CA158756, AI089779, and DA028378 to MW and HL097748 to CPL. NR 36 TC 9 Z9 10 U1 0 U2 1 PU FERRATA STORTI FOUNDATION PI PAVIA PA VIA GIUSEPPE BELLI 4, 27100 PAVIA, ITALY SN 0390-6078 J9 HAEMATOLOGICA JI Haematologica PD FEB PY 2014 VL 99 IS 2 BP 282 EP 291 DI 10.3324/haematol.2013.092452 PG 10 WC Hematology SC Hematology GA AH6PU UT WOS:000336253900020 PM 24056813 ER PT J AU Sanchez, R St-Cyr, J Lalonde, ME Healy, J Richer, C Gagne, V Laverdiere, C Silverman, LB Sallan, SE Neuberg, D Kutok, JL Kritikou, EA Krajinovic, M Sinnett, D AF Sanchez, Rocio St-Cyr, Janick Lalonde, Marie-Eve Healy, Jasmine Richer, Chantal Gagne, Vincent Laverdiere, Caroline Silverman, Lewis B. Sallan, Stephen E. Neuberg, Donna Kutok, Jeffery L. Kritikou, Ekaterini A. Krajinovic, Maja Sinnett, Daniel TI Impact of promoter polymorphisms in key regulators of the intrinsic apoptosis pathway on the outcome of childhood acute lymphoblastic leukemia SO HAEMATOLOGICA LA English DT Article ID ACUTE MYELOID-LEUKEMIA; BCL-2 FAMILY-MEMBERS; CHRONIC LYMPHOCYTIC-LEUKEMIA; GENETIC POLYMORPHISMS; PROGNOSTIC-SIGNIFICANCE; IN-VITRO; EXPRESSION; CELLS; RISK; SUSCEPTIBILITY AB The introduction of multiagent treatment protocols has led to a remarkable increase in survival rates for children diagnosed with acute lymphoblastic leukemia, yet for a subpopulation of patients, resistance to chemotherapeutics remains an obstacle to successful treatment. Here we investigate the role of the mitochondrial (or intrinsic) apoptosis pathway in modulating the onset and outcomes of childhood acute lymphoblastic leukemia. Cell death is a highly regulated process that plays an essential role in regulating cell homeostasis, particularly in tissues with high intrinsic proliferating capacity such as the hematopoietic system. Following the underlying paradigm that cis-acting genetic variation can influence disease risk and outcomes by modulating gene expression, we performed a systematic analysis of the proximal promoter regions of 21 genes involved in apoptosis. Using gene reporter assays, we show that promoter variations in 11 intrinsic apoptosis genes, including ADPRT, APAF1, BCL2, BAD, BID, MCL1, BIRC4, BCL2L1, ENDOG, YWHAB, and YWHAQ, influence promoter activity in an allele-specific manner. We also show that correlated promoter variation and increased expression of MCL1 is associated with reduced overall survival among high-risk patients receiving higher doses of corticosteroid, suggesting that increased expression of this anti-apoptosis gene could lead to reduced cell death and influence treatment response in a disease- and dose-responsive manner. C1 [Sanchez, Rocio; St-Cyr, Janick; Lalonde, Marie-Eve; Healy, Jasmine; Richer, Chantal; Gagne, Vincent; Laverdiere, Caroline; Kritikou, Ekaterini A.; Krajinovic, Maja; Sinnett, Daniel] CHU St Justine, Res Ctr, Div Hematol Oncol, Montreal, PQ, Canada. [Laverdiere, Caroline; Krajinovic, Maja; Sinnett, Daniel] Univ Montreal, Fac Med, Dept Pediat, Montreal, PQ H3C 3J7, Canada. [Silverman, Lewis B.; Sallan, Stephen E.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Silverman, Lewis B.; Sallan, Stephen E.] Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USA. [Neuberg, Donna] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Kutok, Jeffery L.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. RP Sinnett, D (reprint author), CHU St Justine, Res Ctr, Div Hematol Oncol, Montreal, PQ, Canada. EM daniel.sinnett@umontreal.ca FU Canadian Institutes for Health Research; Genome Quebec; Genome Canada; National Cancer Institute/NIH [CA068484] FX This study was supported by research funds provided by the Canadian Institutes for Health Research, as well as Genome Quebec and Genome Canada. DS holds the Francois-Karl Viau Chair in Pediatric Oncogenomics. Dana-Farber Cancer Institute ALL treatment protocols are supported by the National Cancer Institute/NIH grant CA068484. NR 42 TC 4 Z9 4 U1 0 U2 0 PU FERRATA STORTI FOUNDATION PI PAVIA PA VIA GIUSEPPE BELLI 4, 27100 PAVIA, ITALY SN 0390-6078 J9 HAEMATOLOGICA JI Haematologica PD FEB PY 2014 VL 99 IS 2 BP 314 EP 321 DI 10.3324/haematol.2013.085340 PG 8 WC Hematology SC Hematology GA AH6PU UT WOS:000336253900024 PM 24038028 ER PT J AU Long, MD Hutfless, S Kappelman, MD Khalili, H Kaplan, GG Bernstein, CN Colombel, JF Gower-Rousseau, C Herrinton, L Velayos, F Loftus, EV Nguyen, GC Ananthakrishnan, AN Sonnenberg, A Chan, A Sandler, RS Atreja, A Shah, SA Rothman, KJ Leleiko, NS Bright, R Boffetta, P Myers, KD Sands, BE AF Long, Millie D. Hutfless, Susan Kappelman, Michael D. Khalili, Hamed Kaplan, Gilaad G. Bernstein, Charles N. Colombel, Jean Frederic Gower-Rousseau, Corinne Herrinton, Lisa Velayos, Fernando Loftus, Edward V., Jr. Nguyen, Geoffrey C. Ananthakrishnan, Ashwin N. Sonnenberg, Amnon Chan, Andrew Sandler, Robert S. Atreja, Ashish Shah, Samir A. Rothman, Kenneth J. Leleiko, Neal S. Bright, Renee Boffetta, Paolo Myers, Kelly D. Sands, Bruce E. TI Challenges in Designing a National Surveillance Program for Inflammatory Bowel Disease in the United States SO INFLAMMATORY BOWEL DISEASES LA English DT Review DE outcomes research/measurements; clinical areas; epidemiology ID POPULATION-BASED COHORT; ROCHESTER EPIDEMIOLOGY PROJECT; MEDICAL-RECORDS-LINKAGE; TUMOR-NECROSIS-FACTOR; COMPLICATIONS FOLLOWING COLECTOMY; MANAGED CARE ORGANIZATION; PEDIATRIC CROHNS-DISEASE; IMMUNE-MEDIATED DISEASES; BONE-MINERAL DENSITY; ULCERATIVE-COLITIS AB This review describes the history of U.S. government funding for surveillance programs in inflammatory bowel diseases (IBD), provides current estimates of the incidence and prevalence of IBD in the United States, and enumerates a number of challenges faced by current and future IBD surveillance programs. A rationale for expanding the focus of IBD surveillance beyond counts of incidence and prevalence, to provide a greater understanding of the burden of IBD, disease etiology, and pathogenesis, is provided. Lessons learned from other countries are summarized, in addition to potential resources that may be used to optimize a new form of IBD surveillance in the United States. A consensus recommendation on the goals and available resources for a new model for disease surveillance are provided. This new model should focus on "surveillance of the burden of disease," including (1) natural history of disease and (2) outcomes and complications of the disease and/or treatments. C1 [Long, Millie D.; Kappelman, Michael D.; Sandler, Robert S.] Univ N Carolina, Dept Med, Div Gastroenterol & Hepatol, Chapel Hill, NC 27599 USA. [Long, Millie D.; Kappelman, Michael D.; Sandler, Robert S.] Univ N Carolina, Dept Pediat, Div Gastroenterol & Hepatol, Chapel Hill, NC 27599 USA. [Hutfless, Susan] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Khalili, Hamed; Ananthakrishnan, Ashwin N.; Chan, Andrew] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Crohns & Colitis, Boston, MA USA. [Kaplan, Gilaad G.] Univ Calgary, Fac Med, Dept Community Hlth Sci, Calgary, AB, Canada. [Bernstein, Charles N.] Univ Manitoba, Dept Internal Med, Winnipeg, MB, Canada. [Colombel, Jean Frederic; Atreja, Ashish; Bright, Renee; Boffetta, Paolo; Sands, Bruce E.] Icahn Sch Med Mt Sinai, New York, NY USA. [Gower-Rousseau, Corinne] Hosp & Univ Lille Nord France, Epidemiol Unit, Epimad Registry, Lille, France. [Herrinton, Lisa] Kaiser Permanente No Calif, Oakland, CA USA. [Velayos, Fernando] Univ Calif San Francisco, UCSF Ctr Colitis & Crohns Dis, San Francisco, CA 94143 USA. [Loftus, Edward V., Jr.] Mayo Clin, Div Gastroenterol & Hepatol, Rochester, MN USA. [Nguyen, Geoffrey C.] Univ Toronto, Mt Sinai Hosp, Ctr Inflammatory Bowel Dis, Toronto, ON M5G 1X5, Canada. [Sonnenberg, Amnon; Shah, Samir A.] Portland VA Med Ctr, Portland, OR USA. [Leleiko, Neal S.] Brown Univ, Alpert Med Sch, Providence, RI 02912 USA. [Rothman, Kenneth J.] Res Triangle Inst, RTI Hlth Solut, Res Triangle Pk, NC 27709 USA. [Rothman, Kenneth J.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Myers, Kelly D.] QForma Inc, Santa Fe, NM USA. RP Long, MD (reprint author), Univ N Carolina, Dept Med, Div Gastroenterol & Hepatol, Campus Box 7080, Chapel Hill, NC 27599 USA. EM millie_long@med.unc.edu RI Loftus, Edward/E-8304-2011; Nguyen, Geoffrey/C-4614-2015; OI Nguyen, Geoffrey/0000-0001-7083-7429; leleiko, neal/0000-0001-7699-1400; Hutfless, Susan/0000-0002-6311-2611; Kaplan, Gilaad/0000-0003-2719-0556 FU Crohn's and Colitis Foundation of America; [3U01DP002676-01S1 REVISED] FX This work was funded in part by the Crohn's and Colitis Foundation of America and 3U01DP002676-01S1 REVISED. NR 110 TC 9 Z9 9 U1 0 U2 11 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 FEB PY 2014 VL 20 IS 2 BP 398 EP 415 DI 10.1097/01.MIB.0000435441.30107.8b PG 18 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AH0DT UT WOS:000335790000026 PM 24280882 ER PT J AU Dunham, RM Vujkovic-Cvijin, I Yukl, SA Broadhurst, MJ Loke, P Albright, RG Wong, JK Lederman, MM Somsouk, M Hunt, PW Martin, JN Deeks, SG McCune, JM AF Dunham, Richard M. Vujkovic-Cvijin, Ivan Yukl, Steven A. Broadhurst, Mara J. Loke, P'ng Albright, Rebecca G. Wong, Joseph K. Lederman, Michael M. Somsouk, Ma Hunt, Peter W. Martin, Jeffrey N. Deeks, Steven G. McCune, Joseph M. TI Discordance Between Peripheral and Colonic Markers of Inflammation During Suppressive ART SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE colon biopsy; ART; microbial translocation; inflammation; HIV; CD4 T-cell recovery ID ACTIVE ANTIRETROVIRAL THERAPY; VIRUS TYPE-1 INFECTION; T-CELL-ACTIVATION; IMMUNE ACTIVATION; HIV-INFECTION; MICROBIAL TRANSLOCATION; LYMPHOID-TISSUE; I INTERFERON; CD4(+); IMMUNODEFICIENCY AB Objective: Persistent systemic inflammation is associated with the inability of some HIV-infected patients to normalize circulating CD4(+) T-cell levels after years of suppressive antiretroviral therapy. In this study, we sought to understand whether such systemic inflammation is also associated with detectable signs of inflammation in biopsies from the rectosigmoid colon. Design: Immunologic and virological parameters were studied in the peripheral blood and in rectosigmoid colon biopsies from individuals with viral suppression for at least 2 years and with peripheral CD4(+) T-cell levels of <350 cells per cubic millimeter (immunologic nonresponders, n = 18) or >500 cells per cubic millimeter (immunologic responders, n = 16). Methods: Peripheral blood and rectosigmoid colon biopsies were analyzed by flow cytometry, enzyme-linked immunosorbent assay, and quantitative polymerase chain reaction. Results: Nonresponders had elevated T-cell activation and inflammatory cytokines in the circulation, but inflammatory gene expression in colon biopsies was not different as compared with responders, and there was little relationship between blood and colon markers of inflammation. Blood inflammatory markers were positively associated with soluble CD14 levels indicative of monocyte activation. Conclusions: These findings demonstrate that, in the context of treated HIV disease, it is easier to detect parameters of inflammation (including blood monocyte activation) in the peripheral blood than in isolated rectosigmoid colon biopsies. Accordingly, interventions to block such inflammation in this population might be most conveniently and accurately assessed in blood. C1 [Dunham, Richard M.] GlaxoSmithKline, HIV Discovery Performance Unit, Res Triangle Pk, NC USA. [Vujkovic-Cvijin, Ivan; Broadhurst, Mara J.; Loke, P'ng; Albright, Rebecca G.; McCune, Joseph M.] Univ Calif San Francisco, Dept Med, Div Expt Med, San Francisco, CA 94143 USA. [Vujkovic-Cvijin, Ivan; Broadhurst, Mara J.] Univ Calif San Francisco, Biomed Sci Grad Program, San Francisco, CA 94143 USA. [Yukl, Steven A.; Wong, Joseph K.] Univ Calif San Francisco, Dept Med, Div Infect Dis, San Francisco, CA 94143 USA. [Yukl, Steven A.; Wong, Joseph K.] San Francisco VA Med Ctr, San Francisco, CA USA. [Lederman, Michael M.] Case Western Reserve Univ, Dept Med, Div Infect Dis & HIV Med, Cleveland, OH 44106 USA. [Somsouk, Ma] Univ Calif San Francisco, Dept Med, Div Gastroenterol, San Francisco, CA 94143 USA. [Hunt, Peter W.; Martin, Jeffrey N.; Deeks, Steven G.] Univ Calif San Francisco, San Francisco Gen Hosp, Dept Med, Posit Hlth Program, San Francisco, CA 94143 USA. RP McCune, JM (reprint author), Univ Calif San Francisco, Dept Med, Div Expt Med, Box 1234, San Francisco, CA 94143 USA. EM mike.mccune@ucsf.edu OI Vujkovic-Cvijin, Ivan/0000-0002-8611-4900 FU American Foundation for AIDS Research [107854-48-RGRL]; University of California, San Francisco (UCSF)/Gladstone Center for AIDS Research [P30 AI27763]; Hurlbut-Johnson Fund; UCSF/GIVI Center for AIDS Research; NIAID [U19 AI096109, R37 AI040312, K23 CA157929, R24 AI067039, F32 AI091534]; California HIV/AIDS Research Program [ID09-SF-067]; UCSF Clinical and Translational Science Institute [RR024131-01]; US Department of Veterans Affairs [1 IK2 CX000520-01] FX Supported by the American Foundation for AIDS Research (107854-48-RGRL to J.M.M. and S.G.D.). Additional support was provided by in part by the University of California, San Francisco (UCSF)/Gladstone Center for AIDS Research (P30 AI27763), the Hurlbut-Johnson Fund administered by the AIDS Research Institute at UCSF (to R. M. D.), the UCSF/GIVI Center for AIDS Research (to R. M. D. and S.A.Y.), NIAID (U19 AI096109 to J.M.M. and S. G. D.), R37 AI040312 (to J.M.M.), K23 CA157929 (to M. S.), R24 AI067039 (to J.N.M.), and F32 AI091534 (to R. M. D.), the California HIV/AIDS Research Program (ID09-SF-067 to P.W.H.), the UCSF Clinical and Translational Science Institute (RR024131-01), and the US Department of Veterans Affairs (1 IK2 CX000520-01 to S.A.Y.). NR 42 TC 8 Z9 8 U1 0 U2 0 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 FEB 1 PY 2014 VL 65 IS 2 BP 133 EP 141 DI 10.1097/01.qai.0000437172.08127.0b PG 9 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA AG8DZ UT WOS:000335650300015 PM 24121758 ER PT J AU Taylor, BS Liang, YY Garduno, LS Walter, EA Gerardi, MB Anstead, GM Bullock, D Turner, BJ AF Taylor, Barbara S. Liang, Yuanyuan Garduno, L. Sergio Walter, Elizabeth A. Gerardi, Margit B. Anstead, Gregory M. Bullock, Delia Turner, Barbara J. TI High Risk of Obesity and Weight Gain for HIV-Infected Uninsured Minorities SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE obesity; health disparities; weight gain; HIV; observational cohort ID BODY-MASS INDEX; HUMAN-IMMUNODEFICIENCY-VIRUS; CORONARY-HEART-DISEASE; ACTIVE ANTIRETROVIRAL THERAPY; LIFE-STYLE INTERVENTION; HEALTH-INSURANCE STATUS; IMMUNE CELL COUNTS; UNITED-STATES; SOCIOECONOMIC-STATUS; US ADULTS AB Background: Obesity and HIV disproportionately affect minorities and have significant health risks, but few studies have examined disparities in weight change in HIV-seropositive (HIV+) cohorts. Objective: To determine racial and health insurance disparities in significant weight gain in a predominately Hispanic HIV+ cohort. Methods: Our observational cohort study of 1214 nonunderweight HIV+ adults from 2007 to 2010 had significant weight gain [>= 3% annual body mass index (BMI) increase] as the primary outcome. The secondary outcome was continuous BMI over time. A 4-level race-ethnicity/insurance predictor reflected the interaction between race-ethnicity and insurance: insured white (non-Hispanic), uninsured white, insured minority (Hispanic or black), or uninsured minority. Logistic and mixed-effects models adjusted for baseline BMI, age, gender, household income, HIV transmission category, antiretroviral therapy type, CD4(+) count, plasma HIV-1 RNA, observation months, and visit frequency. Results: The cohort was 63% Hispanic and 14% black; 13.3% were insured white, 10.0% uninsured white, 40.9% insured minority, and 35.7% uninsured minority. At baseline, 37.5% were overweight, 22.1% obese. Median observation was 3.25 years. Twenty-four percent of the cohort had significant weight gain, which was more likely for uninsured minority patients than insured whites [adjusted odds ratio = 2.85, 95% confidence intervals (CIs): 1.66 to 4.90]. The rate of BMI increase in mixed-effects models was greatest for uninsured minorities. Of 455 overweight at baseline, 29% were projected to become obese in 4 years. Conclusions and Relevance: In this majority Hispanic HIV+ cohort, 60% were overweight or obese at baseline, and uninsured minority patients gained weight more rapidly. These data should prompt greater attention by HIV providers for prevention of obesity. C1 [Taylor, Barbara S.; Garduno, L. Sergio; Walter, Elizabeth A.; Gerardi, Margit B.; Anstead, Gregory M.; Bullock, Delia] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, Div Infect Dis, San Antonio, TX 78229 USA. [Taylor, Barbara S.; Liang, Yuanyuan; Turner, Barbara J.] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Taylor, Barbara S.; Liang, Yuanyuan; Turner, Barbara J.] Univ Texas Sch Publ Hlth, San Antonio, TX USA. [Liang, Yuanyuan] Univ Texas Hlth Sci Ctr San Antonio, Dept Epidemiol & Biostat, San Antonio, TX 78229 USA. [Walter, Elizabeth A.; Anstead, Gregory M.] South Texas Vet Hlth Care Syst, Dept Med, Div Infect Dis, San Antonio, TX USA. [Gerardi, Margit B.] Univ Texas Hlth Sci Ctr San Antonio, Sch Nursing, Dept Family & Community Hlth Syst, San Antonio, TX 78229 USA. RP Taylor, BS (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Med, Div Infect Dis, 7703 Floyd Curl Dr,MSC 7881, San Antonio, TX 78229 USA. EM taylorb4@uthscsa.edu FU University Health System (UHS) FX The authors gratefully recognize University Health System (UHS) for their support of this project. Specific thanks are due to Lisa Wammack, Tracy Jeffers, and Michelle Silva of UHS for their assistance in developing the data repository for the South Texas HIV Cohort, and all of the patients and providers at the UHS Family Focused AIDS Clinical Treatment & Services clinic. NR 67 TC 14 Z9 14 U1 2 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 FEB 1 PY 2014 VL 65 IS 2 BP E33 EP E40 DI 10.1097/QAI.0000000000000010 PG 8 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA AG8DZ UT WOS:000335650300001 PM 24121754 ER PT J AU van der Wilden, GM Chang, YC Cropano, C Subramanian, M Schipper, IB Yeh, DD King, DR de Moya, MA Fagenholz, PJ Velmahos, GC AF van der Wilden, Gwendolyn M. Chang, Yuchiao Cropano, Catrina Subramanian, Melanie Schipper, Inger B. Yeh, D. Dante King, David R. de Moya, Marc A. Fagenholz, Peter J. Velmahos, George C. TI Fulminant Clostridium difficile colitis: Prospective development of a risk scoring system SO JOURNAL OF TRAUMA AND ACUTE CARE SURGERY LA English DT Article DE Fulminant Clostridium difficile colitis; clinical prediction rule; risk scoring system ID CLINICAL-PRACTICE GUIDELINES; PSEUDOMEMBRANOUS COLITIS; HOSPITALIZED-PATIENTS; HYPERVIRULENT STRAIN; EMERGENCY COLECTOMY; INFECTION; MORTALITY; PREDICTORS; VALIDATION; EPIDEMIC AB BACKGROUND: Of the patients with a Clostridium difficile infection, 2% to 8% will progress to fulminant C. difficile colitis (fCDC), which carries high morbidity and mortality. No system exists to rapidly identify patients at risk for developing fCDC and possibly in need of surgical intervention. Our aim was to design a simple and accurate risk scoring system (RSS) for daily clinical practice. METHODS: We prospectively enrolled all patients diagnosed with a C. difficile infection and compared patients with and without fCDC. An expert panel, combined with data derived from previous studies, identified four risk factors, and a multivariable logistic regression model was performed to determine their effect in predicting fCDC. The RSS was created based on the predictive power of each factor, and calibration, discrimination, and test characteristics were subsequently determined. In addition, the RSS was compared with a previously proposed severity scoring system. RESULTS: A total of 746 patients diagnosed with C. difficile infection were enrolled between November 2010 and October 2012. Based on the log (odds ratio) of each risk factor, age greater than 70 years was assigned 2 points, white blood cell count equal to or greater than 20,000/mu L or equal to or less than 2,000/mu L was assigned 1 point, cardiorespiratory failure was assigned 7 points, and diffuse abdominal tenderness on physical examination was assigned 6 points. With the use of this system, the discriminatory value of the RSS (c statistic) was 0.98 (95% confidence interval, 0.96-1).The Ho smer-Lemeshow goodness-of-fit test showed a p value of 0.78, and the Brier score was 0.019. A value of 6 points was determined to be the threshold for reliably dividing low-risk (<6) from high-risk (>= 6) patients. CONCLUSION: The RSS is a valid and reliable tool to identify at the bedside patients who are at risk for developing fCDC. External validation is needed before widespread implementation. Copyright (C) 2014 by Lippincott Williams & Wilkins C1 [van der Wilden, Gwendolyn M.; Cropano, Catrina; Subramanian, Melanie; Yeh, D. Dante; King, David R.; de Moya, Marc A.; Fagenholz, Peter J.; Velmahos, George C.] Massachusetts Gen Hosp, Div Trauma Emergency Surg & Crit Care, Dept Surg, Boston, MA 02114 USA. [Chang, Yuchiao] Massachusetts Gen Hosp, Div Biostat, Dept Med, Boston, MA 02114 USA. [Chang, Yuchiao] Harvard Univ, Sch Med, Boston, MA USA. [van der Wilden, Gwendolyn M.; Schipper, Inger B.] Leiden Univ, Med Ctr, Dept Trauma Surg, Leiden, Netherlands. [van der Wilden, Gwendolyn M.; Schipper, Inger B.] Leiden Univ, Leiden, Netherlands. RP Velmahos, GC (reprint author), Massachusetts Gen Hosp, 165 Cambridge St,Suite 810, Boston, MA 02114 USA. EM gvelmahos@partners.org OI King, David/0000-0003-1028-1478 NR 42 TC 11 Z9 12 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 2163-0755 EI 2163-0763 J9 J TRAUMA ACUTE CARE JI J. Trauma Acute Care Surg. PD FEB PY 2014 VL 76 IS 2 BP 424 EP 430 DI 10.1097/TA.0000000000000105 PG 7 WC Critical Care Medicine; Surgery SC General & Internal Medicine; Surgery GA AH8KG UT WOS:000336386100024 PM 24458048 ER PT J AU Huang, LY Wang, M Dai, TH Sperandio, FF Huang, YY Xuan, Y Chiang, LY Hamblin, MR AF Huang, Liyi Wang, Min Dai, Tianhong Sperandio, Felipe F. Huang, Ying-Ying Xuan, Yi Chiang, Long Y. Hamblin, Michael R. TI Antimicrobial photodynamic therapy with decacationic monoadducts and bisadducts of [70] fullerene: in vitro and in vivo studies SO NANOMEDICINE LA English DT Article DE antimicrobial photodynamic therapy; bioluminescence imaging; decacationic C-70 fullerene; deca(tertiaryamino)malonate arm; hydroxyl radical; mouse model of burn infection; singlet oxygen ID GRAM-POSITIVE BACTERIA; ESCHERICHIA-COLI-B; ACINETOBACTER-BAUMANNII; SINGLET OXYGEN; NEGATIVE BACTERIA; BURN INFECTIONS; METHYLENE-BLUE; ANTIBIOTIC ERA; II MECHANISMS; INACTIVATION AB Background: Antimicrobial photodynamic therapy uses photosensitizers designed to bind to microorganisms and generate reactive oxygen species when illuminated with visible light. Materials & methods: We synthesized a highly water-soluble [70]fullerene monoadduct, C-70[>M(C3N6+C3)(2)]-(I-)(10) (LC17), and bisadduct, C-70[>M(C3N6+C3)(2)][>M(C3N6C3)(2)] (LC18), both with a well-defined decacationic quaternary ammonium iodide moiety with ten positive charges per C-70 to give water solubility and bacterial binding. We determined the antimicrobial effects against human pathogens, Gram-positive (Staphylococcus aureus) and Gram-negative species (Escherichia coli and Acinetobacter baumannii) when activated by UVA or white light. Results: White light was more effective with LC17, while UVA light was more effective with LC18. Both compounds were effective in a mouse model of Gram-negative third-degree burn infections determined by bioluminescence imaging. Discussion & conclusion: We propose that the attachment of an additional deca(tertiary-ethylenylamino)malonate arm to C-70 allowed the moiety to act as a potent electron donor and increased the generation yield of hydroxyl radicals under UVA illumination. Original submitted 13 June 2012; Revised submitted 10 January 2013; Published online 5 June 2013 C1 [Huang, Liyi] Guangxi Med Univ, Dept Infect Dis, Affiliated Coll & Hosp 1, Nanning 530021, Peoples R China. [Huang, Liyi; Dai, Tianhong; Sperandio, Felipe F.; Huang, Ying-Ying; Xuan, Yi; Hamblin, Michael R.] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. [Huang, Liyi; Dai, Tianhong; Huang, Ying-Ying; Hamblin, Michael R.] Harvard Univ, Dept Dermatol, Sch Med, Boston, MA 02115 USA. [Wang, Min; Chiang, Long Y.] Univ Massachusetts, Dept Chem, Lowell, MA 01854 USA. [Sperandio, Felipe F.] Univ Sao Paulo, Sch Dent, Dept Oral Pathol, BR-05508000 Sao Paulo, Brazil. [Huang, Ying-Ying] Guangxi Med Univ, Aesthet & Plast Ctr, Nanning 530021, Peoples R China. [Xuan, Yi] Tufts Univ, Medford, MA 02155 USA. [Hamblin, Michael R.] MIT, Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. RP Hamblin, MR (reprint author), Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. EM hamblin@helix.mgh.harvard.edu OI Hamblin, Michael/0000-0001-6431-4605 FU NIH [R01CA137108, R01AI050875]; Airlift Research Foundation Extremity Trauma Research Grant [109421]; Basic Research Grant from the Orthopaedic Trauma Association [2012-16]; CAPES Foundation, Ministry of Education of Brazil [0310-11-5] FX This work was supported by NIH R01CA137108 and R01AI050875. T Dai was supported by an Airlift Research Foundation Extremity Trauma Research Grant (grant no. 109421) and a Basic Research Grant from the Orthopaedic Trauma Association (grant no. 2012-16), and FF Sperandio by CAPES Foundation, Ministry of Education of Brazil (grant no. 0310-11-5). 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 54 TC 5 Z9 5 U1 4 U2 31 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1743-5889 EI 1748-6963 J9 NANOMEDICINE-UK JI Nanomedicine PD FEB PY 2014 VL 9 IS 2 BP 253 EP 266 DI 10.2217/nnm.13.22 PG 14 WC Biotechnology & Applied Microbiology; Nanoscience & Nanotechnology SC Biotechnology & Applied Microbiology; Science & Technology - Other Topics GA AB0YA UT WOS:000331517000017 PM 23738632 ER PT J AU Hong, JX Liu, ZG Hua, J Wei, AJ Xue, F Yang, YJ Sun, XH Xu, JJ AF Hong, Jiaxu Liu, Zuguo Hua, Jing Wei, Anji Xue, Feng Yang, Yujing Sun, Xinghuai Xu, Jianjiang TI Evaluation of Age-Related Changes in Noninvasive Tear Breakup Time SO OPTOMETRY AND VISION SCIENCE LA English DT Article DE physiology; tear breakup time; imaging; aging ID STABILITY ANALYSIS SYSTEM; DEFICIENCY DRY EYE; FILM STABILITY; UP TIME; INTERFERENCE IMAGES; KINETIC-ANALYSIS; KERATOGRAPH; CHINESE; GENDER AB Purpose To establish normal noninvasive tear film breakup time (NI-BUT) values in the Chinese population and investigate age-related changes in NI-BUT using a newly developed Keratograph. Methods Forty normal volunteers with a mean age of 32.8 16.7 years were recruited for this study. Clinical and demographic data, including age, gender, fluorescein tear film breakup time (FBUT), and Schirmer I test values were collected from the subjects. Noninvasive tear film breakup time was measured using a new method based on a corneal topographer equipped with a modified scan software. The correlations between the NI-BUT, age, and gender were determined. Results In total, a significant difference between the NI-BUT and the FBUT was found (4.9 +/- 2.4 seconds vs. 9.0 +/- 3.0 seconds; p < 0.001). No statistically significant difference in the NI-BUT was observed between the male and female subjects (5.5 +/- 2.0 seconds vs. 4.5 +/- 2.5 seconds; p = 0.137). In addition, no significant correlation was detected between the NI-BUT and age (0.143, p = 0.321). Conclusions The NI-BUT values found in this study are much lower than those of previous reports. Our results show no significant differences in tear film stability with age. The tear physiology of the Chinese population may not be the same as in Western populations. C1 [Hong, Jiaxu; Wei, Anji; Xue, Feng; Yang, Yujing; Sun, Xinghuai; Xu, Jianjiang] Fudan Univ, Eye Ear Nose & Throat Hosp, Sch Shanghai Med, Dept Ophthalmol & Visual Sci, Shanghai 200031, Peoples R China. [Hong, Jiaxu] Fudan Univ, Hlth Commun Inst, Shanghai 200031, Peoples R China. [Liu, Zuguo; Hua, Jing] Xiamen Univ, Xiamen, Fujian, Peoples R China. [Hua, Jing] Harvard Univ, Sch Med, Schepens Eye Res Inst, Boston, MA USA. [Hua, Jing] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Boston, MA USA. [Sun, Xinghuai] Inst B