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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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.
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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
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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
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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