FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Holmes, MD Wang, J Hankinson, SE Tamimi, RM Chen, WE AF Holmes, Michelle D. Wang, Jun Hankinson, Susan E. Tamimi, Rulla M. Chen, Wendy E. TI Protein Intake and Breast Cancer Survival in the Nurses' Health Study SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID DIETARY-PROTEIN; PHYSICAL-ACTIVITY; BODY-COMPOSITION; DIAGNOSIS; WEIGHT; FAT; METABOLISM; RECURRENCE; CARCINOMA; MORTALITY AB Purpose Greater protein intake has been associated with better breast cancer survival in several prospective studies, including among 1,982 women in the Nurses' Health Study. We proposed to extend this previous finding. We hypothesized that protein, essential amino acid, branched-chain amino acid, and leucine intakes are associated with improved survival and that these associations are stronger in tumors expressing insulin receptor (IR). Patients and Methods We included 6,348 women diagnosed with stage I to III breast cancer between 1976 and 2004. There were 1,046 distant recurrences. Relative risks (RRs) and 95% CIs were calculated according to quintiles of updated postdiagnostic diet using adjusted Cox proportional hazards models based on follow-up until 2010. Results There was an inverse association between energy-adjusted protein intake and recurrence. Multivariable RRs for increasing quintiles of intake compared with the lowest were 0.95 (95% CI, 0.79 to 1.15), 0.92 (95% CI, 0.76 to 1.11), 0.75 (95% CI, 0.61 to 0.91), and 0.84 (95% CI, 0.69 to 1.03; trend P = .02). For animal protein intake, the RRs were 0.88 (95% CI, 0.73 to 1.06), 0.85 (95% CI, 0.70 to 1.02), 0.75 (95% CI, 0.62 to 0.92), and 0.78 (95% CI, 0.63 to 0.95; trend P = .003). Neither essential amino acids, branched-chain amino acids, nor any individual amino acid stood out as being the source of the association. The association also did not differ by IR status. There was no clear association with any protein-containing foods. Conclusion We found a modest survival advantage with higher intake of protein, regardless of IR status. There was no clear mechanism for this association, although it is consistent with prior studies. Our data suggest that there is likely no advantage for women with a history of breast cancer in restricting protein intake or protein-containing foods. (C) 2016 by American Society of Clinical Oncology C1 [Holmes, Michelle D.; Hankinson, Susan E.; Tamimi, Rulla M.; Chen, Wendy E.] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. [Holmes, Michelle D.; Tamimi, Rulla M.] Harvard TH Chan Sch Publ Hlth, Boston, MA USA. [Chen, Wendy E.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Wang, Jun; Hankinson, Susan E.] Univ Massachusetts, Amherst, MA 01003 USA. RP Holmes, MD (reprint author), Brigham & Womens Hosp, Channing Div Network Med, 181 Longwood Ave, Boston, MA 02115 USA. EM michelle.holmes@channing.harvard.edu FU Bayer HealthCare Pharmaceuticals (Inst) FX Bayer HealthCare Pharmaceuticals (Inst) NR 29 TC 1 Z9 1 U1 5 U2 5 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD JAN 20 PY 2017 VL 35 IS 3 BP 325 EP + DI 10.1200/JCO.2016.68.3292 PG 17 WC Oncology SC Oncology GA EH7PR UT WOS:000391965400010 PM 28095274 ER PT J AU Sulman, EP Ismaila, N Armstrong, TS Tsien, C Batchelor, TT Cloughesy, T Galanis, E Gilbert, M Gondi, V Lovely, M Mehta, M Mumber, MP Sloan, A Chang, SM AF Sulman, Erik P. Ismaila, Nofisat Armstrong, Terri S. Tsien, Christina Batchelor, Tracy T. Cloughesy, Tim Galanis, Evanthia Gilbert, Mark Gondi, Vinai Lovely, Mary Mehta, Minesh Mumber, Matthew P. Sloan, Andrew Chang, Susan M. TI Radiation Therapy for Glioblastoma: American Society of Clinical Oncology Clinical Practice Guideline Endorsement of the American Society for Radiation Oncology Guideline SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID NEWLY-DIAGNOSED GLIOBLASTOMA; RANDOMIZED PHASE-III; RECURRENT MALIGNANT GLIOMA; QUALITY-OF-LIFE; HYPOFRACTIONATED RADIOTHERAPY; ADJUVANT TEMOZOLOMIDE; ANAPLASTIC GLIOMAS; TRIAL; MULTIFORME; BEVACIZUMAB AB Purpose The American Society for Radiation Oncology (ASTRO) produced an evidence-based guideline on radiation therapy for glioblastoma. Because of its relevance to the ASCO membership, ASCO reviewed the guideline and applied a set of procedures and policies used to critically examine guidelines developed by other organizations. Methods The ASTRO guideline on radiation therapy for glioblastoma was reviewed for developmental rigor by methodologists. An ASCO endorsement panel updated the literature search and reviewed the content and recommendations. Results The ASCO endorsement panel determined that the recommendations from the ASTRO guideline, published in 2016, are clear, thorough, and based on current scientific evidence. ASCO endorsed the ASTRO guideline on radiation therapy for glioblastoma and added qualifying statements. Recommendations Partial-brain fractionated radiotherapy with concurrent and adjuvant temozolomide is the standard of care after biopsy or resection of newly diagnosed glioblastoma in patients up to 70 years of age. Hypofractionated radiotherapy for elderly patients with fair to good performance status is appropriate. The addition of concurrent and adjuvant temozolomide to hypofractionated radiotherapy seems to be safe and efficacious without impairing quality of life for elderly patients with good performance status. Reasonable options for patients with poor performance status include hypofractionated radiotherapy alone, temozolomide alone, or best supportive care. Focal reirradiation represents an option for select patients with recurrent glioblastoma, although this is not supported by prospective randomized evidence. Additional information is available at www.asco.org/glioblastoma-radiotherapy-endorsement and www.asco.org/guidelineswiki. (C) 2016 by American Society of Clinical Oncology C1 [Ismaila, Nofisat] Amer Soc Clin Oncol, 2318 Mill Rd,Ste 800, Alexandria, VA 22314 USA. [Sulman, Erik P.; Armstrong, Terri S.] MD Anderson Canc Ctr, Houston, TX 77030 USA. [Armstrong, Terri S.] Univ Texas Hlth Sci Ctr Houston, Houston, TX 77030 USA. [Tsien, Christina] Washington Univ Phys, St Louis, MO USA. [Batchelor, Tracy T.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Cloughesy, Tim] Univ Calif Los Angeles, Los Angeles, CA USA. [Lovely, Mary; Chang, Susan M.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Galanis, Evanthia] Mayo Clin, Rochester, MN USA. [Gilbert, Mark] NCI, Bethesda, MD 20892 USA. [Mehta, Minesh] Univ Maryland, Sch Med, Baltimore, MD 21201 USA. [Gondi, Vinai] Northwestern Med Canc Ctr, Warrenville, IL USA. [Mumber, Matthew P.] Harbin Clin Radiat Oncol, Rome, GA USA. [Sloan, Andrew] Univ Hosp Cleveland Med Ctr, Cleveland, OH USA. RP Sulman, EP (reprint author), Amer Soc Clin Oncol, 2318 Mill Rd,Ste 800, Alexandria, VA 22314 USA. EM guidelines@asco.org OI mehta, minesh/0000-0002-4812-5713 FU AbbVie (Inst); Novocure (Inst); Pfizer (Inst); Genentech (Inst); Merck (Inst); Novelos Therapeutics (Inst); Novartis (Inst); Schering-Plough (Inst); Quest Diagnostics (Inst); Agios Pharmaceuticals (Inst); Roche (Inst) FX AbbVie (Inst), Novocure (Inst); Pfizer (Inst); Genentech (Inst), Merck (Inst); Novocure (Inst), Novelos Therapeutics (Inst); Novartis (Inst), Schering-Plough (Inst), Quest Diagnostics (Inst), Agios Pharmaceuticals (Inst), Roche (Inst) NR 40 TC 0 Z9 0 U1 1 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD JAN 20 PY 2017 VL 35 IS 3 BP 361 EP + DI 10.1200/JCO.2016.70.7562 PG 11 WC Oncology SC Oncology GA EH7PR UT WOS:000391965400014 PM 27893327 ER PT J AU Davoli, T Uno, H Wooten, EC Elledge, SJ AF Davoli, Teresa Uno, Hajime Wooten, Eric C. Elledge, Stephen J. TI Tumor aneuploidy correlates with markers of immune evasion and with reduced response to immunotherapy SO SCIENCE LA English DT Article ID COPY-NUMBER ALTERATION; DIFFERENTIAL EXPRESSION ANALYSIS; ONCOGENE-INDUCED SENESCENCE; NEGATIVE BREAST-CANCER; DNA-DAMAGE RESPONSE; CELL LUNG-CANCER; GENE-EXPRESSION; GENOMIC INSTABILITY; CHROMOSOMAL INSTABILITY; CTLA-4 BLOCKADE AB Immunotherapies based on immune checkpoint blockade are highly effective in a subset of patients. An ongoing challenge is the identification of biomarkers that predict which patients will benefit from these therapies. Aneuploidy, also known as somatic copy number alterations (SCNAs), is widespread in cancer and is posited to drive tumorigenesis. Analyzing 12 human cancer types, we find that, for most, highly aneuploid tumors show reduced expression of markers of cytotoxic infiltrating immune cells, especially CD8(+) T cells, and increased expression of cell proliferation markers. Different types of SCNAs predict the proliferation and immune signatures, implying distinct underlying mechanisms. Using published data from two clinical trials of immune checkpoint blockade therapy for metastatic melanoma, we found that tumor aneuploidy inversely correlates with patient survival. Together with other tumor characteristics such as tumor mutational load, aneuploidy may thus help identify patients most likely to respond to immunotherapy. C1 [Davoli, Teresa; Wooten, Eric C.; Elledge, Stephen J.] Harvard Med Sch, Div Genet, Brigham & Womens Hosp, Howard Hughes Med Inst,Dept Genet, Boston, MA 02115 USA. [Uno, Hajime] Dana Farber Canc Inst, Boston, MA 02215 USA. RP Elledge, SJ (reprint author), Harvard Med Sch, Div Genet, Brigham & Womens Hosp, Howard Hughes Med Inst,Dept Genet, Boston, MA 02115 USA. EM selledge@genetics.med.harvard.edu FU Department of Defense Breast Cancer Innovator Award; Ludwig Foundation; NIH [K99/R00] FX We thank K. Naxerova, P. Park, S. Sunyaev, and K. Wucherpfennig for critical reading of the manuscript and helpful advice. We thank L. F. de Andrade, L. Sironi, F. Ferrari, and members of the Elledge laboratory for helpful advice. We thank T. Chan, V. Makarov, L. Garraway, and E. V. Allen for providing sequencing data. This work was funded by a Department of Defense Breast Cancer Innovator Award, The Ludwig Foundation, NIH grant to S.J.E., and NIH Pathway to Independence Award (K99/R00) to T.D. S.J.E. is an investigator with the Howard Hughes Medical Institute. NR 71 TC 2 Z9 2 U1 11 U2 11 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 JAN 20 PY 2017 VL 355 IS 6322 BP 261 EP U75 DI 10.1126/science.aaf8399 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EI0ZP UT WOS:000392204800028 ER PT J AU Kipps, TJ Stevenson, FK Wu, CJ Croce, CM Packham, G Wierda, WG O'Brien, S Gribben, J Rai, K AF Kipps, Thomas J. Stevenson, Freda K. Wu, Catherine J. Croce, Carlo M. Packham, Graham Wierda, William G. O'Brien, Susan Gribben, John Rai, Kanti TI Chronic lymphocytic leukaemia SO NATURE REVIEWS DISEASE PRIMERS LA English DT Article ID B-CELL-RECEPTOR; PREVIOUSLY UNTREATED PATIENTS; TYROSINE KINASE INHIBITOR; GENOME-WIDE ASSOCIATION; GENE MUTATION STATUS; RICHTER SYNDROME; DNA METHYLATION; OPEN-LABEL; HIGH-RISK; T-CELLS AB Chronic lymphocytic leukaemia (CLL) is a malignancy of CD5(+) B cells that is characterized by the accumulation of small, mature-appearing lymphocytes in the blood, marrow and lymphoid tissues. Signalling via surface immunoglobulin, which constitutes the major part of the B cell receptor, and several genetic alterations play a part in CLL pathogenesis, in addition to interactions between CLL cells and other cell types, such as stromal cells, T cells and nurse-like cells in the lymph nodes. The clinical progression of CLL is heterogeneous and ranges from patients who require treatment soon after diagnosis to others who do not require therapy for many years, if at all. Several factors, including the immunoglobulin heavy-chain variable region gene (IGHV) mutational status, genomic changes, patient age and the presence of comorbidities, should be considered when defining the optimal management strategies, which include chemotherapy, chemoimmunotherapy and/or drugs targeting B cell receptor signalling or inhibitors of apoptosis, such as BCL-2. Research on the biology of CLL has profoundly enhanced our ability to identify patients who are at higher risk for disease progression and our capacity to treat patients with drugs that selectively target distinctive phenotypic or physiological features of CLL. How these and other advances have shaped our current understanding and treatment of patients with CLL is the subject of this Primer. C1 [Kipps, Thomas J.] Univ Calif San Diego, Moores Canc Ctr, Dept Med, Div Hematol Oncol, 3855 Hlth Sci Dr MC 0820, La Jolla, CA 92093 USA. [Stevenson, Freda K.; Packham, Graham] Univ Southampton, Southampton Canc Res UK Ctr, Fac Med, Southampton, Hants, England. [Wu, Catherine J.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Croce, Carlo M.] Ohio State Univ, Dept Mol Virol, Immunol & Med Genet, Columbus, OH 43210 USA. [Wierda, William G.] MD Anderson Canc Ctr, Dept Hematol, 1515 Holcombe Blvd, Houston, TX 77030 USA. [O'Brien, Susan] Univ Calif Irvine, Dept Med, Div Hematol, Irvine, CA USA. [Gribben, John] Queen Mary Univ London, Barts Canc Inst, Dept Haemato Oncol, London, England. [Rai, Kanti] Feinstein Inst Med Res, Northwell Hlth, CLL Res & Treatment Program, New Hyde Pk, New York, NY USA. RP Kipps, TJ (reprint author), Univ Calif San Diego, Moores Canc Ctr, Dept Med, Div Hematol Oncol, 3855 Hlth Sci Dr MC 0820, La Jolla, CA 92093 USA. EM tkipps@ucsd.edu FU US NIH [PO1-CA81534]; Bloodwise, Kay Kendall Leukaemia Fund, Cancer Research UK; Southampton Experimental Cancer Medicine Centre; Southampton Cancer Research UK Centre; Leukemia & Lymphoma Society (LLS) Specialized Center of Research Program (SCOR) grant [1R01HL116452, 1R01CA182461]; CLL Global Reseach Foundation; Blood Cancer Research Fund; [U10CA180861] FX The authors thank H.-Y. Wang and E. Broome, Department of Pathology, University of California San Diego, for their contributions to Figures 5-7. The authors also thank A. Greaves, University of California San Diego, for help in figure development. This Primer is supported by the US NIH PO1-CA81534 for the CLL Research Consortium; members include K.R., W.G.W., T.J.K., C.M.C., C.J.W. and J.G. The authors also acknowledge support to F.K.S. and G.P. from Bloodwise, Kay Kendall Leukaemia Fund, Cancer Research UK, the Southampton Experimental Cancer Medicine Centre, and the Southampton Cancer Research UK Centre (F.K.S. and G.P.). The authors also acknowledge support from the Leukemia & Lymphoma Society (LLS) Specialized Center of Research Program (SCOR) grant (T.J.K.), 1R01HL116452, 1R01CA182461, CLL Global Reseach Foundation (W.G.W.), the Blood Cancer Research Fund (T.J.K.), and U10CA180861. NR 212 TC 2 Z9 2 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2056-676X J9 NAT REV DIS PRIMERS JI Nat. Rev. Dis. Primers PD JAN 19 PY 2017 VL 3 AR 16096 DI 10.1038/nrdp.2016.96 PG 21 WC Medicine, General & Internal SC General & Internal Medicine GA EQ2II UT WOS:000397892000001 PM 28102226 ER PT J AU Buisson, R Niraj, J Rodrigue, A Ho, CK Kreuzer, J Foo, TK Hardy, EJL Dellaire, G Haas, W Xia, B Masson, JY Zou, L AF Buisson, Remi Niraj, Joshi Rodrigue, Amelie Ho, Chu Kwen Kreuzer, Johannes Foo, Tzeh Keong Hardy, Emilie J. -L. Dellaire, Graham Haas, Wilhelm Xia, Bing Masson, Jean-Yves Zou, Lee TI Coupling of Homologous Recombination and the Checkpoint by ATR SO MOLECULAR CELL LA English DT Article ID DNA-END RESECTION; SINGLE-STRANDED-DNA; DEPENDENT PHOSPHORYLATION; MEDIATED PHOSPHORYLATION; DAMAGE RESPONSE; PALB2 PROMOTES; FANCONI-ANEMIA; CANCER-CELLS; BETA-TRCP; S-PHASE AB ATR is a key regulator of cell-cycle checkpoints and homologous recombination (HR). Paradoxically, ATR inhibits CDKs during checkpoint responses, but CDK activity is required for efficient HR. Here, we show that ATR promotes HR after CDK-driven DNA end resection. ATR stimulates the BRCA1-PALB2 interaction after DNA damage and promotes PALB2 localization to DNA damage sites. ATR enhances BRCA1-PALB2 binding at least in part by inhibiting CDKs. The optimal interaction of BRCA1 and PALB2 requires phosphorylation of PALB2 at S59, an ATR site, and hypo-phosphorylation of S64, a CDK site. The PALB2-S59A/S64E mutant is defective for localization to DNA damage sites and HR, whereas the PALB2-S59E/S64A mutant partially bypasses ATR for its localization. Thus, HR is a biphasic process requiring both high-CDK and low-CDK periods. As exemplified by the regulation of PALB2 by ATR, ATR promotes HR by orchestrating a "CDKto-ATR switch'' post-resection, directly coupling the checkpoint to HR. C1 [Buisson, Remi; Ho, Chu Kwen; Kreuzer, Johannes; Hardy, Emilie J. -L.; Haas, Wilhelm; Zou, Lee] Harvard Med Sch, Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Niraj, Joshi; Rodrigue, Amelie; Masson, Jean-Yves] Univ Laval, Canc Res Ctr, Dept Mol Biol Med Biochem, CHU Quebec Res Ctr,Oncol Axis, Quebec City, PQ G1V 0A6, Canada. [Foo, Tzeh Keong; Xia, Bing] Rutgers Canc Inst New Jersey, Dept Radiat Oncol, New Brunswick, NJ 08903 USA. [Dellaire, Graham] Dalhousie Univ, Dept Pathol, Halifax, NS B3H 4R2, Canada. [Zou, Lee] Harvard Med Sch, Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. RP Zou, L (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA.; Masson, JY (reprint author), Univ Laval, Canc Res Ctr, Dept Mol Biol Med Biochem, CHU Quebec Res Ctr,Oncol Axis, Quebec City, PQ G1V 0A6, Canada.; Zou, L (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. EM jean-yves.masson@crchudequebec.ulaval.ca; zou.lee@mgh.harvard.edu OI FOO, TZEH KEONG/0000-0003-0168-7054 FU Marsha Rivkin Scholar Award; Susan G. Komen Fellowship; Jim and Ann Orr Massachusetts General Hospital Research Scholar Award; NIH [GM076388, CA197779, CA138804, CA188096]; Federal Share of Program Income; CIHR FX We thank the members of the L.Z. and Dyson labs for helpful discussions. R.B. is supported by a Marsha Rivkin Scholar Award and a Susan G. Komen Fellowship. L.Z. is the James and Patricia Poitras Endowed Chair in Cancer Research and is supported by a Jim and Ann Orr Massachusetts General Hospital Research Scholar Award. J.-Y.M. is an FRQS Chercheur National and FRQS Chair. This work is supported by grants from the NIH (GM076388 and CA197779 to L.Z.; CA138804 and CA188096 to B.X.), Federal Share of Program Income (to L.Z.), and CIHR (to J.-Y.M.). NR 43 TC 3 Z9 3 U1 0 U2 0 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 JAN 19 PY 2017 VL 65 IS 2 BP 336 EP 346 DI 10.1016/j.molcel.2016.12.007 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA EO1AZ UT WOS:000396431300013 PM 28089683 ER PT J AU Allen, SI Foulds, J Pachas, GN Veldheer, S Cather, C Azzouz, N Hrabovsky, S Hameed, A Yingst, J Hammett, E Modesto, J Krebs, NM Zhu, JJ Liao, J Muscat, JE Richie, J Evins, AE AF Allen, Sophia I. Foulds, Jonathan Pachas, Gladys N. Veldheer, Susan Cather, Corinne Azzouz, Nour Hrabovsky, Shari Hameed, Ahmad Yingst, Jessica Hammett, Erin Modesto, Jennifer Krebs, Nicolle M. Zhu, Junjia Liao, Jason Muscat, Joshua E. Richie, John Evins, A. Eden TI A two-site, two-arm, 34-week, double-blind, parallel-group, randomized controlled trial of reduced nicotine cigarettes in smokers with mood and/or anxiety disorders: trial design and protocol SO BMC PUBLIC HEALTH LA English DT Article DE Tobacco; Cigarettes; RCT; Mood; Anxiety; Spectrum; Cotinine; NNAL ID PSYCHOMETRIC EVALUATION; PSYCHOLOGICAL DISTRESS; PSYCHIATRIC-DISORDERS; SMOKING-BEHAVIOR; MENTAL-ILLNESS; EXPOSURE; WITHDRAWAL; QUESTIONNAIRE; DEPENDENCE; POPULATION AB Background: The U.S. Food and Drug Administration can set standards for cigarettes that could include reducing their nicotine content. Such a standard should improve public health without causing unintended serious consequences for sub-populations. This study evaluates the effect of progressive nicotine reduction in cigarettes on smoking behavior, toxicant exposure, and psychiatric symptoms in smokers with comorbid mood and/or anxiety disorders using a two-site, two-arm, double-blind, parallel group, randomized controlled trial (RCT) in four phases over 34 weeks. Methods: Adult smokers (N=200) of 5 or more cigarettes per day will be randomized across two sites (Penn State and Massachusetts General). Participants must have not had a quit attempt in the prior month, nor be planning to quit in the next 6 months, meet criteria for a current or lifetime unipolar mood and/or anxiety disorder based on the structured Mini-International Neuropsychiatric Interview, and must not have an unstable medical or psychiatric condition. After a week of smoking their own cigarettes, participants receive two weeks of Spectrum research cigarettes with usual nicotine content (11.6 mg). After this baseline period, participants will be randomly assigned to continue smoking Spectrum research cigarettes that contain either (a) Usual Nicotine Content (11.6 mg); or (b) Reduced Nicotine Content: the nicotine content per cigarette is progressively reduced from approximately 11.6 mg to 0.2 mg in five steps over 18 weeks. At the end of the randomization phase, participants will be offered the choice to either (a) quit smoking with assistance, (b) continue smoking free research cigarettes, or (c) return to purchasing their own cigarettes, for the final 12 weeks of the study. The primary outcome measure is blood cotinine; key secondary outcomes are: exhaled carbon monoxide, urinary total NNAL-4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol and 1-hydroxypyrene, oxidative stress biomarkers including 8-isoprostanes, measures of psychiatric symptoms (e.g., depression, anxiety), smoking behavior and dependence (e.g., cigarette consumption, quit attempts), and health effects (e.g., blood pressure, respiratory symptoms). Discussion: Results from this study will inform FDA on the potential effects of regulating the nicotine content of cigarettes and help determine whether smokers with mood and/or anxiety disorders can safely transition to significantly reduced nicotine content cigarettes. C1 [Allen, Sophia I.; Foulds, Jonathan; Veldheer, Susan; Hrabovsky, Shari; Yingst, Jessica; Hammett, Erin; Modesto, Jennifer; Krebs, Nicolle M.; Zhu, Junjia; Liao, Jason; Muscat, Joshua E.; Richie, John] Penn State Univ, Coll Med, Dept Publ Hlth Sci, Tobacco Ctr Regulatory Sci, MC CH69,500 Univ Dr,POB 850, Hershey, PA 17033 USA. [Hameed, Ahmad] Penn State Univ, Coll Med, Dept Psychiat, Hershey, PA USA. [Pachas, Gladys N.; Cather, Corinne; Azzouz, Nour; Evins, A. Eden] Massachusetts Gen Hosp, Dept Psychiat, Ctr Addict Med, Boston, MA 02114 USA. [Pachas, Gladys N.; Cather, Corinne; Azzouz, Nour; Evins, A. Eden] Harvard Med Sch, Boston, MA USA. RP Allen, SI (reprint author), Penn State Univ, Coll Med, Dept Publ Hlth Sci, Tobacco Ctr Regulatory Sci, MC CH69,500 Univ Dr,POB 850, Hershey, PA 17033 USA. EM sallen@phs.psu.edu OI Yingst, Jessica/0000-0003-3028-668X; Allen, Sophia/0000-0002-1809-3749 FU National Institute on Drug Abuse of the National Institutes of Health [P50DA036107]; Center for Tobacco Products of the U.S. Food and Drug Administration; Penn State Clinical & Translational Research Institute, Pennsylvania State University CTSA, NIH/NCATS [UL1 TR000127] FX Proposed research reported in this publication is supported by the National Institute on Drug Abuse of the National Institutes of Health under Award Number P50DA036107 (JM & JF PIs for parent grant; JF and AEE PIs for this study) and the Center for Tobacco Products of the U.S. Food and Drug Administration. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or the Food and Drug Administration. Participants at the Penn State University site are seen at the Clinical Research Center supported by the Penn State Clinical & Translational Research Institute, Pennsylvania State University CTSA, NIH/NCATS Grant Number UL1 TR000127. NR 65 TC 0 Z9 0 U1 5 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2458 J9 BMC PUBLIC HEALTH JI BMC Public Health PD JAN 19 PY 2017 VL 17 AR 100 DI 10.1186/s12889-016-3946-4 PG 13 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA EJ0QC UT WOS:000392914200001 PM 28103841 ER PT J AU Olson, KR Davarpanah, AH Schaefer, EA Elias, N Misdraji, J AF Olson, Kristian R. Davarpanah, Amir H. Schaefer, Esperance A. Elias, Nahel Misdraji, Joseph TI Case 2-2017: An 18-Year-Old Woman with Acute Liver Failure SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID WILSONS-DISEASE; AUTOIMMUNE HEPATITIS; TRANSPLANTATION; DIAGNOSIS; EXPERIENCE; PREGNANCY; PATHOLOGY; OUTCOMES; CHILDREN; SCORE C1 [Olson, Kristian R.; Schaefer, Esperance A.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Olson, Kristian R.] Massachusetts Gen Hosp, Dept Pediat, Boston, MA 02114 USA. [Davarpanah, Amir H.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA USA. [Elias, Nahel] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Misdraji, Joseph] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Olson, Kristian R.; Schaefer, Esperance A.] Harvard Med Sch, Dept Med, Boston, MA 02115 USA. [Olson, Kristian R.] Harvard Med Sch, Dept Pediat, Boston, MA 02115 USA. [Davarpanah, Amir H.] Harvard Med Sch, Dept Radiol, Boston, MA USA. [Elias, Nahel] Harvard Med Sch, Dept Surg, Boston, MA USA. [Misdraji, Joseph] Harvard Med Sch, Dept Pathol, Boston, MA USA. RP Olson, KR (reprint author), Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA.; Olson, KR (reprint author), Massachusetts Gen Hosp, Dept Pediat, Boston, MA 02114 USA.; Olson, KR (reprint author), Harvard Med Sch, Dept Med, Boston, MA 02115 USA.; Olson, KR (reprint author), Harvard Med Sch, Dept Pediat, Boston, MA 02115 USA. NR 25 TC 0 Z9 0 U1 3 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 JAN 19 PY 2017 VL 376 IS 3 BP 268 EP 278 DI 10.1056/NEJMcpc1613467 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA EI0XO UT WOS:000392199100012 PM 28099829 ER PT J AU Caio, G AF Caio, Giacomo TI Myocarditis with Immune Checkpoint Blockade SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter ID AUTOANTIBODIES; TISSUE C1 [Caio, Giacomo] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Caio, G (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. EM gcaio@mghharvard.edu NR 3 TC 0 Z9 0 U1 1 U2 1 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JAN 19 PY 2017 VL 376 IS 3 BP 291 EP 292 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA EI0XO UT WOS:000392199100026 PM 28099833 ER PT J AU Freund, NT Wang, HQ Scharf, L Nogueira, L Horwitz, JA Bar-On, Y Golijanin, J Sievers, SA Sok, D Cai, H Lorenzi, JCC Halper-Stromberg, A Toth, I Piechocka-Trocha, A Gristick, HB van Gils, MJ Sanders, RW Wang, LX Seaman, MS Burton, DR Gazumyan, A Walker, BD West, AP Bjorkman, PJ Nussenzweig, MC AF Freund, Natalia T. Wang, Haoqing Scharf, Louise Nogueira, Lilian Horwitz, Joshua A. Bar-On, Yotam Golijanin, Jovana Sievers, Stuart A. Sok, Devin Cai, Hui Lorenzi, Julio C. Cesar Halper-Stromberg, Ariel Toth, Ildiko Piechocka-Trocha, Alicja Gristick, Harry B. van Gils, Marit J. Sanders, Rogier W. Wang, Lai-Xi Seaman, Michael S. Burton, Dennis R. Gazumyan, Anna Walker, Bruce D. West, Anthony P., Jr. Bjorkman, Pamela J. Nussenzweig, Michel C. TI Coexistence of potent HIV-1 broadly neutralizing antibodies and antibody-sensitive viruses in a viremic controller SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; EM STRUCTURE DETERMINATION; CD4 BINDING-SITE; HUMANIZED MICE; ENVELOPE GLYCOPROTEINS; TREATMENT INTERRUPTION; DISEASE PROGRESSION; GLYCAN RECOGNITION; ELITE CONTROLLERS; TYPE-1 INFECTION AB Some HIV-1-infected patients develop broad and potent HIV-1 neutralizing antibodies (bNAbs) that when passively transferred to mice or macaques can treat or prevent infection. However, bNAbs typically fail to neutralize coexisting autologous viruses due to antibody-mediated selection against sensitive viral strains. We describe an HIV-1 controller expressing HLA-B57*01 and HLA-B27*05 who maintained low viral loads for 30 years after infection and developed broad and potent serologic activity against HIV-1. Neutralization was attributed to three different bNAbs targeting nonoverlapping sites on the HIV-1 envelope trimer (Env). One of the three, BG18, an antibody directed against the glycan-V3 portion of Env, is the most potent member of this class reported to date and, as revealed by crystallography and electron microscopy, recognizes HIV-1 Env in a manner that is distinct from other bNAbs in this class. Single-genome sequencing of HIV-1 from serum samples obtained over a period of 9 years showed a diverse group of circulating viruses, 88.5% (31 of 35) of which remained sensitive to at least one of the temporally coincident autologous bNAbs and the individual's serum. Thus, bNAb-sensitive strains of HIV-1 coexist with potent neutralizing antibodies that target the virus and may contribute to control in this individual. When administered as a mix, the three bNAbs controlled viremia in HIV-1(YU2)-infected humanized mice. Our finding suggests that combinations of bNAbs may contribute to control of HIV-1 infection. C1 [Freund, Natalia T.; Nogueira, Lilian; Horwitz, Joshua A.; Bar-On, Yotam; Golijanin, Jovana; Lorenzi, Julio C. Cesar; Halper-Stromberg, Ariel; Gazumyan, Anna; Nussenzweig, Michel C.] Rockefeller Univ, Lab Mol Immunol, New York, NY 10065 USA. [Wang, Haoqing; Scharf, Louise; Sievers, Stuart A.; Gristick, Harry B.; West, Anthony P., Jr.; Bjorkman, Pamela J.] CALTECH, Div Biol & Biol Engn, Pasadena, CA 91125 USA. [Sok, Devin; Burton, Dennis R.] Scripps Res Inst, Dept Immunol & Microbial Sci, Ctr HIV AIDS Vaccine Immunol & Immunogen Discover, La Jolla, CA 92037 USA. [Sok, Devin; Burton, Dennis R.] Scripps Res Inst, Int AIDS Vaccine Initiat, Neutralizing Antibody Ctr, La Jolla, CA 92037 USA. [Cai, Hui; Wang, Lai-Xi] Univ Maryland, Dept Chem & Biochem, 8051 Regents Dr, College Pk, MD 20742 USA. [Toth, Ildiko; Piechocka-Trocha, Alicja; Burton, Dennis R.; Walker, Bruce D.] MIT, Massachusetts Gen Hosp, Ragon Inst, Cambridge, MA 02129 USA. [Toth, Ildiko; Piechocka-Trocha, Alicja; Burton, Dennis R.; Walker, Bruce D.] Harvard Univ, Cambridge, MA 02129 USA. [van Gils, Marit J.; Sanders, Rogier W.] Univ Amsterdam, Acad Med Ctr, Dept Med Microbiol, Amsterdam, Netherlands. [Seaman, Michael S.] Harvard Med Sch, Ctr Virol & Vaccine Res, Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Walker, Bruce D.] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. [Scharf, Louise] 23andMe, Mountain View, CA 94041 USA. [Sievers, Stuart A.] Kite Pharma, Santa Monica, CA 90404 USA. RP Nussenzweig, MC (reprint author), Rockefeller Univ, Lab Mol Immunol, New York, NY 10065 USA. EM nussen@rockefeller.edu FU Robertson Foundation; Rockefeller University; Bill and Melinda Gates Foundation [OPP1033115]; Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery Scripps grant [UM1 AI 100663]; NIH HIV Vaccine Research and Design grant [1 P01 AI100148]; NIH [2 P50 GM082545-06]; Gordon and Betty Moore Foundation; Melinda and Bill Gates Foundation [OPP1032144]; California HIV/AIDS Research Program (CHRP) [F12-CT-214] FX This work was supported by the Robertson Foundation, the Rockefeller University, the Bill and Melinda Gates Foundation grant OPP1033115, the Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery Scripps grant UM1 AI 100663, the NIH HIV Vaccine Research and Design grant 1 P01 AI100148 (to M.C.N. and P.J.B.), the NIH grant 2 P50 GM082545-06 (to P.J.B.), the Molecular Observatory and EM funding at Caltech supported by the Gordon and Betty Moore Foundation, the Melinda and Bill Gates Foundation Collaboration for AIDS Vaccine Discovery grant OPP1032144 (to M.S.S.), and the California HIV/AIDS Research Program (CHRP grant F12-CT-214 to S.A.S.). NR 104 TC 0 Z9 0 U1 1 U2 1 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 JAN 18 PY 2017 VL 9 IS 373 AR eaal2144 DI 10.1126/scitranslmed.aal2144 PG 13 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA EL2JX UT WOS:000394447000002 ER PT J AU Coccolini, F Stahel, PF Montori, G Biffl, W Horer, TM Catena, F Kluger, Y Moore, EE Peitzman, AB Ivatury, R Coimbra, R Fraga, GP Pereira, B Rizoli, S Kirkpatrick, A Leppaniemi, A Manfredi, R Magnone, S Chiara, O Solaini, L Ceresoli, M Allievi, N Arvieux, C Velmahos, G Balogh, Z Naidoo, N Weber, D Abu-Zidan, F Sartelli, M Ansaloni, L AF Coccolini, Federico Stahel, Philip F. Montori, Giulia Biffl, Walter Horer, Tal M. Catena, Fausto Kluger, Yoram Moore, Ernest E. Peitzman, Andrew B. Ivatury, Rao Coimbra, Raul Fraga, Gustavo Pereira Pereira, Bruno Rizoli, Sandro Kirkpatrick, Andrew Leppaniemi, Ari Manfredi, Roberto Magnone, Stefano Chiara, Osvaldo Solaini, Leonardo Ceresoli, Marco Allievi, Niccolo Arvieux, Catherine Velmahos, George Balogh, Zsolt Naidoo, Noel Weber, Dieter Abu-Zidan, Fikri Sartelli, Massimo Ansaloni, Luca TI Pelvic trauma: WSES classification and guidelines SO WORLD JOURNAL OF EMERGENCY SURGERY LA English DT Review DE Pelvic; Trauma; Management; Guidelines; Mechanic; Injury; Angiography; REBOA; ABO; Preperitoneal pelvic packing; External fixation; Internal fixation; X-ray; Pelvic ring fractures ID ENDOVASCULAR BALLOON OCCLUSION; HEMODYNAMICALLY UNSTABLE PATIENTS; TRANSFORAMINAL SACRAL FRACTURES; DAMAGE CONTROL ORTHOPEDICS; NONCOMPRESSIBLE TORSO HEMORRHAGE; RANDOMIZED-CLINICAL-TRIAL; RING INJURIES; BLUNT TRAUMA; AORTA REBOA; C-CLAMP AB Complex pelvic injuries are among the most dangerous and deadly trauma related lesions. Different classification systems exist, some are based on the mechanism of injury, some on anatomic patterns and some are focusing on the resulting instability requiring operative fixation. The optimal treatment strategy, however, should keep into consideration the hemodynamic status, the anatomic impairment of pelvic ring function and the associated injuries. The management of pelvic trauma patients aims definitively to restore the homeostasis and the normal physiopathology associated to the mechanical stability of the pelvic ring. Thus the management of pelvic trauma must be multidisciplinary and should be ultimately based on the physiology of the patient and the anatomy of the injury. This paper presents the World Society of Emergency Surgery (WSES) classification of pelvic trauma and the management Guidelines. C1 [Coccolini, Federico; Montori, Giulia; Manfredi, Roberto; Magnone, Stefano; Solaini, Leonardo; Ceresoli, Marco; Allievi, Niccolo; Ansaloni, Luca] Papa Giovanni XXIII Hosp, Gen Emergency & Trauma Surg, Pzza OMS 1, I-24128 Bergamo, Italy. [Stahel, Philip F.] Denver Hlth Med Ctr, Dept Orthoped Surg, Denver, CO USA. [Stahel, Philip F.] Denver Hlth Med Ctr, Dept Neurosurg, Denver, CO USA. [Stahel, Philip F.] Univ Colorado, Sch Med, Denver, CO USA. [Biffl, Walter] Queens Med Ctr, Acute Care Surg, Honolulu, HI USA. [Horer, Tal M.] Orebro Univ Hosp, Dept Cardiothorac & Vasc Surg, Orebro, Sweden. [Horer, Tal M.] Orebro Univ Hosp, Dept Surg, Orebro, Sweden. [Horer, Tal M.] Univ Orebro, Orebro, Sweden. [Catena, Fausto] Maggiore Hosp, Emergency & Trauma Surg, Parma, Italy. [Kluger, Yoram] Rambam Hlth Care Campus Haifa, Div Gen Surg, Haifa, Israel. [Moore, Ernest E.] Denver Hlth, Trauma Surg, Denver, CO USA. [Peitzman, Andrew B.] Univ Pittsburgh, Dept Surg, Pittsburgh, PA USA. [Ivatury, Rao] Virginia Commonwealth Univ, Richmond, VA USA. [Coimbra, Raul] UC San Diego Hlth Syst, Dept Surg, San Diego, CA USA. [Fraga, Gustavo Pereira; Pereira, Bruno] Univ Estadual Campinas, FCM, Campinas, SP, Brazil. [Rizoli, Sandro] St Michaels Hosp, Trauma & Acute Care Serv, Toronto, ON, Canada. [Kirkpatrick, Andrew] Foothills Med Ctr, Gen Acute Care Abdominal Wall Reconstruct & Traum, Calgary, AB, Canada. [Leppaniemi, Ari] Univ Hosp Meilahti, Abdominal Ctr, Helsinki, Finland. [Chiara, Osvaldo] Osped Niguarda Ca Granda, Emergency & Trauma Surg, Milan, Italy. [Arvieux, Catherine] Univ Grenoble Alpes, Digest & Emergency Surg, Grenoble, France. [Velmahos, George] Harvard Med Sch, Massachusetts Gen Hosp, Div Trauma Emergency Surg & Surg Crit Care, Boston, MA USA. [Balogh, Zsolt] John Hunter Hosp, Dept Traumatol, Newcastle, NSW, Australia. [Balogh, Zsolt] Univ Newcastle, Newcastle, NSW, Australia. [Naidoo, Noel] Univ KwaZulu Natal, Dept Surg, Durban, South Africa. [Weber, Dieter] Royal Perth Hosp, Dept Gen Surg, Perth, WA, Australia. [Abu-Zidan, Fikri] UAE Univ, Coll Med & Hlth Sci, Dept Surg, Al Ain, U Arab Emirates. [Sartelli, Massimo] Macerata Hosp, Gen & Emergency Surg, Macerata, Italy. RP Coccolini, F (reprint author), Papa Giovanni XXIII Hosp, Gen Emergency & Trauma Surg, Pzza OMS 1, I-24128 Bergamo, Italy. EM federico.coccolini@gmail.com NR 160 TC 0 Z9 0 U1 1 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1749-7922 J9 WORLD J EMERG SURG JI World J. Emerg. Surg. PD JAN 18 PY 2017 VL 12 AR 5 DI 10.1186/s13017-017-0117-6 PG 18 WC Emergency Medicine; Surgery SC Emergency Medicine; Surgery GA EM7GG UT WOS:000395478900002 PM 28115984 ER PT J AU Reznik, E Wang, QG La, K Schultz, N Sander, C AF Reznik, Ed Wang, Qingguo La, Konnor Schultz, Nikolaus Sander, Chris TI Mitochondrial respiratory gene expression is suppressed in many cancers SO ELIFE LA English DT Article ID RENAL-CELL CARCINOMA; RNA-SEQ DATA; GENOMIC LANDSCAPE; BIOGENESIS; LONGEVITY; DISEASE; DNA AB The fundamental metabolic decision of a cell, the balance between respiration and fermentation, rests in part on expression of the mitochondrial genome (mtDNA) and coordination with expression of the nuclear genome (nuDNA). Previously we described mtDNA copy number depletion across many solid tumor types (Reznik et al., 2016). Here, we use orthogonal RNA-sequencing data to quantify mtDNA expression (mtRNA), and report analogously lower expression of mtRNA in tumors (relative to normal tissue) across a majority of cancer types. Several cancers exhibit a trio of mutually consistent evidence suggesting a drop in respiratory activity: depletion of mtDNA copy number, decreases in mtRNA levels, and decreases in expression of nuDNA-encoded respiratory proteins. Intriguingly, a minority of cancer types exhibit a drop in mtDNA expression but an increase in nuDNA expression of respiratory proteins, with unknown implications for respiratory activity. Our results indicate suppression of respiratory gene expression across many cancer types. C1 [Reznik, Ed; Wang, Qingguo; La, Konnor; Schultz, Nikolaus] Mem Sloan Kettering Canc Ctr, Ctr Mol Oncol, 1275 York Ave, New York, NY 10021 USA. [Sander, Chris] Harvard Med Sch, Dept Cell Biol, Boston, MA 02115 USA. [Sander, Chris] Dana Farber Canc Inst, cBio Ctr, Boston, MA 02115 USA. [Wang, Qingguo] Lipscomb Univ, Coll Comp & Technol, Nashville, TN USA. RP Reznik, E; Schultz, N (reprint author), Mem Sloan Kettering Canc Ctr, Ctr Mol Oncol, 1275 York Ave, New York, NY 10021 USA.; Sander, C (reprint author), Harvard Med Sch, Dept Cell Biol, Boston, MA 02115 USA.; Sander, C (reprint author), Dana Farber Canc Inst, cBio Ctr, Boston, MA 02115 USA. EM reznike@mskcc.org; schultz@cbio.mskcc.org; sander.research@gmail.com OI Wang, Qingguo/0000-0002-5125-3724; Reznik, Ed/0000-0002-6511-5947 FU National Cancer Institute [5U24CA143840, P30-CA008748]; National Institutes of Health [P41GM103504]; Marie-Josee and Henry R. Kravis Center for Molecular Oncology; Roberston Foundation; Prostate Cancer Foundation FX National Cancer Institute 5U24CA143840 Ed Reznik Nikolaus Schultz Chris Sander; National Institutes of Health P41GM103504 Ed Reznik Nikolaus Schultz Chris Sander; Marie-Josee and Henry R. Kravis Center for Molecular Oncology Ed Reznik Qingguo Wang Konnor La Nikolaus Schultz; National Cancer Institute P30-CA008748 Ed Reznik Qingguo Wang Konnor La Nikolaus Schultz Chris Sander; Roberston Foundation Nikolaus Schultz; Prostate Cancer Foundation Nikolaus Schult; The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. NR 40 TC 1 Z9 1 U1 1 U2 1 PU ELIFE SCIENCES PUBLICATIONS LTD PI CAMBRIDGE PA SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND SN 2050-084X J9 ELIFE JI eLife PD JAN 18 PY 2017 VL 6 AR e21592 DI 10.7554/eLife.21592 PG 16 WC Biology SC Life Sciences & Biomedicine - Other Topics GA EJ7HC UT WOS:000393391400001 ER PT J AU Tam, CP Fahrenbach, AC Bjorkbom, A Prywes, N Izgu, EC Szostak, JW AF Tam, Chun Pong Fahrenbach, Albert C. Bjorkbom, Anders Prywes, Noam Izgu, Enver Cagri Szostak, Jack W. TI Downstream Oligonucleotides Strongly Enhance the Affinity of GMP to RNA Primer-Template Complexes SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID DIRECTED SYNTHESIS; RING CURRENTS; EXTENSION; POLYMERASE; TRANSCRIPTION; BINDING; ORIGIN; DNA; NUCLEOTIDES; REPLICATION AB Origins of life hypotheses often invoke a transitional phase of nonenzymatic template-directed RNA replication prior to the emergence of ribozyme-catalyzed copying of genetic information. Here, using NMR and ITC, we interrogate the binding affinity of guanosine 5'-monophosphate (GMP) for primer template complexes when either another GMP, or a helper oligonucleotide, can bind downstream. Binding of GMP to a primer template complex cannot be significantly enhanced by the possibility of downstream monomer binding, because the affinity of the downstream monomer is weaker than that of the first monomer. Strikingly, GMP binding affinity can be enhanced by ca. 2, orders of magnitude when a helper oligonucleotide is stably bound downstream of the monomer binding site. We compare these thermodynamic parameters to those previously reported for T7 RNA polymerase-mediated replication to help address questions of binding affinity in related nonenzymatic processes. C1 [Tam, Chun Pong; Fahrenbach, Albert C.; Bjorkbom, Anders; Prywes, Noam; Izgu, Enver Cagri; Szostak, Jack W.] Massachusetts Gen Hosp, Howard Hughes Med Inst, Dept Mol Biol, 185 Cambridge St, Boston, MA 02114 USA. [Tam, Chun Pong; Fahrenbach, Albert C.; Bjorkbom, Anders; Prywes, Noam; Izgu, Enver Cagri; Szostak, Jack W.] Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, 185 Cambridge St, Boston, MA 02114 USA. [Tam, Chun Pong; Prywes, Noam; Szostak, Jack W.] Harvard Univ, Dept Chem & Chem Biol, 12 Oxford St, Cambridge, MA 02138 USA. [Fahrenbach, Albert C.; Szostak, Jack W.] Tokyo Inst Technol, Earth Life Sci Inst, Meguro Ku, 2-12-1-1E-1 Ookayama, Tokyo 1528550, Japan. [Bjorkbom, Anders] Abo Akad Univ, Dept Biosci, FI-20520 Turku, Finland. EM szostak@molbio.mgh.harvard.edu FU Simons Foundation [290363]; Earth-Life Science Institute at the Tokyo Institute of Technology; Academy of Finland FX J.W.S. is an Investigator of the Howard Hughes Medical Institute. This work was supported in part by a grant from the Simons Foundation to J.W.S. (290363). A.C.F. is supported by a Research Fellowship from the Earth-Life Science Institute at the Tokyo Institute of Technology. A.B. was supported by a grant from the Academy of Finland. We thank Dr. Victor Lelyveld, Dr. Seung Soo Oh, Dr. Li Li, Dr. Aaron Engelhart, Dr. Christian Hentrich, Dr. Lijun Zhou, and the rest of the Szostak lab for helpful discussions. NR 39 TC 0 Z9 0 U1 8 U2 8 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 JAN 18 PY 2017 VL 139 IS 2 BP 571 EP 574 DI 10.1021/jacs.6b09760 PG 4 WC Chemistry, Multidisciplinary SC Chemistry GA EI4JH UT WOS:000392459300002 PM 28055190 ER PT J AU Chen, YC Backus, KM Merkulova, M Yang, C Brown, D Cravatt, BF Zhang, C AF Chen, Ying-Chu Backus, Keriann M. Merkulova, Maria Yang, Christina Brown, Dennis Cravatt, Benjamin F. Zhang, Chao TI Covalent Modulators of the Vacuolar ATPase SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID YEAST V-ATPASE; SITE-DIRECTED MUTAGENESIS; H+-ATPASE; MUTATIONAL ANALYSIS; CANCER-CELLS; SUBUNIT-C; IDENTIFICATION; INHIBITORS AB The vacuolar H+ ATPase (V-ATPase) is a complex multisubunit machine that regulates important cellular processes through controlling acidity of intracellular compartments in eukaryotes. Existing small molecule modulators of V-ATPase either are restricted to targeting one membranous subunit of V-ATPase or have poorly understood mechanisms of action. Small molecules with novel and defined mechanisms of inhibition are thus needed to functionally characterize V-ATPase and to fully evaluate the therapeutic relevance of V-ATPase in human diseases. We have discovered electrophilic quinazolines that covalently modify a soluble catalytic subunit of V-ATPase with high potency and exquisite proteomic selectivity as revealed by fluorescence imaging and chemical proteomic activity-based profiling. The site of covalent modification was mapped to a cysteine residue located in a region of V-ATPase subunit A that is thought to regulate the dissociation of V-ATPase. We further demonstrate that a previously reported V-ATPase inhibitor, 3-bromopyruvate, also targets the same cysteine residue and that our electrophilic quinazolines modulate the function of V-ATPase in cells. With their well-defined mechanism of action and high proteomic specificity, the described quinazolines offer a powerful set of chemical probes to investigate the physiological and pathological roles of V-ATPase. C1 [Chen, Ying-Chu; Zhang, Chao] Univ Southern Calif, Dept Chem, Los Angeles, CA 90089 USA. [Chen, Ying-Chu; Zhang, Chao] Univ Southern Calif, Loker Hydrocarbon Res Inst, Los Angeles, CA 90089 USA. [Yang, Christina; Zhang, Chao] Univ Southern Calif, Dept Biol Sci, Mol & Computat Biol Program, Los Angeles, CA 90089 USA. [Backus, Keriann M.; Cravatt, Benjamin F.] Scripps Res Inst, Dept Physiol Chem, La Jolla, CA 92307 USA. [Merkulova, Maria; Brown, Dennis] Massachusetts Gen Hosp, Ctr Syst Biol, Program Membrane Biol, Boston, MA 02114 USA. [Merkulova, Maria; Brown, Dennis] Massachusetts Gen Hosp, Richard B Simches Res Ctr, Div Nephrol, Boston, MA 02114 USA. [Merkulova, Maria; Brown, Dennis] Harvard Med Sch, Dept Med, Boston, MA 02114 USA. EM zhang.chao@usc.edu FU National Science Foundation [CHE-1455306]; American Cancer Society [IRG-58-007-51]; University of Southern California; National Institute of Health [R37 DK042956] FX We thank Prof. Yi Tang (University of California, Los Angeles) for generous help with high-resolution mass spectrometry. This work was supported in part by the National Science Foundation (CHE-1455306), American Cancer Society (IRG-58-007-51), University of Southern California, and National Institute of Health (R37 DK042956 to D.B.). NR 23 TC 0 Z9 0 U1 6 U2 6 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 JAN 18 PY 2017 VL 139 IS 2 BP 639 EP 642 DI 10.1021/jacs.6b12511 PG 4 WC Chemistry, Multidisciplinary SC Chemistry GA EI4JH UT WOS:000392459300019 PM 28010062 ER PT J AU Velasco, C Mateo, J Santos, A Mota-Cobian, A Herranz, F Pellico, J Mota, RA Espana, S Ruiz-Cabello, J AF Velasco, Carlos Mateo, Jesus Santos, Arnoldo Mota-Cobian, Adriana Herranz, Fernando Pellico, Juan Mota, Ruben A. Espana, Samuel Ruiz-Cabello, Jesus TI Assessment of regional pulmonary blood flow using Ga-68-DOTA PET SO EJNMMI RESEARCH LA English DT Article DE PET; Pulmonary blood flow; Gallium-68; Fluorescent microspheres ID POSITRON-EMISSION-TOMOGRAPHY; MYOCARDIAL-PERFUSION; LUNG PERFUSION; PIG MODEL; QUANTIFICATION; MICROSPHERES; VALIDATION; CT; DEPOSITION; VOLUME AB Background: In vivo determination of regional pulmonary blood flow (PBF) is a valuable tool for the evaluation of many lung diseases. In this study, the use of Ga-68-DOTA PET for the in vivo quantitative determination of regional PBF is proposed. This methodology was implemented and tested in healthy pigs and validated using fluorescent microspheres. The study was performed on young large white pigs (n = 4). To assess the reproducibility and consistency of the method, three PET scans were obtained for each animal. Each radiotracer injection was performed simultaneously to the injection of fluorescent microspheres. PBF images were generated applying a two-compartment exchange model over the dynamic PET images. PET and microspheres values were compared by regression analysis and Bland-Altman plot. Results: The capability of the proposed technique to produce 3D regional PBF images was demonstrated. The correlation evaluation between Ga-68-DOTA PET and microspheres showed a good and significant correlation (r = 0.74, P < 0.001). Conclusions: Assessment of PBF with the proposed technique allows combining the high quantitative accuracy of PET imaging with the use of Ga-68/Ge-68 generators. Thus, Ga-68-DOTA PET emerges as a potential inexpensive method for measuring PBF in clinical settings with an extended use. C1 [Velasco, Carlos; Mateo, Jesus; Santos, Arnoldo; Mota-Cobian, Adriana; Herranz, Fernando; Pellico, Juan; Mota, Ruben A.; Espana, Samuel; Ruiz-Cabello, Jesus] Ctr Nacl Invest Cardiovasc Carlos III, C Melchor Fernandez Almagro 3, Madrid 28029, Spain. [Velasco, Carlos; Mateo, Jesus; Santos, Arnoldo; Herranz, Fernando; Pellico, Juan; Espana, Samuel; Ruiz-Cabello, Jesus] CIBER Enfermedades Resp, C Monforte de Lemos 3-5, Madrid 28029, Spain. [Santos, Arnoldo] Harvard Med Sch, Massachusetts Gen Hosp, Dept Anesthesia, 55 Fruit St, Boston, MA 02114 USA. [Mota, Ruben A.] Charles River, Carrer Argenters 7, Barcelona 08290, Spain. RP Espana, S (reprint author), Ctr Nacl Invest Cardiovasc Carlos III, C Melchor Fernandez Almagro 3, Madrid 28029, Spain.; Espana, S (reprint author), CIBER Enfermedades Resp, C Monforte de Lemos 3-5, Madrid 28029, Spain. EM sespana@cnic.es RI Ruiz-Cabello, Jesus/A-9570-2012; Espana, Samuel/E-9240-2010 OI Ruiz-Cabello, Jesus/0000-0001-8681-5056; Espana, Samuel/0000-0001-9092-4597 FU Spanish Ministry of Economy and Competitiveness (MINECO) [SAF2014-58920-R]; Carlos III Institute of Health [FIS-FEDER PI14-01427]; Spanish Ministry of Education [FPU014/01794]; M+Vision Advanced fellowships from the community of Madrid; MINECO; Pro CNIC Foundation; Severo Ochoa Center of Excellence (MINECO award) [SEV-2015-0505] FX This work was supported by a grant from the Spanish Ministry of Economy and Competitiveness (MINECO) (SAF2014-58920-R) and a grant from the Carlos III Institute of Health (FIS-FEDER PI14-01427). C. Velasco is a recipient of a fellowship from the Spanish Ministry of Education (FPU014/01794). S. Espana and A. Santos are recipients of M+Vision Advanced fellowships from the community of Madrid. The CNIC is supported by the MINECO and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (MINECO award SEV-2015-0505). NR 36 TC 0 Z9 0 U1 3 U2 3 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 2191-219X J9 EJNMMI RES JI EJNMMI Res. PD JAN 18 PY 2017 VL 7 AR 7 DI 10.1186/s13550-017-0259-2 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA EI5QZ UT WOS:000392550700001 PM 28101850 ER PT J AU Hibar, DP Adams, HHH Jahanshad, N Chauhan, G Stein, JL Hofer, E Renteria, ME Bis, JC Arias-Vasquez, A Ikram, MK Desrivieres, S Vernooij, MW Abramovic, L Alhusaini, S Amin, N Andersson, M Arfanakis, K Aribisala, BS Armstrong, NJ Athanasiu, L Axelsson, T Beecham, AH Beiser, A Bernard, M Blanton, SH Bohlken, MM Boks, MP Bralten, J Brickman, AM Carmichael, O Chakravarty, MM Chen, Q Ching, CRK Chouraki, V Cuellar-Partida, G Crivello, F Den Braber, A Doan, NT Ehrlich, S Giddaluru, S Goldman, AL Gottesman, RF Grimm, O Griswold, ME Guadalupe, T Gutman, BA Hass, J Haukvik, UK Hoehn, D Holmes, AJ Hoogman, M Janowitz, D Jia, T Jorgensen, KN Karbalai, N Kasperaviciute, D Kim, S Klein, M Kraemer, B Lee, PH Liewald, DCM Lopez, LM Luciano, M Macare, C Marquand, AF Matarin, M Mather, KA Mattheisen, M McKay, DR Milaneschi, Y Maniega, SM Nho, K Nugent, AC Nyquist, P Loohuis, LMO Oosterlaan, J Papmeyer, M Pirpamer, L Putz, B Ramasamy, A Richards, JS Risacher, SL Roiz-Santianez, R Rommelse, N Ropele, S Rose, EJ Royle, NA Rundek, T Samann, PG Saremi, A Satizabal, CL Schmaal, L Schork, AJ Shen, L Shin, J Shumskaya, E Smith, AV Sprooten, E Strike, LT Teumer, A Tordesillas-Gutierrez, D Toro, R Trabzuni, D Trompet, S Vaidya, D Van der Grond, J Van der Lee, SJ Van der Meer, D Van Donkelaar, MMJ Van Eijk, KR Van Erp, TGM Van Rooij, D Walton, E Westlye, LT Whelan, CD Windham, BG Winkler, AM Wittfeld, K Woldehawariat, G Wolf, C Wolfers, T Yanek, LR Yang, JY Zijdenbos, A Zwiers, MP Agartz, I Almasy, L Ames, D Amouyel, P Andreassen, OA Arepalli, S Assareh, AA Barral, S Bastin, ME Becker, DM Becker, JT Bennett, DA Blangero, J van Bokhoven, H Boomsma, DI Brodaty, H Brouwer, RM Brunner, HG Buckner, RL Buitelaar, JK Bulayeva, KB Cahn, W Calhoun, VD Cannon, DM Cavalleri, GL Cheng, CY Cichon, S Cookson, MR Corvin, A Crespo-Facorro, B Curran, JE Czisch, M Dale, AM Davies, GE De Craen, AJM De Geus, EJC De Jager, PL De Zubicaray, GI Deary, IJ Debette, S DeCarli, C Delanty, N Depondt, C DeStefano, A Dillman, A Djurovic, S Donohoe, G Drevets, WC Duggirala, R Dyer, TD Enzinger, C Erk, S Espeseth, T Fedko, IO Fernandez, G Ferrucci, L Fisher, SE Fleischman, DA Ford, I Fornage, M Foroud, TM Fox, PT Francks, C Fukunaga, M Gibbs, JR Glahn, DC Gollub, RL Goring, HHH Green, RC Gruber, O Gudnason, V Guelfi, S Haberg, AK Hansell, NK Hardy, J Hartman, CA Hashimoto, R Hegenscheid, K Heinz, A Le Hellard, S Hernandez, DG Heslenfeld, DJ Ho, BC Hoekstra, PJ Hoffmann, W Hofman, A Holsboer, F Homuth, G Hosten, N Hottenga, JJ Huentelman, M Pol, HEH Ikeda, M Jack, CR Jenkinson, M Johnson, R Jonsson, EG Jukema, JW Kahn, RS Kanai, R Kloszewska, I Knopman, DS Kochunov, P Kwok, JB Lawrie, SM Lemaitre, H Liu, XM Longo, DL Lopez, OL Lovestone, S Martinez, O Martinot, JL Mattay, VS McDonald, C McIntosh, AM McMahon, FJ McMahon, KL Mecocci, P Melle, I Meyer-Lindenberg, A Mohnke, S Montgomery, GW Morris, DW Mosley, TH Muhleisen, TW Muller-Myhsok, B Nalls, MA Nauck, M Nichols, TE Niessen, WJ Nothen, MM Nyberg, L Ohi, K Olvera, RL Ophoff, RA Pandolfo, M Paus, T Pausova, Z Penninx, BWJH Pike, GB Potkin, SG Psaty, BM Reppermund, S Rietschel, M Roffman, JL Romanczuk-Seiferth, N Rotter, JI Ryten, M Sacco, RL Sachdev, PS Saykin, AJ Schmidt, R Schmidt, H Schofield, PR Sigursson, S Simmons, A Singleton, A Sisodiya, SM Smith, C Smoller, JW Soininen, H Steen, VM Stott, DJ Sussmann, JE Thalamuthu, A Toga, AW Traynor, BJ Troncoso, J Tsolaki, M Tzourio, C Uitterlinden, AG Hernandez, MCV Van der Brug, M van der Lugt, A van der Wee, NJA Van Haren, NEM van't Ent, D Van Tol, MJ Vardarajan, BN Vellas, B Veltman, DJ Volzke, H Walter, H Wardlaw, JM Wassink, TH Weale, ME Weinberger, DR Weiner, MW Wen, W Westman, E White, T Wong, TY Wright, CB Zielke, RH Zonderman, AB Martin, NG Van Duijn, CM Wright, MJ Longstreth, WT Schumann, G Grabe, HJ Franke, B Launer, LJ Medland, SE Seshadri, S Thompson, PM Ikram, MA AF Hibar, Derrek P. Adams, Hieab H. H. Jahanshad, Neda Chauhan, Ganesh Stein, Jason L. Hofer, Edith Renteria, Miguel E. Bis, Joshua C. Arias-Vasquez, Alejandro Ikram, M. Kamran Desrivieres, Sylvane Vernooij, Meike W. Abramovic, Lucija Alhusaini, Saud Amin, Najaf Andersson, Micael Arfanakis, Konstantinos Aribisala, Benjamin S. Armstrong, Nicola J. Athanasiu, Lavinia Axelsson, Tomas Beecham, Ashley H. Beiser, Alexa Bernard, Manon Blanton, Susan H. Bohlken, Marc M. Boks, Marco P. Bralten, Janita Brickman, Adam M. Carmichael, Owen Chakravarty, M. Mallar Chen, Qiang Ching, Christopher R. K. Chouraki, Vincent Cuellar-Partida, Gabriel Crivello, Fabrice Den Braber, Anouk Nhat Trung Doan Ehrlich, Stefan Giddaluru, Sudheer Goldman, Aaron L. Gottesman, Rebecca F. Grimm, Oliver Griswold, Michael E. Guadalupe, Tulio Gutman, Boris A. Hass, Johanna Haukvik, Unn K. Hoehn, David Holmes, Avram J. Hoogman, Martine Janowitz, Deborah Jia, Tianye Jorgensen, Kjetil N. Karbalai, Nazanin Kasperaviciute, Dalia Kim, Sungeun Klein, Marieke Kraemer, Bernd Lee, Phil H. Liewald, David C. M. Lopez, Lorna M. Luciano, Michelle Macare, Christine Marquand, Andre F. Matarin, Mar Mather, Karen A. Mattheisen, Manuel McKay, David R. Milaneschi, Yuri Maniega, Susana Munoz Nho, Kwangsik Nugent, Allison C. Nyquist, Paul Loohuis, Loes M. Olde Oosterlaan, Jaap Papmeyer, Martina Pirpamer, Lukas Puetz, Benno Ramasamy, Adaikalavan Richards, Jennifer S. Risacher, Shannon L. Roiz-Santianez, Roberto Rommelse, Nanda Ropele, Stefan Rose, Emma J. Royle, Natalie A. Rundek, Tatjana Saemann, Philipp G. Saremi, Arvin Satizabal, Claudia L. Schmaal, Lianne Schork, Andrew J. Shen, Li Shin, Jean Shumskaya, Elena Smith, Albert V. Sprooten, Emma Strike, Lachlan T. Teumer, Alexander Tordesillas-Gutierrez, Diana Toro, Roberto Trabzuni, Daniah Trompet, Stella Vaidya, Dhananjay Van der Grond, Jeroen Van der Lee, Sven J. Van der Meer, Dennis Van Donkelaar, Marjolein M. J. Van Eijk, Kristel R. Van Erp, Theo G. M. Van Rooij, Daan Walton, Esther Westlye, Lars T. Whelan, Christopher D. Windham, Beverly G. Winkler, Anderson M. Wittfeld, Katharina Woldehawariat, Girma Wolf, Christiane Wolfers, Thomas Yanek, Lisa R. Yang, Jingyun Zijdenbos, Alex Zwiers, Marcel P. Agartz, Ingrid Almasy, Laura Ames, David Amouyel, Philippe Andreassen, Ole A. Arepalli, Sampath Assareh, Amelia A. Barral, Sandra Bastin, Mark E. Becker, Diane M. Becker, James T. Bennett, David A. Blangero, John van Bokhoven, Hans Boomsma, Dorret I. Brodaty, Henry Brouwer, Rachel M. Brunner, Han G. Buckner, Randy L. Buitelaar, Jan K. Bulayeva, Kazima B. Cahn, Wiepke Calhoun, Vince D. Cannon, Dara M. Cavalleri, Gianpiero L. Cheng, Ching-Yu Cichon, Sven Cookson, Mark R. Corvin, Aiden Crespo-Facorro, Benedicto Curran, Joanne E. Czisch, Michael Dale, Anders M. Davies, Gareth E. De Craen, Anton J. M. De Geus, Eco J. C. De Jager, Philip L. De Zubicaray, Greig I. Deary, Ian J. Debette, Stephanie DeCarli, Charles Delanty, Norman Depondt, Chantal DeStefano, Anita Dillman, Allissa Djurovic, Srdjan Donohoe, Gary Drevets, Wayne C. Duggirala, Ravi Dyer, Thomas D. Enzinger, Christian Erk, Susanne Espeseth, Thomas Fedko, Iryna O. Fernandez, Guillen Ferrucci, Luigi Fisher, Simon E. Fleischman, Debra A. Ford, Ian Fornage, Myriam Foroud, Tatiana M. Fox, Peter T. Francks, Clyde Fukunaga, Masaki Gibbs, J. Raphael Glahn, David C. Gollub, Randy L. Goring, Harald H. H. Green, Robert C. Gruber, Oliver Gudnason, Vilmundur Guelfi, Sebastian Haberg, Asta K. Hansell, Narelle K. Hardy, John Hartman, Catharina A. Hashimoto, Ryota Hegenscheid, Katrin Heinz, Andreas Le Hellard, Stephanie Hernandez, Dena G. Heslenfeld, Dirk J. Ho, Beng-Choon Hoekstra, Pieter J. Hoffmann, Wolfgang Hofman, Albert Holsboer, Florian Homuth, Georg Hosten, Norbert Hottenga, Jouke-Jan Huentelman, Matthew Pol, Hilleke E. Hulshoff Ikeda, Masashi Jack, Clifford R., Jr. Jenkinson, Mark Johnson, Robert Joensson, Erik G. Jukema, J. Wouter Kahn, Rene S. Kanai, Ryota Kloszewska, Iwona Knopman, David S. Kochunov, Peter Kwok, John B. Lawrie, Stephen M. Lemaitre, Herve Liu, Xinmin Longo, Dan L. Lopez, Oscar L. Lovestone, Simon Martinez, Oliver Martinot, Jean-Luc Mattay, Venkata S. McDonald, Colm McIntosh, Andrew M. McMahon, Francis J. McMahon, Katie L. Mecocci, Patrizia Melle, Ingrid Meyer-Lindenberg, Andreas Mohnke, Sebastian Montgomery, Grant W. Morris, Derek W. Mosley, Thomas H. Muhleisen, Thomas W. Mueller-Myhsok, Bertram Nalls, Michael A. Nauck, Matthias Nichols, Thomas E. Niessen, Wiro J. Nothen, Markus M. Nyberg, Lars Ohi, Kazutaka Olvera, Rene L. Ophoff, Roel A. Pandolfo, Massimo Paus, Tomas Pausova, Zdenka Penninx, Brenda W. J. H. Pike, G. Bruce Potkin, Steven G. Psaty, Bruce M. Reppermund, Simone Rietschel, Marcella Roffman, Joshua L. Romanczuk-Seiferth, Nina Rotter, Jerome I. Ryten, Mina Sacco, Ralph L. Sachdev, Perminder S. Saykin, Andrew J. Schmidt, Reinhold Schmidt, Helena Schofield, Peter R. Sigursson, Sigurdur Simmons, Andrew Singleton, Andrew Sisodiya, Sanjay M. Smith, Colin Smoller, Jordan W. Soininen, Hilkka Steen, Vidar M. Stott, David J. Sussmann, Jessika E. Thalamuthu, Anbupalam Toga, Arthur W. Traynor, Bryan J. Troncoso, Juan Tsolaki, Magda Tzourio, Christophe Uitterlinden, Andre G. Hernandez, Maria C. Valdes Van der Brug, Marcel van der Lugt, Aad van der Wee, Nic J. A. Van Haren, Neeltje E. M. van't Ent, Dennis Van Tol, Marie-Jose Vardarajan, Badri N. Vellas, Bruno Veltman, Dick J. Voelzke, Henry Walter, Henrik Wardlaw, Joanna M. Wassink, Thomas H. Weale, Michael E. Weinberger, Daniel R. Weiner, Michael W. Wen, Wei Westman, Eric White, Tonya Wong, Tien Y. Wright, Clinton B. Zielke, Ronald H. Zonderman, Alan B. Martin, Nicholas G. Van Duijn, Cornelia M. Wright, Margaret J. Longstreth, W. T. Schumann, Gunter Grabe, Hans J. Franke, Barbara Launer, Lenore J. Medland, Sarah E. Seshadri, Sudha Thompson, Paul M. Ikram, M. Arfan TI Novel genetic loci associated with hippocampal volume SO NATURE COMMUNICATIONS LA English DT Article ID GENOME-WIDE ASSOCIATION; TEMPORAL-LOBE EPILEPSY; SUSCEPTIBILITY LOCI; ALZHEIMERS-DISEASE; BIPOLAR DISORDER; COMMON VARIANTS; BRAIN-REGIONS; MEMORY; SUBFIELDS; METAANALYSIS AB The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (r(g) = -0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness. C1 [Hibar, Derrek P.; Jahanshad, Neda; Stein, Jason L.; Ching, Christopher R. K.; Gutman, Boris A.; Saremi, Arvin; Whelan, Christopher D.; Thompson, Paul M.] Univ Southern Calif, Imaging Genet Ctr, USC Mark & Mary Stevens Neuroimaging & Informat I, Keck Sch Med, Marina Del Rey, CA 90292 USA. [Adams, Hieab H. H.; Ikram, M. Kamran; Vernooij, Meike W.; Amin, Najaf; Van der Lee, Sven J.; Uitterlinden, Andre G.; Van Duijn, Cornelia M.; Ikram, M. Arfan] Erasmus Univ, Med Ctr, Dept Epidemiol, NL-3015 CE Rotterdam, Netherlands. [Adams, Hieab H. H.; Vernooij, Meike W.; Niessen, Wiro J.; van der Lugt, Aad; White, Tonya; Ikram, M. Arfan] Erasmus MC, Dept Radiol & Nucl Med, NL-3015 CE Rotterdam, Netherlands. [Chauhan, Ganesh; Debette, Stephanie; Tzourio, Christophe] Univ Bordeaux, INSERM Unit U1219, F-33076 Bordeaux, France. [Stein, Jason L.] UNC, Dept Genet, Chapel Hill, NC 27599 USA. [Stein, Jason L.] UNC, UNC Neurosci Ctr, Chapel Hill, NC 27599 USA. [Hofer, Edith; Pirpamer, Lukas; Ropele, Stefan; Enzinger, Christian; Schmidt, Reinhold] Med Univ Graz, Dept Neurol, Clin Div Neurogeriatr, Auenbruggerpl 22, A-8036 Graz, Austria. [Hofer, Edith] Med Univ Graz, Inst Med Informat Stat & Documentat, Auenbruggerpl 22, A-8036 Graz, Austria. [Renteria, Miguel E.; Cuellar-Partida, Gabriel; Strike, Lachlan T.; Hansell, Narelle K.; Montgomery, Grant W.; Martin, Nicholas G.; Medland, Sarah E.] QIMR Berghofer Med Res Inst, Brisbane, Qld 4006, Australia. [Bis, Joshua C.] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, 1730 Minor Ave Suite 1360, Seattle, WA 98101 USA. [Arias-Vasquez, Alejandro; Bralten, Janita; Hoogman, Martine; Klein, Marieke; Shumskaya, Elena; Van Donkelaar, Marjolein M. J.; Wolfers, Thomas; van Bokhoven, Hans; Brunner, Han G.; Franke, Barbara] Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, NL-6525 GA Nijmegen, Netherlands. [Arias-Vasquez, Alejandro; Rommelse, Nanda; Franke, Barbara] Radboud Univ Nijmegen, Med Ctr, Dept Psychiat, NL-6525 GA Nijmegen, Netherlands. [Arias-Vasquez, Alejandro; Richards, Jennifer S.; Van Rooij, Daan; Buitelaar, Jan K.; Fernandez, Guillen] Radboud Univ Nijmegen, Med Ctr, Dept Cognit Neurosci, NL-6525 GA Nijmegen, Netherlands. [Arias-Vasquez, Alejandro; Bralten, Janita; Hoogman, Martine; Klein, Marieke; Marquand, Andre F.; Richards, Jennifer S.; Rommelse, Nanda; Shumskaya, Elena; Van Donkelaar, Marjolein M. J.; Van Rooij, Daan; Wolfers, Thomas; Zwiers, Marcel P.; van Bokhoven, Hans; Brunner, Han G.; Buitelaar, Jan K.; Fernandez, Guillen; Fisher, Simon E.; Francks, Clyde; Franke, Barbara] Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, NL-6525 GA Nijmegen, Netherlands. [Ikram, M. Kamran; Cheng, Ching-Yu; Wong, Tien Y.] Duke NUS Grad Med Sch, Acad Med Res Inst, Singapore 169857, Singapore. [Ikram, M. Kamran; Cheng, Ching-Yu; Wong, Tien Y.] Singapore Natl Eye Ctr, Singapore Eye Res Inst, Singapore 168751, Singapore. [Ikram, M. Kamran] Natl Univ Hlth Syst, MACC, Singapore 119228, Singapore. [Ikram, M. Kamran; De Jager, Philip L.] Natl Univ Singapore, Dept Pharmacol, Singapore 119077, Singapore. [Desrivieres, Sylvane; Jia, Tianye; Macare, Christine; Schumann, Gunter] Kings Coll London, MRC SGDP Ctr, Inst Psychiat Psychol & Neurosci, London SE5 8AF, England. [Abramovic, Lucija; Bohlken, Marc M.; Boks, Marco P.; Brouwer, Rachel M.; Cahn, Wiepke; Pol, Hilleke E. Hulshoff; Kahn, Rene S.; Ophoff, Roel A.; Van Haren, Neeltje E. M.] UMC Utrecht, Brain Ctr Rudolf Magnus, Dept Psychiat, NL-3584 CX Utrecht, Netherlands. [Alhusaini, Saud] McGill Univ, Dept Neurol & Neurosurg, Montreal Neurol Inst, Montreal, PQ H3A 2B4, Canada. [Alhusaini, Saud; Whelan, Christopher D.; Cavalleri, Gianpiero L.; Delanty, Norman] Royal Coll Surgeons Ireland, 123 St Stephens Green, Dublin 2, Ireland. [Andersson, Micael; Nyberg, Lars] Umea Univ, Dept Integrat Med Biol, S-90187 Umea, Sweden. [Andersson, Micael; Nyberg, Lars] Umea Univ, Umea Ctr Funct Brain Imaging, S-90187 Umea, Sweden. [Arfanakis, Konstantinos] IIT, Dept Biomed Engn, Chicago, IL 60612 USA. 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[Armstrong, Nicola J.; Mather, Karen A.; Assareh, Amelia A.; Brodaty, Henry; Reppermund, Simone; Sachdev, Perminder S.; Thalamuthu, Anbupalam; Wen, Wei] Univ New South Wales, Ctr Healthy Brain Ageing, Sch Psychiat, Sydney, NSW 2052, Australia. [Armstrong, Nicola J.] Murdoch Univ, Math & Stat, Perth, WA 6150, Australia. [Athanasiu, Lavinia; Nhat Trung Doan; Haukvik, Unn K.; Jorgensen, Kjetil N.; Agartz, Ingrid; Andreassen, Ole A.; Joensson, Erik G.; Melle, Ingrid] Univ Oslo, NORMENT KG Jebsen Ctr, Inst Clin Med, N-0315 Oslo, Norway. [Athanasiu, Lavinia; Westlye, Lars T.; Andreassen, Ole A.; Espeseth, Thomas; Melle, Ingrid] Oslo Univ Hosp, NORMENT KG Jebsen Ctr, Div Mental Hlth & Addict, N-0424 Oslo, Norway. [Axelsson, Tomas] Uppsala Univ, Dept Med Sci Mol Med & Sci Life Lab, Box 1432, SE-75144 Uppsala, Sweden. [Beecham, Ashley H.; Blanton, Susan H.] Univ Miami, Miller Sch Med, Dr John T Macdonald Fdn Dept Human Genet, Miami, FL 33136 USA. [Beecham, Ashley H.; Blanton, Susan H.; Sacco, Ralph L.] Univ Miami, Miller Sch Med, John P Hussman Inst Human Gen, Miami, FL 33136 USA. [Beiser, Alexa; Chouraki, Vincent; Satizabal, Claudia L.; Debette, Stephanie; Seshadri, Sudha] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Beiser, Alexa; DeStefano, Anita] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA. [Beiser, Alexa; Chouraki, Vincent; Satizabal, Claudia L.; DeStefano, Anita; Seshadri, Sudha] Framingham Heart Dis Epidemiol Study, 17 Mt Wayte Ave, Framingham, MA 01703 USA. [Bernard, Manon; Shin, Jean; Pausova, Zdenka] Univ Toronto, Hosp Sick Children, Toronto, ON M5G 1X8, Canada. [Brickman, Adam M.; Barral, Sandra; Vardarajan, Badri N.] Columbia Univ, Med Ctr, Taub Inst Res Alzheimers Dis & Aging Brain, 639 West 1168th St, New York, NY 10032 USA. [Brickman, Adam M.; Barral, Sandra; Vardarajan, Badri N.] Columbia Univ, Med Ctr, GH Sergievsky Ctr, 639 West 1168th St, New York, NY 10032 USA. [Brickman, Adam M.; Barral, Sandra; Vardarajan, Badri N.] Columbia Univ, Med Ctr, Dept Neurol, 639 West 1168th St, New York, NY 10032 USA. [Carmichael, Owen] Pennington Biomed Res Ctr, 6400 Perkins Rd, Baton Rouge, LA 70808 USA. [Chakravarty, M. Mallar] Douglas Mental Hlth Univ Inst, Cerebral Imaging Ctr, Montreal, PQ H4H 1R3, Canada. [Chakravarty, M. Mallar] McGill Univ, Dept Psychiat & Biomed Engn, Montreal, PQ H3A 2B4, Canada. [Chen, Qiang; Goldman, Aaron L.; Mattay, Venkata S.; Weinberger, Daniel R.] Lieber Inst Brain Dev, Baltimore, MD 21205 USA. [Ching, Christopher R. K.] Univ Calif Los Angeles, Sch Med, Interdept Neurosci Grad Program, Los Angeles, CA 90095 USA. [Chouraki, Vincent; Amouyel, Philippe] Univ Lille, CHU Lille, INSERM, Inst Pasteur Lille,RID AGE Risk Factors & Mol Det, F-59000 Lille, France. [Crivello, Fabrice] Univ Bordeaux, IMN UMR5293, GIN, CNRS,CEA, 146 Rue Leo Saignat, F-33076 Bordeaux, France. [Den Braber, Anouk; Boomsma, Dorret I.; De Geus, Eco J. C.; Fedko, Iryna O.; Hottenga, Jouke-Jan; van't Ent, Dennis] Vrije Univ Amsterdam, Biol Psychol, Amsterdam Neurosci, NL-1081 BT Amsterdam, Netherlands. [Den Braber, Anouk; Boomsma, Dorret I.; De Geus, Eco J. C.; Fedko, Iryna O.; Hottenga, Jouke-Jan; van't Ent, Dennis] Vrije Univ Amsterdam, Med Ctr, NL-1081 BT Amsterdam, Netherlands. [Ehrlich, Stefan; Walton, Esther] Tech Univ Dresden, Fac Med, Div Psychol & Social Med & Dev Neurosci, D-01307 Dresden, Germany. [Ehrlich, Stefan; Holmes, Avram J.; Lee, Phil H.; Buckner, Randy L.; Gollub, Randy L.; Roffman, Joshua L.; Smoller, Jordan W.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Ehrlich, Stefan; Gollub, Randy L.] Massachusetts Gen Hosp, Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Giddaluru, Sudheer; Djurovic, Srdjan; Le Hellard, Stephanie; Steen, Vidar M.] Univ Bergen, Dept Clin Sci, NORMENT KG Jebsen Ctr Psychosis Res, N-5021 Bergen, Norway. 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[Hoehn, David; Karbalai, Nazanin; Puetz, Benno; Saemann, Philipp G.; Czisch, Michael; Holsboer, Florian; Mueller-Myhsok, Bertram] Max Planck Inst Psychiat, D-80804 Munich, Germany. [Holmes, Avram J.] Yale Univ, Dept Psychol, New Haven, CT 06520 USA. [Janowitz, Deborah; Wittfeld, Katharina; Grabe, Hans J.] Univ Med Greifswald, Dept Psychiat, D-17489 Greifswald, Germany. [Kasperaviciute, Dalia; Matarin, Mar; Sisodiya, Sanjay M.] UCL Inst Neurol, London, England. [Kasperaviciute, Dalia; Matarin, Mar; Sisodiya, Sanjay M.] Epilepsy Soc, St Peter, Bucks, England. [Kasperaviciute, Dalia] Imperial Coll London, Dept Med, London SW7 2AZ, England. [Kim, Sungeun; Nho, Kwangsik; Risacher, Shannon L.; Shen, Li; Saykin, Andrew J.] Indiana Univ Sch Med, Ctr Neuroimaging Radiol & Imaging Sci, Indianapolis, IN 46202 USA. [Kim, Sungeun; Nho, Kwangsik; Shen, Li] Indiana Univ Sch Med, Ctr Computat Biol & Bioinformat, Indianapolis, IN 46202 USA. 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[Mattheisen, Manuel] iPSYCH, Lundbeck Fdn Initiat Integrat Psychiat Res, DK-8000 Aarhus, Denmark. [Mattheisen, Manuel] iPSYCH, Lundbeck Fdn Initiat Integrat Psychiat Res, DK-8000 Copenhagen, Denmark. [Mattheisen, Manuel] Aarhus Univ, iSEQ, Ctr Integrated Sequencing, DK-8000 Aarhus, Denmark. [McKay, David R.; Sprooten, Emma; Winkler, Anderson M.; Glahn, David C.] Yale Univ, Dept Psychiat, New Haven, CT 06511 USA. [McKay, David R.; Sprooten, Emma; Glahn, David C.] Olin Neuropsychiat Res Ctr, Hartford, CT 06114 USA. [Milaneschi, Yuri] VU Univ Med Ctr GGZ inGeest, Dept Psychiat, EMGO Inst Hlth & Care Res, NL-1081 HL Amsterdam, Netherlands. [Milaneschi, Yuri] VU Univ Med Ctr GGZ inGeest, Neurosci Campus Amsterdam, NL-1081 HL Amsterdam, Netherlands. [Nugent, Allison C.; Woldehawariat, Girma; Cannon, Dara M.; Drevets, Wayne C.; Liu, Xinmin; McMahon, Francis J.] NIMH, Human Genet Branch, Intramural Res Program, 35 Convent Dr,Rm 1A202, Bethesda, MD 20892 USA. 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[Schmaal, Lianne] Orygen, Natl Ctr Excellence Youth Mental Hlth, Melbourne, Vic 3502, Australia. [Schmaal, Lianne] Univ Melbourne, Ctr Youth Mental Hlth, Melbourne, Vic 3502, Australia. [Schmaal, Lianne; Penninx, Brenda W. J. H.; Veltman, Dick J.] Vrije Univ Amsterdam, Med Ctr, Dept Psychiat, Neurosci Campus Amsterdam, NL-1007 MB Amsterdam, Netherlands. [Schork, Andrew J.] Univ Calif San Diego, Multimodal Imaging Lab, Dept Neurosci, San Diego, CA 92093 USA. [Schork, Andrew J.] Univ Calif San Diego, Dept Cognit Sci, San Diego, CA 92161 USA. [Smith, Albert V.; Gudnason, Vilmundur; Sigursson, Sigurdur] Iceland Heart Assoc, IS-201 Kopavogur, Iceland. [Smith, Albert V.; Gudnason, Vilmundur] Univ Iceland, Fac Med, IS-101 Reykjavik, Iceland. [Sprooten, Emma] Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA. [Strike, Lachlan T.; Hansell, Narelle K.; Wright, Margaret J.] Univ Queensland, Queensland Brain Inst, Brisbane, Qld 4072, Australia. [Teumer, Alexander; Hoffmann, Wolfgang; Voelzke, Henry] Univ Med Greifswald, Inst Community Med, D-17489 Greifswald, Germany. [Tordesillas-Gutierrez, Diana] Valdecilla Biomed Res Inst IDIVAL, Neuroimaging Unit, Technol Facilities, Santander 39011, Cantabria, Spain. [Toro, Roberto] Inst Pasteur, F-75015 Paris, France. [Trabzuni, Daniah] King Faisal Specialist Hosp & Res Ctr, Dept Genet, Riyadh 11211, Saudi Arabia. [Trompet, Stella; Jukema, J. Wouter] Leiden Univ, Med Ctr, Dept Cardiol, NL-2300 RC Leiden, Netherlands. [Vaidya, Dhananjay; Yanek, Lisa R.; Becker, Diane M.] Johns Hopkins Univ, Sch Med, Dept Med, GeneSTAR Res Ctr, 1830 Monument St Suite 8028, Baltimore, MD 21287 USA. [Van der Grond, Jeroen] Leiden Univ, Med Ctr, Dept Radiol, NL-2300 RC Leiden, Netherlands. [Van der Meer, Dennis; Van Rooij, Daan; Hartman, Catharina A.; Hoekstra, Pieter J.] Univ Groningen, Univ Med Ctr Groningen, Dept Psychiat, NL-9700 RB Groningen, Netherlands. [Van Eijk, Kristel R.] UMC Utrecht, Brain Ctr Rudolf Magnus, Human Neurogenet Unit, NL-3584 CG Utrecht, Netherlands. [Van Erp, Theo G. M.; Potkin, Steven G.] Univ Calif Irvine, Dept Psychiat & Human Behav, Irvine, CA 92617 USA. [Walton, Esther; Westlye, Lars T.; Espeseth, Thomas] Georgia State Univ, Dept Psychol, Atlanta, GA 30302 USA. [Windham, Beverly G.; Mosley, Thomas H.] Univ Oslo, Dept Psychol, NORMENT KG Jebsen Ctr, N-0317 Oslo, Norway. [Winkler, Anderson M.; Jenkinson, Mark; Nichols, Thomas E.] Univ Mississippi, Med Ctr, Dept Med, Jackson, MS 39216 USA. [Wittfeld, Katharina; Hoffmann, Wolfgang] Univ Oxford, FMRIB Ctr, Oxford OX3 9DU, England. [Wolf, Christiane] German Ctr Neurodegenerat Dis DZNE Rostock Greifs, D-17487 Greifswald, Germany. [Yang, Jingyun; Bennett, David A.] Univ Wurzburg, Dept Psychiat Psychosomat & Psychotherapy, D-97080 Wurzburg, Germany. [Zijdenbos, Alex] Rush Univ, Med Ctr, Dept Neurol Sci, Chicago, IL 60612 USA. [Agartz, Ingrid; Joensson, Erik G.] Biospective Inc, 6100 Ave Royalmount, Montreal, PQ H4P 2R2, Canada. [Almasy, Laura; Blangero, John; Curran, Joanne E.; Duggirala, Ravi; Dyer, Thomas D.; Goring, Harald H. H.] Karolinska Inst, Dept Clin Neurosci, Ctr Psychiat Res, SE-17177 Stockholm, Sweden. [Almasy, Laura] Univ Texas Brownsville, Rio Grande Valley Sch Med, South Texas Diabet & Obes Inst, Brownsville, TX 78250 USA. [Almasy, Laura] Univ Texas, Rio Grande Valley Sch Med, South Texas Diabet & Obes Inst, Edinburg, TX 78250 USA. [Almasy, Laura] Univ Texas San Antonio, Rio Grande Valley Sch Med, South Texas Diabet & Obes Inst, San Antonio, TX 78250 USA. [Almasy, Laura] Univ Penn, Dept Genet, Perelman Sch Med, Philadelphia, PA 19104 USA. [Ames, David] Childrens Hosp Philadelphia, Dept Biomed & Hlth Informat, Philadelphia, PA 19104 USA. [Ames, David] Royal Melbourne Hosp, Natl Ageing Res Inst, Parkville, Vic 3052, Australia. [Arepalli, Sampath; Cookson, Mark R.; Dillman, Allissa; Gibbs, J. Raphael; Hernandez, Dena G.; Nalls, Michael A.; Traynor, Bryan J.] Univ Melbourne, Acad Unit Psychiat Old Age, Melbourne, Vic 3101, Australia. [Becker, James T.] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Brodaty, Henry] Univ Pittsburgh, Dept Psychiat, 3501 Forbes Ave,Suite 830, Pittsburgh, PA 15213 USA. [Brunner, Han G.] Univ New South Wales, Dementia Collaborat Res Centre Assessment & Bette, Sydney, NSW 2052, Australia. [Buckner, Randy L.] Maastricht Univ, Med Ctr, Dept Clin Genet, NL-6200 MD Maastricht, Netherlands. [Buckner, Randy L.] Maastricht Univ, Med Ctr, GROW Sch Oncol & Dev Biol, NL-6200 MD Maastricht, Netherlands. [Bulayeva, Kazima B.] Harvard Univ, Dept Psychol, Ctr Brain Sci, Cambridge, MA 02138 USA. [Calhoun, Vince D.] Dagestan State Univ, Dept Evolut & Genet, Makhachkala 367000, Dagestan, Russia. [Calhoun, Vince D.] Mind Res Network, Albuquerque, NM 87106 USA. [Calhoun, Vince D.] LBERI, Albuquerque, NM 87106 USA. [Cannon, Dara M.; McDonald, Colm] Univ New Mexico, Dept ECE, Albuquerque, NM 87131 USA. [Cheng, Ching-Yu; Wong, Tien Y.] Natl Univ Ireland Galway, Ctr Neuroimaging & Cognit Genom NICOG, Clin Neuroimaging Lab, NCBES Galway Neurosci Ctr,Coll Med Nursing & Hlth, Galway H91 TK33, Ireland. [Cichon, Sven] Natl Univ Singapore, Dept Ophthalmol, Yong Loo Lin Sch Med, Singapore 119077, Singapore. [Cichon, Sven; Muhleisen, Thomas W.; Nothen, Markus M.] Univ Basel, Dept Biome, Div Med Genet, CH-4031 Basel, Switzerland. [Cichon, Sven; Muhleisen, Thomas W.] Univ Bonn, Inst Human Genet, D-53127 Bonn, Germany. [Dale, Anders M.] Res Ctr Julich, Inst Neurosci & Med INM 1, D-52425 Julich, Germany. [Dale, Anders M.] Univ Calif San Diego, Ctr Multimodal Imaging & Genet, San Diego, CA 92093 USA. [Davies, Gareth E.] Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA. [Davies, Gareth E.] Univ Calif San Diego, Dept Radiol, La Jolla, CA 92093 USA. [Davies, Gareth E.] Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA. [Davies, Gareth E.] Univ Calif San Diego, Dept Cognit Sci, La Jolla, CA 92093 USA. [De Craen, Anton J. M.] Avera Inst Human Genet, Sioux Falls, SD 57108 USA. [De Jager, Philip L.] Leiden Univ, Med Ctr, Dept Gerontol & Geriatr, NL-2300 RC Leiden, Netherlands. [De Jager, Philip L.] Brigham & Womens Hosp, Program Translat NeuroPsychiat Gen, Dept Neurol, Boston, MA 02115 USA. [De Jager, Philip L.] Brigham & Womens Hosp, Program Translat NeuroPsychiat Gen, Dept Psychiat, Boston, MA 02115 USA. [De Jager, Philip L.] Harvard Med Sch, Boston, MA 02115 USA. [De Jager, Philip L.] Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA. [De Zubicaray, Greig I.] Broad Inst, Cambridge, MA 02142 USA. [Debette, Stephanie] Queensland Univ Technol, Fac Hlth & Inst Hlth & Biomed Innovat, Brisbane, Qld 4059, Australia. [DeCarli, Charles; Martinez, Oliver] Bordeaux Univ Hosp, Dept Neurol, F-33076 Bordeaux, France. [Delanty, Norman] Univ Calif Davis, Imaging Dementia & Aging IDeA Lab, Dept Neurol, 4860 Y St,Suite 3700, Sacramento, CA 95817 USA. [Delanty, Norman] Univ Calif Davis, Ctr Neurosci, 4860 Y St,Suite 3700, Sacramento, CA 95817 USA. [Depondt, Chantal; Pandolfo, Massimo] Beaumont Hosp, Div Neurol, Dublin 9, Ireland. [Djurovic, Srdjan] Univ Libre Bruxelles, Dept Neurol, Hop Erasme, B-1070 Brussels, Belgium. [Donohoe, Gary; Morris, Derek W.] Oslo Univ Hosp, Dept Med Genet, N-0420 Oslo, Norway. [Donohoe, Gary] Natl Univ Ireland Galway, Cognit Genet & Cognit Therapy Grp, Neuroimaging Cognit & Genom Ctr NICOG, Sch Psychol & Discipline Biochem, Galway H91 TK33, Ireland. [Donohoe, Gary] Natl Univ Ireland Galway, Sch Psychol & Discipline Biochem, NCBES Galway Neurosci Ctr, Galway H91 TK33, Ireland. [Drevets, Wayne C.] Trinity Coll Dublin, Neuropsychiat Genet Res Grp, Dept Psychiat, Dublin 8, Ireland. [Drevets, Wayne C.] Trinity Coll Dublin, Trinity Coll, Inst Psychiat, Dublin 8, Ireland. 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[Haberg, Asta K.] Brigham & Womens Hosp, Dept Med, Div Genet, 75 Francis St, Boston, MA 02115 USA. [Haberg, Asta K.] Norwegian Univ Sci & Technol NTNU, Fac Med, Dept Neurosci, N-7491 Trondheim, Norway. [Hashimoto, Ryota; Ohi, Kazutaka] Univ Trondheim Hosp, Dept Radiol, St Olavs Hosp, N-7030 Trondheim, Norway. [Hashimoto, Ryota] Osaka Univ, Dept Psychiat, Grad Sch Med, Suita, Osaka 5650871, Japan. [Hegenscheid, Katrin; Hosten, Norbert] Osaka Univ, Mol Res Ctr Childrens Mental Dev, United Grad Sch Child Dev, Suita, Osaka 5650871, Japan. [Hernandez, Dena G.] Univ Med Greifswald, Inst Diagnost Radiol & Neuroradiol, D-17489 Greifswald, Germany. [Heslenfeld, Dirk J.] German Ctr Neurodegenerat Dis DZNE, D-72076 Tubingen, Germany. [Ho, Beng-Choon] Vrije Univ Amsterdam, Dept Psychol, NL-1081 BT Amsterdam, Netherlands. [Holsboer, Florian] Univ Iowa, Dept Psychiat, Iowa City, IA 52242 USA. [Hofman, Albert; Homuth, Georg] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Huentelman, Matthew] HMNC Brain Hlth, D-80539 Munich, Germany. [Ikeda, Masashi] Univ Med Greifswald, Interfac Inst Genet & Funct Genom, D-17489 Greifswald, Germany. [Jack, Clifford R., Jr.] Translat Genom Res Inst, Neurogen Div, 445N Fifth St, Phoenix, AZ 85004 USA. [Johnson, Robert; Zielke, Ronald H.] Fujita Hlth Univ, Sch Med, Dept Psychiat, Toyoake, Aichi 4701192, Japan. [Kanai, Ryota] Mayo Clin, Dept Radiol, Rochester, MN 55905 USA. [Kanai, Ryota] Univ Maryland, Sch Med, NICHD Brain & Tissue Bank Dev Disorders, Baltimore, MD 21201 USA. [Kanai, Ryota] Univ Sussex, Sch Psychol, Brighton BN1 9QH, E Sussex, England. [Kloszewska, Iwona] UCL, Inst Cognit Neurosci, London WC1N 3AR, England. [Knopman, David S.] Araya Brain Imaging, Dept Neuroinformat, Tokyo 1020093, Japan. [Kochunov, Peter] Med Univ Lodz, PL-90419 Lodz, Poland. [Kwok, John B.; Schofield, Peter R.] Mayo Clin, Dept Neurol, Rochester, MN 55905 USA. [Kwok, John B.; Schofield, Peter R.] Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, Dept Psychiat, Catonsville, MD 21228 USA. [Lemaitre, Herve; Martinot, Jean-Luc] Neurosci Res Australia, Randwick, NSW 2031, Australia. [Liu, Xinmin] UNSW, Sch Med Sci, Sydney, NSW 2052, Australia. [Longo, Dan L.] Univ Paris 05, Univ Paris Saclay, INSERM UMR Neuroimaging & Psychiat 1000, Serv Hosp Freric Joliot,Univ Paris Sud,Maison Sol, F-91400 Orsay, France. [Lopez, Oscar L.] Columbia Univ, Med Ctr, New York, NY 10032 USA. [Lovestone, Simon] NIA, Genet Lab, NIH, Baltimore, MD 21224 USA. [Mattay, Venkata S.] Univ Oxford, Dept Psychiat, Oxford OX3 7JX, England. [McMahon, Katie L.; Wright, Margaret J.] Johns Hopkins Univ, Sch Med, Dept Radiol, Baltimore, MD 21205 USA. [Mecocci, Patrizia] Univ Queensland, Ctr Adv Imaging, Brisbane, Qld 4072, Australia. [Mueller-Myhsok, Bertram] Univ Perugia, Dept Med, Sect Gerontol & Geriatr, I-06132 Perugia, Italy. [Mueller-Myhsok, Bertram] Munich Cluster Syst Neurol SyNergy, D-81377 Munich, Germany. [Nauck, Matthias] Univ Liverpool, Inst Translat Med, Liverpool L69 3BX, Merseyside, England. [Nauck, Matthias] Univ Med Greifswald, Inst Clin Chem & Lab Med, D-17489 Greifswald, Germany. [Nichols, Thomas E.] German Ctr Cardiovascular Res DZHK eV, Partner Site Greifswald, D-17475 Greifswald, Germany. [Niessen, Wiro J.] Univ Warwick, Dept Stat, Coventry CV4 7AL, W Midlands, England. [Niessen, Wiro J.] Univ Warwick, WMG, Coventry CV4 7AL, W Midlands, England. [Niessen, Wiro J.] Erasmus MC, Dept Med Informat, NL-3015 CE Rotterdam, Netherlands. [Nothen, Markus M.] Delft Univ Technol, Fac Sci Appl, NL-2628 CD Delft, Netherlands. [Paus, Tomas] Univ Bonn, Dept Gen, Life & Brain Ctr, D-53127 Bonn, Germany. [Paus, Tomas] Univ Toronto, Rotman Res Inst, Toronto, ON M6A 2E1, Canada. [Paus, Tomas] Univ Toronto, Dept Psychol, Toronto, ON M5T 1R8, Canada. [Paus, Tomas] Univ Toronto, Dept Psychiat, Toronto, ON M5T 1R8, Canada. [Pausova, Zdenka] Child Mind Inst, New York, NY 10022 USA. [Pike, G. Bruce] Univ Toronto, Dept Physiol, Toronto, ON M5S 3E2, Canada. [Pike, G. Bruce] Univ Toronto, Dept Nutr Sci, Toronto, ON M5S 3E2, Canada. [Pike, G. Bruce] Univ Calgary, Dept Radiol, Calgary, AB T2N 4N1, Canada. [Psaty, Bruce M.] Univ Calgary, Dept Clin Neurosci, Calgary, AB T2N 4N1, Canada. [Reppermund, Simone] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Reppermund, Simone] Univ Washington, Dept Med, Seattle, WA USA. [Reppermund, Simone] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. [Reppermund, Simone] USA Grp Hlth Res Inst, Grp Hlth, 1730 Minor Ave Suite 1360, Seattle, WA 98101 USA. [Rotter, Jerome I.] Univ New South Wales, Dept Dev Disabil Neuropsychiat, Sch Psychiat, Sydney, NSW 2052, Australia. [Sacco, Ralph L.; Wright, Clinton B.] Harbor UCLA Med Ctr, Inst Translat Genom & Populat Sci, Los Angeles Biomed Res Inst & Pediat, Torrance, CA 90502 USA. [Sachdev, Perminder S.; Wen, Wei] Univ Miami, Miller Sch Med, Evelyn F McKnight Brain Inst, Miami, FL 33136 USA. [Schmidt, Helena] Prince Wales Hosp, Neuropsychiat Inst, Randwick, NSW 2031, Australia. [Simmons, Andrew] Med Univ Graz, Inst Mol Biol & Biochem, Harrachgasse 21-3, A-8010 Graz, Austria. [Simmons, Andrew] Kings Coll London, Inst Psychiat, Dept Neuroimaging, London SE5 8AF, England. [Simmons, Andrew] Kings Coll London, Biomed Res Ctr Mental Hlth, London SE5 8AF, England. [Smith, Colin] Kings Coll London, Biomed Res Unit Dementia, London SE5 8AF, England. [Soininen, Hilkka] Univ Edinburgh, Acad Dept Neuropathol, Ctr Clin Brain Sci, MRC Edinburgh Brain Bank, Edinburgh EH16 4SB, Midlothian, Scotland. [Soininen, Hilkka] Univ Eastern Finland, Inst Clin Med, Neurol, FI-70211 Kuopio, Finland. [Stott, David J.] Kuopio Univ Hosp, Neuroctr Neurol, FI-70211 Kuopio, Finland. [Toga, Arthur W.] Univ Glasgow, Fac Med, Inst Cardiovasc & Med Sci, Glasgow G4 0SF, Lanark, Scotland. [Troncoso, Juan] Univ Southern Calif, Lab Neuro Imaging, Inst Neuroimaging & Informat, Keck Sch Med, Los Angeles, CA 90033 USA. [Tsolaki, Magda] Johns Hopkins Univ, Dept Pathol, Baltimore, MD 21205 USA. [Tzourio, Christophe] Aristotle Univ Thessaloniki, Dept Neurol 3, G Papanicolaou Hosp, Thessaloniki 57010, Greece. [Uitterlinden, Andre G.] Univ Bordeaux, INSERM, Bordeaux Populat Hlth Res Ctr, UMR1219, F-33000 Bordeaux, France. [Van der Brug, Marcel] Erasmus MC, Dept Internal Med, NL-3015 CE Rotterdam, Netherlands. [van der Wee, Nic J. A.] Genentech Inc, San Francisco, CA 94080 USA. [Van Tol, Marie-Jose] Leiden Univ, Med Ctr, Dept Psychiat, NL-2333 ZA Leiden, Netherlands. [Van Tol, Marie-Jose] Leiden Univ, Med Ctr, Leiden Inst Brain & Cognit, NL-2333 ZA Leiden, Netherlands. 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T.] NIA, Lab Epidemiol & Populat Sci, NIH, Bethesda, MD 20892 USA. [Launer, Lenore J.] Univ Washington, Dept Neurol, 325 Ninth Ave, Washington, DC 98104 USA. [Launer, Lenore J.] Univ Washington, Dept Epidemiol, 325 Ninth Ave, Seattle, WA 98104 USA. [Ikram, M. Arfan] NIA, Intramural Res Program, NIH, Bethesda, MD 20892 USA. Erasmus MC, Dept Neurol, NL-3015 CE Rotterdam, Netherlands. [Brodaty, Henry; Lovestone, Simon] Univ Pittsburgh, Dept Neurol, 3501 Forbes Ave,Suite 830, Pittsburgh, PA 15213 USA. [Brodaty, Henry] Univ Pittsburgh, Dept Psychol, 3501 Forbes Ave,Suite 830, Pittsburgh, PA 15213 USA. RP Thompson, PM (reprint author), Univ Southern Calif, Imaging Genet Ctr, USC Mark & Mary Stevens Neuroimaging & Informat I, Keck Sch Med, Marina Del Rey, CA 90292 USA.; Thompson, PM (reprint author), Erasmus Univ, Med Ctr, Dept Epidemiol, NL-3015 CE Rotterdam, Netherlands.; Ikram, MA (reprint author), Erasmus MC, Dept Radiol & Nucl Med, NL-3015 CE Rotterdam, Netherlands.; Ikram, MA (reprint author), NIA, Intramural Res Program, NIH, Bethesda, MD 20892 USA. EM pthomp@usc.edu; m.a.ikram@erasmusmc.nl RI McDonald, Colm/C-1430-2009; Zwiers, Marcel/D-2968-2009; Tzourio, christophe/B-4015-2009; Simmons, Andrew/B-8848-2008; Fernandez, Guillen/B-3771-2009; Franke, Barbara/D-4836-2009; OI Vaidya, Dhananjay/0000-0002-7164-1601; Zwiers, Marcel/0000-0001-5483-2935; McIntosh, Andrew/0000-0002-0198-4588; Tzourio, christophe/0000-0002-6517-2984; Simmons, Andrew/0000-0003-2306-5811; Fernandez, Guillen/0000-0002-5522-0604; Franke, Barbara/0000-0003-4375-6572; Westlye, Lars T./0000-0001-8644-956X; Westman, Eric/0000-0002-3115-2977; Jonsson, Erik/0000-0001-8368-6332 FU Medical Research Council [MC_UU_12013/2, MR/K026992/1]; NIBIB NIH HHS [U54 EB020403]; NIMH NIH HHS [R00 MH102357, T32 MH073526]; NINDS NIH HHS [T32 NS048004]; Wellcome Trust [104036] NR 55 TC 0 Z9 0 U1 7 U2 7 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD JAN 18 PY 2017 VL 8 AR 13624 DI 10.1038/ncomms13624 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EI0HW UT WOS:000392154900001 PM 28098162 ER PT J AU Nakazawa, H Chang, K Shinozaki, S Yasukawa, T Ishimaru, K Yasuhara, S Yu, YM Martyn, JAJ Tompkins, RG Shimokado, K Kaneki, M AF Nakazawa, Harumasa Chang, Kyungho Shinozaki, Shohei Yasukawa, Takashi Ishimaru, Kazuhiro Yasuhara, Shingo Yu, Yong-Ming Martyn, J. A. Jeevendra Tompkins, Ronald. G. Shimokado, Kentaro Kaneki, Masao TI iNOS as a Driver of Inflammation and Apoptosis in Mouse Skeletal Muscle after Burn Injury: Possible Involvement of Sirt1 S-Nitrosylation-Mediated Acetylation of p65 NF-kappa B and p53 SO PLOS ONE LA English DT Article ID INDUCIBLE NITRIC-OXIDE; ENDOPLASMIC-RETICULUM STRESS; INSULIN-RESISTANCE; TNF-ALPHA; EXPRESSION; SYNTHASE; ACTIVATION; ATROPHY; MICE; HYPERGLYCEMIA AB Inflammation and apoptosis develop in skeletal muscle after major trauma, including burn injury, and play a pivotal role in insulin resistance and muscle wasting. We and others have shown that inducible nitric oxide synthase (iNOS), a major mediator of inflammation, plays an important role in stress (e.g., burn)-induced insulin resistance. However, it remains to be determined how iNOS induces insulin resistance. Moreover, the interrelation between inflammatory response and apoptosis is poorly understood, although they often develop simultaneously. Nuclear factor (NF)-kappa B and p53 are key regulators of inflammation and apoptosis, respectively. Sirt1 inhibits p65 NF-kappa B and p53 by deacetylating these transcription factors. Recently, we have shown that iNOS induces S-nitrosylation of Sirt1, which inactivates Sirt1 and thereby increases acetylation and activity of p65 NF-kappa B and p53 in various cell types, including skeletal muscle cells. Here, we show that iNOS enhances burn-induced inflammatory response and apoptotic change in mouse skeletal muscle along with S-nitrosylation of Sirt1. Burn injury induced robust expression of iNOS in skeletal muscle and gene disruption of iNOS significantly inhibited burn induced increases in inflammatory gene expression and apoptotic change. In parallel, burn increased Sirt1 S-nitrosylation and acetylation and DNA-binding capacity of p65 NF kappa B and p53, all of which were reversed or ameliorated by iNOS deficiency. These results indicate that iNOS functions not only as a downstream effector but also as an upstream enhancer of burn-induced inflammatory response, at least in part, by Sirt1 S-nitrosylationdependent activation (acetylation) of p65 NF-kappa B. Our data suggest that Sirt1 S-nitrosylation may play a role in iNOS-mediated enhanced inflammatory response and apoptotic change, which, in turn, contribute to muscle wasting and supposedly to insulin resistance after burn injury. C1 [Nakazawa, Harumasa; Chang, Kyungho; Shinozaki, Shohei; Yasukawa, Takashi; Ishimaru, Kazuhiro; Yasuhara, Shingo; Martyn, J. A. Jeevendra; Kaneki, Masao] Harvard Med Sch, Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Charlestown, MA 02139 USA. [Nakazawa, Harumasa; Yasukawa, Takashi; Ishimaru, Kazuhiro; Yasuhara, Shingo; Yu, Yong-Ming; Martyn, J. A. Jeevendra; Tompkins, Ronald. G.; Kaneki, Masao] Shriners Hosp Children, Boston, MA 02114 USA. [Shinozaki, Shohei; Shimokado, Kentaro] Tokyo Med & Dent Univ, Dept Geriatr & Vasc Med, Grad Sch, Tokyo, Japan. [Yu, Yong-Ming; Tompkins, Ronald. G.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Surg, Boston, MA USA. RP Kaneki, M (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Charlestown, MA 02139 USA.; Kaneki, M (reprint author), Shriners Hosp Children, Boston, MA 02114 USA. EM mkaneki@helix.mgh.harvard.edu FU National Institutes of Health (NIH) [R01DK05827, R01GM115552, R01GM117298]; Shriners Hospitals for Children [71000, 85800]; NIH [P50GM02700]; Japan Society for the Promotion of Science (JSPS) FX This work was supported by research grants to MK from National Institutes of Health (NIH) (R01DK05827, R01GM115552, R01GM117298) and Shriners Hospitals for Children (71000, 85800), to RGT from NIH (P50GM02700), and to SS and KS from Japan Society for the Promotion of Science (JSPS) Program for Advancing Strategic International Networks to Accelerate the Circulation of Talented Researchers. The funders had no role in study design, date collection and analysis, decision to publish, or preparation of the manuscript. NR 59 TC 0 Z9 0 U1 4 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 18 PY 2017 VL 12 IS 1 AR e0170391 DI 10.1371/journal.pone.0170391 PG 18 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EI3HH UT WOS:000392380100084 PM 28099528 ER PT J AU Li, YY Chung, GTY Lui, VWY To, KF Ma, BBY Chow, C Woo, JKS Yip, KY Seo, J Hui, EP Mak, MKF Rusan, M Chau, NG Or, YYY Law, MHN Law, PPY Liu, ZWY Ngan, HL Hau, PM Verhoeft, KR Poon, PHY Yoo, SK Shin, JY Lee, SD Lun, SWM Jia, L Chan, AWH Chan, JYK Lai, PBS Fung, CY Hung, ST Wang, L Chang, AMV Chiosea, SI Hedberg, ML Tsao, SW van Hasselt, AC Chan, ATC Grandis, JR Hammerman, PS Lo, KW AF Li, Yvonne Y. Chung, Grace T. Y. Lui, Vivian W. Y. To, Ka-Fai Ma, Brigette B. Y. Chow, Chit Woo, John K. S. Yip, Kevin Y. Seo, Jeongsun Hui, Edwin P. Mak, Michael K. F. Rusan, Maria Chau, Nicole G. Or, Yvonne Y. Y. Law, Marcus H. N. Law, Peggy P. Y. Liu, Zoey W. Y. Ngan, Hoi-Lam Hau, Pok-Man Verhoeft, Krista R. Poon, Peony H. Y. Yoo, Seong-Keun Shin, Jong-Yeon Lee, Sau-Dan Lun, Samantha W. M. Jia, Lin Chan, Anthony W. H. Chan, Jason Y. K. Lai, Paul B. S. Fung, Choi-Yi Hung, Suet-Ting Wang, Lin Chang, Ann Margaret V. Chiosea, Simion I. Hedberg, Matthew L. Tsao, Sai-Wah van Hasselt, Andrew C. Chan, Anthony T. C. Grandis, Jennifer R. Hammerman, Peter S. Lo, Kwok-Wai TI Exome and genome sequencing of nasopharynx cancer identifies NF-kappa B pathway activating mutations SO NATURE COMMUNICATIONS LA English DT Article ID WHOLE-GENOME; CARCINOMA; TUMOR; LANDSCAPE; GENE; SAMPLES; FUSION AB Nasopharyngeal carcinoma (NPC) is an aggressive head and neck cancer characterized by Epstein-Barr virus (EBV) infection and dense lymphocyte infiltration. The scarcity of NPC genomic data hinders the understanding of NPC biology, disease progression and rational therapy design. Here we performed whole-exome sequencing (WES) on 111 micro-dissected EBV-positive NPCs, with 15 cases subjected to further whole-genome sequencing (WGS), to determine its mutational landscape. We identified enrichment for genomic aberrations of multiple negative regulators of the NF-kappa B pathway, including CYLD, TRAF3, NFKBIA and NLRC5, in a total of 41% of cases. Functional analysis confirmed inactivating CYLD mutations as drivers for NPC cell growth. The EBV oncoprotein latent membrane protein 1 (LMP1) functions to constitutively activate NF-kappa B signalling, and we observed mutual exclusivity among tumours with somatic NF-kappa B pathway aberrations and LMP1-overexpression, suggesting that NF-kB activation is selected for by both somatic and viral events during NPC pathogenesis. C1 [Li, Yvonne Y.; Rusan, Maria; Chau, Nicole G.; Hammerman, Peter S.] Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Li, Yvonne Y.; Rusan, Maria; Chau, Nicole G.; Hammerman, Peter S.] Broad Inst Harvard & MIT, Canc Program, Cambridge, MA 02142 USA. [Chung, Grace T. Y.; To, Ka-Fai; Chow, Chit; Mak, Michael K. F.; Or, Yvonne Y. Y.; Law, Marcus H. N.; Law, Peggy P. Y.; Liu, Zoey W. Y.; Hau, Pok-Man; Lun, Samantha W. M.; Chan, Anthony W. H.; Lo, Kwok-Wai] Chinese Univ Hong Kong, Dept Anat & Cellular Pathol, State Key Lab Oncol South China, Hong Kong, Hong Kong, Peoples R China. [Chung, Grace T. Y.; To, Ka-Fai; Chow, Chit; Mak, Michael K. F.; Or, Yvonne Y. Y.; Law, Marcus H. N.; Law, Peggy P. Y.; Liu, Zoey W. Y.; Hau, Pok-Man; Lun, Samantha W. M.; Chan, Anthony W. H.; Lo, Kwok-Wai] Chinese Univ Hong Kong, Li Ka Shing Inst Hlth Sci, Hong Kong, Hong Kong, Peoples R China. [Lui, Vivian W. Y.] Chinese Univ Hong Kong, Sch Biomed Sci, Fac Med, Hong Kong, Hong Kong, Peoples R China. [Lui, Vivian W. Y.; Ngan, Hoi-Lam; Verhoeft, Krista R.; Poon, Peony H. Y.; Fung, Choi-Yi; Hung, Suet-Ting] Univ Hong Kong, Dept Pharmacol & Pharm, Sch Biomed Sci, Li Ka Shing Fac Med, Hong Kong, Hong Kong, Peoples R China. [Ma, Brigette B. Y.; Hui, Edwin P.; Chan, Anthony T. C.] Chinese Univ Hong Kong, Dept Clin Oncol, Sir YK Pao Ctr Canc, State Key Lab Oncol South China, Hong Kong, Hong Kong, Peoples R China. [Woo, John K. S.; Chan, Jason Y. K.; van Hasselt, Andrew C.] Chinese Univ Hong Kong, Prince Wales Hosp, Dept Otorhinolaryngol Head & Neck Surg, Hong Kong, Hong Kong, Peoples R China. [Yip, Kevin Y.; Lee, Sau-Dan] Chinese Univ Hong Kong, Dept Comp Sci & Engn, Hong Kong, Hong Kong, Peoples R China. [Seo, Jeongsun; Yoo, Seong-Keun; Shin, Jong-Yeon] Seoul Natl Univ, Genom Med Inst, Med Res Ctr, Seoul 10799, South Korea. [Jia, Lin; Tsao, Sai-Wah] Univ Hong Kong, Li Ka Shing Fac Med, Sch Biomed Sci, Hong Kong, Hong Kong, Peoples R China. [Jia, Lin; Tsao, Sai-Wah] Univ Hong Kong, Li Ka Shing Fac Med, Ctr Canc Res, Hong Kong, Hong Kong, Peoples R China. [Lai, Paul B. S.] Chinese Univ Hong Kong, Prince Wales Hosp, Dept Surg, Hong Kong, Hong Kong, Peoples R China. [Wang, Lin; Chiosea, Simion I.] Univ Pittsburgh, Med Ctr, Dept Pathol, Pittsburgh, PA 15261 USA. [Chang, Ann Margaret V.] St Lukes Med Ctr, Inst Pathol, Quezon City 1112, Philippines. [Hedberg, Matthew L.] Univ Pittsburgh, Carnegie Mellon Univ, Med Scientist Training Program, Pittsburgh, PA 15261 USA. [Grandis, Jennifer R.] Univ Calif San Francisco, Dept Otolaryngol, San Francisco, CA 94113 USA. RP Hammerman, PS (reprint author), Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA.; Hammerman, PS (reprint author), Broad Inst Harvard & MIT, Canc Program, Cambridge, MA 02142 USA.; Lo, KW (reprint author), Chinese Univ Hong Kong, Dept Anat & Cellular Pathol, State Key Lab Oncol South China, Hong Kong, Hong Kong, Peoples R China.; Lo, KW (reprint author), Chinese Univ Hong Kong, Li Ka Shing Inst Hlth Sci, Hong Kong, Hong Kong, Peoples R China. EM peter_hammerman@dfci.harvard.edu; kwlo@cuhk.edu.hk RI Lui, Vivian/I-5458-2016; Lai, Paul/K-8556-2015 OI Lai, Paul/0000-0002-9469-6728 FU Core Utilities of Cancer Genomics and Pathobiology, Theme-based Research Scheme [T12-401/13-R]; Research Grant Council, Hong Kong; Research Grant Council, Hong Kong [471413, 470312, 471211, 1404415, 14138016, 17114814, 14104415]; Focused Innovations Scheme and Faculty Strategic Research of Faculty of Medicine [4620513]; VC's One-off Discretionary Fund [VCF2014017, VCF2014015]; Chinese University of Hong Kong; Start-up Fund from the School of Biomedical Sciences, Faculty of Medicine; NCI [1F30CA180235, K08 CA163677]; [AoE/M-06/08] FX This study is supported by Core Utilities of Cancer Genomics and Pathobiology, Theme-based Research Scheme (T12-401/13-R), Research Grant Council, Hong Kong. K.-W.L. is funded by Research Grant Council, Hong Kong (#471413, 470312, 471211, 1404415, 14138016, General Research Fund), Focused Innovations Scheme and Faculty Strategic Research (4620513) of Faculty of Medicine, and VC's One-off Discretionary Fund (VCF2014017, VCF2014015), The Chinese University of Hong Kong. S.-W.T. is supported by AoE/M-06/08. V.W.Y.L. is funded by the Research Grant Council, Hong Kong (#17114814, General Research Fund), and the Start-up Fund from the School of Biomedical Sciences, Faculty of Medicine, the Chinese University of Hong Kong. K.-F.T. is funded by the Research Grant Council, Hong Kong (General Research Fund #14138016 and #14104415). M.L.H. is supported by NCI 1F30CA180235. P.S.H. is supported by NCI K08 CA163677. NR 37 TC 0 Z9 0 U1 6 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD JAN 18 PY 2017 VL 8 AR 14121 DI 10.1038/ncomms14121 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EI0IM UT WOS:000392156800001 PM 28098136 ER PT J AU Singhal, AB Topcuoglu, MA AF Singhal, Aneesh B. Topcuoglu, Mehmet A. TI Glucocorticoid-associated worsening in reversible cerebral vasoconstriction syndrome SO NEUROLOGY LA English DT Article ID CENTRAL-NERVOUS-SYSTEM; TERM-FOLLOW-UP; BENIGN ANGIOPATHY; PRIMARY ANGIITIS; FEATURES; RISK; NIMODIPINE; VASOSPASM; STROKE; SERIES AB Objective: Factors predicting poor outcome in patients with the reversible cerebral vasoconstriction syndrome (RCVS) have not been identified. Methods: In this single-center retrospective study, we analyzed the clinical, brain imaging, and angiography data in 162 patients with RCVS. Univariable and multivariable regression analysis were performed to identify predictors of persistent (nontransient) clinical worsening, radiologic worsening, early angiographic progression, and poor discharge outcome (modified Rankin Scale score 4-6). Results: The mean age was 44 +/- 13 years; 78% of patients were women. Persistent clinical worsening occurred in 14% at 6.6 +/- 4.1 days after symptom onset, radiologic worsening in 27% (mainly new infarcts), and angiographic progression in 15%. Clinical worsening correlated with angiographic progression and new nonhemorrhagic lesions. Age and sex did not independently predict any type of worsening. Infarction on baseline imaging predicted poor outcome. Prior serotonergic antidepressant use predicted clinical and angiographic worsening but not poor outcome. Intra-arterial vasodilator therapy independently predicted clinical worsening and poor discharge outcome but was offered to more severe cases. Glucocorticoid treatment proved to be an independent predictor of clinical, imaging, and angiographic worsening and poor outcome. Of the 23 patients with clinical worsening, 17 received glucocorticoids (15 within the preceding 2 days). There were no significant differences in baseline brain lesions and angiographic abnormalities between glucocorticoid-treated and untreated patients. Conclusion: Patients with RCVS at risk for worsening can be identified on basis of baseline features. Iatrogenic factors such as glucocorticoid exposure may contribute to worsening. C1 [Singhal, Aneesh B.; Topcuoglu, Mehmet A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Singhal, Aneesh B.; Topcuoglu, Mehmet A.] Harvard Med Sch, Boston, MA 02115 USA. [Topcuoglu, Mehmet A.] Hacettepe Univ Hosp, Dept Neurol, Ankara, Turkey. RP Singhal, AB (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA.; Singhal, AB (reprint author), Harvard Med Sch, Boston, MA 02115 USA. EM asinghal@partners.org NR 31 TC 1 Z9 1 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD JAN 17 PY 2017 VL 88 IS 3 BP 228 EP 236 PG 9 WC Clinical Neurology SC Neurosciences & Neurology GA EO2YS UT WOS:000396562600007 PM 27940651 ER PT J AU Cote, DJ Bredenoord, AL Smith, TR Ammirati, M Brennum, J Mendez, I Ammar, AS Balak, N Bolles, G Esene, IN Mathiesen, T Broekman, ML AF Cote, David J. Bredenoord, Annelien L. Smith, Timothy R. Ammirati, Mario Brennum, Jannick Mendez, Ivar Ammar, Ahmed S. Balak, Naci Bolles, Gene Esene, Ignatius Ngene Mathiesen, Tiit Broekman, Marike L. TI Ethical clinical translation of stem cell interventions for neurologic disease SO NEUROLOGY LA English DT Article ID PARKINSONS-DISEASE; SPINAL-CORD; HUNTINGTONS-DISEASE; GENE-THERAPY; TRANSPLANTATION; BRAIN; PERSPECTIVES; STANDARDS; PATHOLOGY; RECOVERY AB The application of stem cell transplants in clinical practice has increased in frequency in recent years. Many of the stem cell transplants in neurologic diseases, including stroke, Parkinson disease, spinal cord injury, and demyelinating diseases, are unproven-they have not been tested in prospective, controlled clinical trials and have not become accepted therapies. Stem cell transplant procedures currently being carried out have therapeutic aims, but are frequently experimental and unregulated, and could potentially put patients at risk. In some cases, patients undergoing such operations are not included in a clinical trial, and do not provide genuinely informed consent. For these reasons and others, some current stem cell interventions for neurologic diseases are ethically dubious and could jeopardize progress in the field. We provide discussion points for the evaluation of new stem cell interventions for neurologic disease, based primarily on the new Guidelines for Stem Cell Research and Clinical Translation released by the International Society for Stem Cell Research in May 2016. Important considerations in the ethical translation of stem cells to clinical practice include regulatory oversight, conflicts of interest, data sharing, the nature of investigation (e. g., within vs outside of a clinical trial), informed consent, risk-benefit ratios, the therapeutic misconception, and patient vulnerability. To help guide the translation of stem cells from the laboratory into the neurosurgical clinic in an ethically sound manner, we present an ethical discussion of these major issues at stake in the field of stem cell clinical research for neurologic disease. C1 [Cote, David J.; Smith, Timothy R.] Brigham & Womens Hosp, Cushing Neurosurg Outcomes Ctr, Dept Neurosurg, Boston, MA USA. [Bredenoord, Annelien L.] Brigham & Womens Hosp, Harvard Med Sch, Julius Ctr, Dept Med Human, Boston, MA USA. [Broekman, Marike L.] Univ Med Ctr, Dept Neurosurg, Utrecht, Netherlands. [Ammirati, Mario] Ohio State Univ, Dept Neurosurg, Columbus, OH USA. [Brennum, Jannick] Ohio State Univ, Copenhagen Neurosurg Neurosci Ctr, Columbus, OH USA. [Mendez, Ivar] Univ Copenhagen, Copenhagen, Denmark. [Mendez, Ivar] Univ Saskatchewan, Saskatoon Hlth Reg, Dept Surg, Saskatoon, SK, Canada. [Ammar, Ahmed S.] Royal Univ Hosp, Saskatoon, SK, Canada. [Ammar, Ahmed S.] Univ Dammam, Coll Med, Dept Neurosurg, Dammam, Saudi Arabia. [Balak, Naci] Goztepe Educ & Res Hosp, Dept Neurosurg, Istanbul, Turkey. [Bolles, Gene] Univ Colorado, Sch Med, Denver Hlth Med Ctr, Colorado Springs, CO USA. [Esene, Ignatius Ngene] Ain Shams Univ, Dept Neurosurg, Cairo, Egypt. [Mathiesen, Tiit] Karolinska Hosp & Inst, Dept Neurosurg, Stockholm, Sweden. [Broekman, Marike L.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA USA. RP Broekman, ML (reprint author), Univ Med Ctr, Dept Neurosurg, Utrecht, Netherlands.; Broekman, ML (reprint author), Massachusetts Gen Hosp, Dept Neurol, Boston, MA USA. EM M.L.D.Broekman-4@umcutrecht.nl NR 57 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD JAN 17 PY 2017 VL 88 IS 3 BP 322 EP 328 DI 10.1212/WNL.0000000000003506 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA EO2YS UT WOS:000396562600019 PM 27927932 ER PT J AU Wu, YL Sequist, LV Hu, CP Feng, JF Lu, S Huang, YC Li, W Hou, M Schuler, M Mok, T Yamamoto, N O'Byrne, K Hirsh, V Gibson, N Massey, D Kim, M Yang, JCH AF Wu, Yi-Long Sequist, Lecia V. Hu, Cheng-Ping Feng, Jifeng Lu, Shun Huang, Yunchao Li, Wei Hou, Mei Schuler, Martin Mok, Tony Yamamoto, Nobuyuki O'Byrne, Kenneth Hirsh, Vera Gibson, Neil Massey, Dan Kim, Miyoung Yang, James Chih-Hsin TI EGFR mutation detection in circulating cell-free DNA of lung adenocarcinoma patients: analysis of LUX-Lung 3 and 6 SO BRITISH JOURNAL OF CANCER LA English DT Article DE afatinib; circulating cell-free DNA; ErbB family blocker; EGFR mutation; non-small cell lung cancer ID FACTOR RECEPTOR MUTATIONS; RANDOMIZED PHASE-3 TRIAL; CANCER PATIENTS; OPEN-LABEL; TUMOR-DNA; STANDARD CHEMOTHERAPY; 1ST-LINE TREATMENT; CHINESE PATIENTS; NSCLC PATIENTS; PLASMA DNA AB Background: In the Phase III LUX-Lung 3/6 (LL3/LL6) trials in epidermal growth factor receptor (EGFR) mutation-positive lung adenocarcinoma patients, we evaluated feasibility of EGFR mutation detection using circulating cell-free DNA (cfDNA) and prognostic and predictive utility of cfDNA positivity (cfDNA+). Methods: Paired tumour and blood samples were prospectively collected from randomised patients. Mutations were detected using cfDNA from serum (LL3) or plasma (LL6) by a validated allele-specific quantitative real-time PCR kit. Results: EGFR mutation detection rates in cfDNA were 28.6% (serum) and 60.5% (plasma). Mutation detection in blood was associated with advanced disease characteristics, including higher performance score, number of metastatic sites and bone/liver metastases, and poorer prognosis. In patients with common EGFR mutations, afatinib improved progression-free survival vs chemotherapy in cfDNA+ (LL3: HR, 0.35; P = 0.0009; LL6: HR, 0.25; P < 0.0001) and cfDNA- (LL3: HR, 0.46; P < 0.0001; LL6: HR, 0.12; P < 0.0001) cohorts. A trend towards overall survival benefit with afatinib was observed in cfDNA+ patients. Conclusions: Plasma cfDNA is a promising alternative to biopsy for EGFR testing. Detectable mutation in blood was associated with more advanced disease and poorer prognosis. Afatinib improved outcomes in EGFR mutation-positive patients regardless of blood mutation status. C1 [Wu, Yi-Long] Guangdong Gen Hosp, Guangdong Lung Canc Inst, 106 Zhongshan 2nd Rd, Guangzhou 510080, Guangdong, Peoples R China. [Wu, Yi-Long] Guangdong Acad Med Sci, 106 Zhongshan 2nd Rd, Guangzhou 510080, Guangdong, Peoples R China. [Sequist, Lecia V.] Massachusetts Gen Hosp, 55 Fruit St, Boston, MA 02114 USA. [Sequist, Lecia V.] Harvard Med Sch, 55 Fruit St, Boston, MA 02114 USA. [Hu, Cheng-Ping] Cent S Univ, Xiangya Hosp, 87 Xiangya Rd, Changsha 410018, Hunan, Peoples R China. [Feng, Jifeng] Jiangsu Prov Tumor Hosp, 42 Baiziting, Nanjing 210009, Jiangsu, Peoples R China. [Lu, Shun] Shanghai Jiao Tong Univ, Shanghai Chest Hosp, Shanghai Lung Tumor Clin Med Ctr, 241 Huaihai West Rd, Shanghai 200030, Peoples R China. [Huang, Yunchao] Kunming Med Univ, Affiliated Hosp 3, Yunnan Tumor Hosp, Kunming, Yunnan, Peoples R China. [Li, Wei] Jilin Univ, Ctr Canc, Hosp 1, 71 Xinmin St, Changchun 130021, Peoples R China. [Hou, Mei] Sichuan Univ, West China Hosp, 24 South Sect 1,Yihuan Rd, Chengdu 610065, Peoples R China. [Schuler, Martin] Univ Duisburg Essen, West German Canc Ctr, Hufelandstr 55, D-45147 Essen, Germany. [Schuler, Martin] Partner Site Univ Hosp Essen, German Canc Consortium DKTK, D-45147 Essen, Germany. [Mok, Tony] Chinese Univ Hong Kong, Shatin, Hong Kong, Peoples R China. [Yamamoto, Nobuyuki] Wakayama Med Univ, 811-1 Kimiidera, Wakayama, Wakayama Prefec 6418509, Japan. [O'Byrne, Kenneth] Princess Alexandra Hosp, 199 Ipswich Rd, Brisbane, Qld 4102, Australia. [O'Byrne, Kenneth] Queensland Univ Technol, 199 Ipswich Rd, Woolloongabba, Qld 4102, Australia. [Hirsh, Vera] McGill Univ, 845 Rue Sherbrooke O, Montreal, PQ H3A 0G4, Canada. [Gibson, Neil] Boehringer Ingelheim Pharma GmbH & Co KG, Birkendorfer St 65, D-88400 Biberach, Germany. [Massey, Dan] Boehringer Ingelheim Ltd UK, Ellesfield Ave, Bracknell RG12 8YS, Berks, England. [Kim, Miyoung] Boehringer Ingelheim GmbH & Co KG, Binger St 173, D-55216 Ingelheim, Germany. [Yang, James Chih-Hsin] Natl Taiwan Univ Hosp, 7 Chung Shan South Rd, Taipei 100, Taiwan. RP Wu, YL (reprint author), Guangdong Gen Hosp, Guangdong Lung Canc Inst, 106 Zhongshan 2nd Rd, Guangzhou 510080, Guangdong, Peoples R China.; Wu, YL (reprint author), Guangdong Acad Med Sci, 106 Zhongshan 2nd Rd, Guangzhou 510080, Guangdong, Peoples R China.; Yang, JCH (reprint author), Natl Taiwan Univ Hosp, 7 Chung Shan South Rd, Taipei 100, Taiwan. EM syylwu@live.cn; chihyang@ntu.edu.tw FU Boehringer Ingelheim; GeoMed; Ashfield business; UDG Healthcare plc FX Medical writing assistance, supported financially by Boehringer Ingelheim, was provided by Katie McClendon, PhD, of GeoMed, an Ashfield business, part of UDG Healthcare plc, during the preparation of this article. The authors were fully responsible for all content and editorial decisions, were involved at all stages of manuscript development, and have approved the final version. This study was supported by Boehringer Ingelheim. NR 34 TC 0 Z9 0 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 EI 1532-1827 J9 BRIT J CANCER JI Br. J. Cancer PD JAN 17 PY 2017 VL 116 IS 2 BP 175 EP 185 DI 10.1038/bjc.2016.420 PG 11 WC Oncology SC Oncology GA EL2IQ UT WOS:000394443700005 PM 28006816 ER PT J AU Torrey, H Butterworth, J Mera, T Okubo, Y Wang, LM Baum, D Defusco, A Plager, S Warden, S Huang, D Vanamee, E Foster, R Faustman, DL AF Torrey, Heather Butterworth, John Mera, Toshiyuki Okubo, Yoshiaki Wang, Limei Baum, Danielle Defusco, Audrey Plager, Sara Warden, Sarah Huang, Daniel Vanamee, Eva Foster, Rosemary Faustman, Denise L. TI Targeting TNFR2 with antagonistic antibodies inhibits proliferation of ovarian cancer cells and tumor-associated T-regs SO SCIENCE SIGNALING LA English DT Article ID NECROSIS-FACTOR RECEPTOR; CRYSTAL-STRUCTURE; REGULATORY-CELLS; FACTOR-ALPHA; PERIPHERAL-BLOOD; EXPRESSION; COMPLEX; INDUCTION; CHEMORADIOTHERAPY; APO2L/TRAIL AB Major barriers to cancer therapy include the lack of selective inhibitors of regulatory T cells (T-regs) and the lack of broadly applicable ways to directly target tumors through frequently expressed surface oncogenes. Tumor necrosis factor receptor 2 (TNFR2) is an attractive target protein because of its restricted abundance to highly immunosuppressive T-regs and oncogenic presence on human tumors. We characterized the effect of TNFR2 inhibition using antagonistic antibodies. In culture-based assays, we found that two TNFR2 antagonists inhibited T-reg proliferation, reduced soluble TNFR2 secretion from normal cells, and enabled T effector cell expansion. The antagonistic activity occurred in the presence of added TNF, a natural TNFR2 agonist. These TNFR2 antibodies killed T-regs isolated from ovarian cancer ascites more potently than it killed T-regs from healthy donor samples, suggesting that these antibodies may have specificity for the tumor microenvironment. The TNFR2 antagonists also killed OVCAR3 ovarian cancer cells, which have abundant surface TNFR2. The antibodies stabilized antiparallel dimers in cell surface TNFR2 that rendered the receptor unable to activate the nuclear factor kappa B pathway and trigger cell proliferation. Our data suggest that, by targeting tumor cells and immunosuppressive tumor-associated T-regs, antagonistic TNFR2 antibodies may be an effective treatment for cancers positive for TNFR2. C1 [Torrey, Heather; Butterworth, John; Mera, Toshiyuki; Okubo, Yoshiaki; Wang, Limei; Baum, Danielle; Defusco, Audrey; Plager, Sara; Warden, Sarah; Huang, Daniel; Vanamee, Eva; Faustman, Denise L.] Massachusetts Gen Hosp, Immunobiol, Boston, MA 02129 USA. [Torrey, Heather; Butterworth, John; Mera, Toshiyuki; Okubo, Yoshiaki; Wang, Limei; Baum, Danielle; Defusco, Audrey; Plager, Sara; Warden, Sarah; Huang, Daniel; Vanamee, Eva; Faustman, Denise L.] Harvard Med Sch, Boston, MA 02129 USA. [Foster, Rosemary] Massachusetts Gen Hosp, Dept Obstet & Gynecol, Boston, MA 02114 USA. [Foster, Rosemary] Harvard Med Sch, Vincent Ctr Reprod Biol, Boston, MA 02114 USA. RP Faustman, DL (reprint author), Massachusetts Gen Hosp, Immunobiol, Boston, MA 02129 USA.; Faustman, DL (reprint author), Harvard Med Sch, Boston, MA 02129 USA. EM faustman@helix.mgh.harvard.edu FU Manpei Suzuki Diabetes Foundation; American Autoimmune Related Disease Association FX Y. Okubo was supported in part by a travel grant from the Manpei Suzuki Diabetes Foundation. H. Torrey was supported in part by a fellowship from the American Autoimmune Related Disease Association. The Advanced Medical Research Foundation supported the collection of ascites from ovarian cancer subjects. NR 49 TC 1 Z9 1 U1 3 U2 3 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1945-0877 EI 1937-9145 J9 SCI SIGNAL JI Sci. Signal. PD JAN 17 PY 2017 VL 10 IS 462 AR eaaf8608 DI 10.1126/scisignal.aaf8608 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA EK2VG UT WOS:000393784200002 ER PT J AU Gosmann, C Anahtar, MN Handley, SA Farcasanu, M Abu-Ali, G Bowman, BA Padavattan, N Desai, C Droit, L Moodley, A Dong, M Chen, YZ Ismail, N Ndung'u, T Ghebremichael, MS Wesemann, DR Mitchell, C Dong, KL Huttenhower, C Walker, BD Virgin, HW Kwon, DS AF Gosmann, Christina Anahtar, Melis N. Handley, Scott A. Farcasanu, Mara Abu-Ali, Galeb Bowman, Brittany A. Padavattan, Nikita Desai, Chandni Droit, Lindsay Moodley, Amber Dong, Mary Chen, Yuezhou Ismail, Nasreen Ndung'u, Thumbi Ghebremichael, Musie S. Wesemann, Duane R. Mitchell, Caroline Dong, Krista L. Huttenhower, Curtis Walker, Bruce D. Virgin, Herbert W. Kwon, Douglas S. TI Lactobacillus-Deficient Cervicovaginal Bacterial Communities Are Associated with Increased HIV Acquisition in Young South African Women SO IMMUNITY LA English DT Article ID FEMALE GENITAL-TRACT; T-CELL-ACTIVATION; SEXUAL TRANSMISSION; TH17 CELLS; INFECTION; MICROBIOME; IMMUNODEFICIENCY; SUSCEPTIBILITY; SIV; VAGINOSIS AB Elevated inflammation in the female genital tract is associated with increased HIV risk. Cervicovaginal bacteria modulate genital inflammation; however, their role in HIV susceptibility has not been elucidated. In a prospective cohort of young, healthy South African women, we found that individuals with diverse genital bacterial communities dominated by anaerobes other than Gardnerella were at over 4-fold higher risk of acquiring HIV and had increased numbers of activated mucosal CD4(+) T cells compared to those with Lactobacillus crispatus- dominant communities. We identified specific bacterial taxa linked with reduced (L. crispatus) or elevated (Prevotella, Sneathia, and other anaerobes) inflammation and HIV infection and found that high-risk bacteria increased numbers of activated genital CD4(+) T cells in a murine model. Our results suggest that highly prevalent genital bacteria increase HIV risk by inducing mucosal HIV target cells. These findings might be leveraged to reduce HIV acquisition in women living in sub-Saharan Africa. C1 [Gosmann, Christina; Anahtar, Melis N.; Farcasanu, Mara; Bowman, Brittany A.; Dong, Mary; Ndung'u, Thumbi; Ghebremichael, Musie S.; Dong, Krista L.; Walker, Bruce D.; Kwon, Douglas S.] Massachusetts Gen Hosp, Ragon Inst MGH MIT & Harvard, Cambridge, MA 02139 USA. [Gosmann, Christina; Anahtar, Melis N.; Chen, Yuezhou; Ghebremichael, Musie S.; Wesemann, Duane R.; Kwon, Douglas S.] Harvard Med Sch, Boston, MA 02115 USA. [Handley, Scott A.; Desai, Chandni; Droit, Lindsay; Virgin, Herbert W.] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO 63110 USA. [Abu-Ali, Galeb; Huttenhower, Curtis] Harvard Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Padavattan, Nikita; Ismail, Nasreen; Ndung'u, Thumbi] Univ KwaZulu Natal, Nelson R Mandela Sch Med, HIV Pathogenesis Programme, ZA-4001 Durban, Kwazulu Natal, South Africa. [Moodley, Amber; Dong, Mary; Dong, Krista L.] Females Rising Educ Support & Hlth, ZA-4066 Durban, Kwazulu Natal, South Africa. [Chen, Yuezhou; Wesemann, Duane R.] Brigham & Womens Hosp, Dept Med, Div Rheumatol Immunol & Allergy, 75 Francis St, Boston, MA 02115 USA. [Mitchell, Caroline] Massachusetts Gen Hosp, Vincent Obstet & Gynecol, Boston, MA 02115 USA. [Walker, Bruce D.] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. [Walker, Bruce D.; Kwon, Douglas S.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02115 USA. [Walker, Bruce D.] MIT, Inst Med Engn & Sci, 77 Massachusetts Ave, Cambridge, MA 02139 USA. RP Kwon, DS (reprint author), Massachusetts Gen Hosp, Ragon Inst MGH MIT & Harvard, Cambridge, MA 02139 USA.; Kwon, DS (reprint author), Harvard Med Sch, Boston, MA 02115 USA.; Kwon, DS (reprint author), Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02115 USA. EM dkwon@mgh.harvard.edu FU Collaboration for AIDS Vaccine Discovery of the Bill and Melinda Gates Foundation; International AIDS Vaccine Initiative (IAVI) [UKZNRSA1001]; NIAID [1R01AI111918, R01AI067073]; Harvard Center for AIDS Research; Burroughs Wellcome Fund; National Institute of General Medical Sciences [T32GM007753]; NIH [AI1113217]; Doris Duke Clinical Scientist Development Award FX We would like to thank the FRESH participants; T. Cele for performing the pelvic exams; T. Sikhakhane, S. Ngcobo, and S. Zungu for clinical support; H. Shen for flow cytometry assistance; M. Karpel for performing the IL-8 ELISA. This work was supported by the Collaboration for AIDS Vaccine Discovery of the Bill and Melinda Gates Foundation, the International AIDS Vaccine Initiative (IAVI) (UKZNRSA1001), the NIAID (1R01AI111918 and R01AI067073), and the Harvard Center for AIDS Research. D. S. K. and D. R. W. received additional support from the Burroughs Wellcome Fund, M.N.A. from the National Institute of General Medical Sciences (award number T32GM007753), D. R. W. from the NIH (AI1113217) and C. M. from a Doris Duke Clinical Scientist Development Award. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIGMS or the NIH. NR 34 TC 1 Z9 1 U1 4 U2 4 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 EI 1097-4180 J9 IMMUNITY JI Immunity PD JAN 17 PY 2017 VL 46 IS 1 BP 29 EP 37 DI 10.1016/j.immuni.2016.12.013 PG 9 WC Immunology SC Immunology GA EJ0RP UT WOS:000392918300008 PM 28087240 ER PT J AU Das, A Heesters, BA Bialas, A O'Flynn, J Rifkin, IR Ochando, J Mittereder, N Carlesso, G Herbst, R Carroll, MC AF Das, Abhishek Heesters, Balthasar A. Bialas, Allison O'Flynn, Joseph Rifkin, Ian R. Ochando, Jordi Mittereder, Nanette Carlesso, Gianluca Herbst, Ronald Carroll, Michael C. TI Follicular Dendritic Cell Activation by TLR Ligands Promotes Autoreactive B Cell Responses SO IMMUNITY LA English DT Article ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; TOLL-LIKE RECEPTORS; I INTERFERON; AUTOIMMUNE-DISEASE; GERMINAL-CENTERS; AUTOANTIBODY PRODUCTION; AFFINITY MATURATION; SJOGRENS-SYNDROME; IMMUNE-RESPONSES; DEPENDENT MANNER AB A hallmark of autoimmunity inmurinemodels of lupus is the formation of germinal centers (GCs) in lymphoid tissues where self-reactive B cells expand and differentiate. In the host response to foreign antigens, follicular dendritic cells (FDCs) maintain GCs through the uptake and cycling of complement-opsonized immune complexes. Here, we examined whether FDCs retain self-antigens and the impact of this process in autoantibody secretion in lupus. We found that FDCs took up and retained self-immune complexes composed of ribonucleotide proteins, autoantibody, and complement. This uptake, mediated through CD21, triggered endosomal TLR7 and led to the secretion of interferon (IFN) alpha via an IRF5-dependent pathway. Blocking of FDC secretion of IFN-alpha restored B cell tolerance and reduced the amount of GCs and pathogenic autoantibody. Thus, FDCs are a critical source of the IFN-a driving autoimmunity in this lupus model. This pathway is conserved in humans, suggesting that it may be a viable therapeutic target in systemic lupus erythematosus. C1 [Das, Abhishek; Heesters, Balthasar A.; Bialas, Allison; O'Flynn, Joseph; Carroll, Michael C.] Boston Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA. [Carroll, Michael C.] Harvard Med Sch, Dept Pediat, Boston, MA 02115 USA. [Rifkin, Ian R.] Boston Univ, Sch Med, Boston, MA 02118 USA. [Ochando, Jordi] Icahn Sch Med Mt Sinai, Dept Med, New York, NY 10129 USA. [Mittereder, Nanette; Carlesso, Gianluca] MedImmune LLC, Dept Resp Inflammat & Autoimmun RIA, Gaithersburg, MD 20878 USA. [Herbst, Ronald] MedImmune LLC, Dept Canc Biol, Gaithersburg, MD 20878 USA. RP Carroll, MC (reprint author), Boston Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA.; Carroll, MC (reprint author), Harvard Med Sch, Dept Pediat, Boston, MA 02115 USA. EM michael.carroll@childrens.harvard.edu FU NIH [AI039246]; MedImmune LLC FX The authors thank all members of the M.C.C. lab for suggestions and help with experiments and reading of the manuscript. We acknowledge the valuable assistance of Elisabeth M. Carroll and the editorial assistance from Dr. Christina Usher. The authors thank Drs. T. Taniguchi and T. Mak for access to Irf5-/- and Irf7-/- mice. This work was supported by grants from NIH (AI039246) to M.C.C. and from MedImmune LLC. R.H., N.M., and G.C. are employees of MedImmune, LLC. NR 71 TC 0 Z9 0 U1 3 U2 3 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 EI 1097-4180 J9 IMMUNITY JI Immunity PD JAN 17 PY 2017 VL 46 IS 1 BP 106 EP 119 DI 10.1016/j.immuni.2016.12.014 PG 14 WC Immunology SC Immunology GA EJ0RP UT WOS:000392918300014 PM 28099860 ER PT J AU Ahn, R Woodbridge, A Abraham, A Saba, S Korenstein, D Madden, E Boscardin, WJ Keyhani, S AF Ahn, Rosa Woodbridge, Alexandra Abraham, Ann Saba, Susan Korenstein, Deborah Madden, Erin Boscardin, W. John Keyhani, Salomeh TI Financial ties of principal investigators and randomized controlled trial outcomes: cross sectional study SO BMJ-BRITISH MEDICAL JOURNAL LA English DT Article ID CONFLICTS-OF-INTEREST; MEDICAL-JOURNAL EDITORS; CLINICAL-TRIALS; INDUSTRY SPONSORSHIP; PHARMACEUTICAL-INDUSTRY; INTERNATIONAL-COMMITTEE; DRUG TRIALS; ASSOCIATION; AUTHORS; QUALITY AB OBJECTIVE To examine the association between the presence of individual principal investigators' financial ties to the manufacturer of the study drug and the trial's outcomes after accounting for source of research funding. DESIGN Cross sectional study of randomized controlled trials (RCTs). SETTING Studies published in "core clinical" journals, as identified by Medline, between 1 January 2013 and 31 December 2013. PARTICIPANTS Random sample of RCTs focused on drug efficacy. MAIN OUTCOME MEASURE Association between financial ties of principal investigators and study outcome. RESULTS A total of 190 papers describing 195 studies met inclusion criteria. Financial ties between principal investigators and the pharmaceutical industry were present in 132 (67.7%) studies. Of 397 principal investigators, 231 (58%) had financial ties and 166 (42%) did not. Of all principal investigators, 156 (39%) reported advisor/consultancy payments, 81 (20%) reported speakers' fees, 81 (20%) reported unspecified financial ties, 52 (13%) reported honorariums, 52 (13%) reported employee relationships, 52 (13%) reported travel fees, 41 (10%) reported stock ownership, and 20 (5%) reported having a patent related to the study drug. The prevalence of financial ties of principal investigators was 76% (103/136) among positive studies and 49% (29/59) among negative studies. In unadjusted analyses, the presence of a financial tie was associated with a positive study outcome (odds ratio 3.23, 95% confidence interval 1.7 to 6.1). In the primary multivariate analysis, a financial tie was significantly associated with positive RCT outcome after adjustment for the study funding source (odds ratio 3.57 (1.7 to 7.7). The secondary analysis controlled for additional RCT characteristics such as study phase, sample size, country of first authors, specialty, trial registration, study design, type of analysis, comparator, and outcome measure. These characteristics did not appreciably affect the relation between financial ties and study outcomes (odds ratio 3.37, 1.4 to 7.9). CONCLUSIONS Financial ties of principal investigators were independently associated with positive clinical trial results. These findings may be suggestive of bias in the evidence base. C1 [Ahn, Rosa] Oregon Hlth & Sci Univ, Portland, OR 97239 USA. [Woodbridge, Alexandra; Abraham, Ann; Madden, Erin; Boscardin, W. John; Keyhani, Salomeh] San Francisco VA Med Ctr, San Francisco, CA 94121 USA. [Saba, Susan] Stanford Univ, Sch Med, Palo Alto, CA 94304 USA. [Korenstein, Deborah] Mem Sloan Kettering Canc Ctr, New York, NY 10065 USA. [Boscardin, W. John; Keyhani, Salomeh] Univ Calif San Francisco, San Francisco, CA 94121 USA. RP Keyhani, S (reprint author), San Francisco VA Med Ctr, San Francisco, CA 94121 USA.; Keyhani, S (reprint author), Univ Calif San Francisco, San Francisco, CA 94121 USA. EM salomeh.keyhani@ucsf.edu FU National Institutes of Health [RO1 HL116522-01A1, RO1 HL114563-01A1]; Veterans Affairs Health Services Research and Development Service [1IP1HX001994]; National Cancer Institute [P30 CA008748] FX This project was not directly supported by any research funds. SK is funded by grants from the National Institutes of Health (RO1 HL116522-01A1, RO1 HL114563-01A1) and Veterans Affairs Health Services Research and Development Service (1IP1HX001994). DK's work on this paper was supported by a Cancer Center Support Grant from the National Cancer Institute to Memorial Sloan Kettering Cancer Center (award number P30 CA008748). NR 51 TC 2 Z9 2 U1 2 U2 2 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1756-1833 J9 BMJ-BRIT MED J JI BMJ-British Medical Journal PD JAN 17 PY 2017 VL 356 AR i6770 DI 10.1136/bmj.i6770 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA EJ4CC UT WOS:000393162500004 PM 28096109 ER PT J AU Cohen, EM Morley-Fletcher, A Mehta, DH Lee, YC AF Cohen, Ezra M. Morley-Fletcher, Alessio Mehta, Darshan H. Lee, Yvonne C. TI A systematic review of psychosocial therapies for children with rheumatic diseases SO PEDIATRIC RHEUMATOLOGY LA English DT Review DE Juvenile arthritis; Juvenile fibromyalgia; Psychological therapies; Mind-body therapies; Meditation ID COGNITIVE-BEHAVIORAL THERAPY; RANDOMIZED CONTROLLED-TRIALS; JUVENILE IDIOPATHIC ARTHRITIS; QUALITY-OF-LIFE; FIBROMYALGIA SYNDROME; CLINICAL-TRIAL; CHRONIC PAIN; ADOLESCENTS; METAANALYSIS; ANXIETY AB Background: To assess the quality of evidence for the effects of psychosocial therapies on pain and function in children with rheumatic diseases. Methods: We conducted a literature search of MEDLINE and PsycINFO for randomized clinical trials of psychosocial interventions for pain and disability in children with rheumatic diseases from January 1969 to September 2015. Studies with a sample size less than 10 subjects were excluded. Study quality was assessed using the Jadad score. Results: Five articles met inclusion criteria, for a total of 229 patients, aged 5 to 18 years. Two studies included children with fibromyalgia. Three studies included children with juvenile arthritis. Neither study in fibromyalgia reported the statistical significance of immediate between-group pre-post changes in functioning or pain. One study examining the effects of an internet-based psychosocial intervention in children with juvenile arthritis reported significant differences in post-intervention pain scores (p = 0.03). However, 2 studies did not show improvements in pain scores among children with juvenile arthritis treated with psychosocial interventions vs. a wait-list control or vs. an active control (massage). No studies reported significant between-group differences for functional outcomes in children with juvenile arthritis. Conclusions: The available data were limited by the scarcity of randomized trials. Definite conclusions about the immediate effect of psychosocial interventions on pain and function in children with fibromyalgia could not be made because between-group comparisons of post-treatment change scores were not reported. For children with juvenile inflammatory arthritis, results of between-group comparisons for pain differed across studies, and analyses examining disability revealed no significant differences between groups. C1 [Cohen, Ezra M.] Boston Childrens Hosp, Div Immunol, 300 Longwood Ave, Boston, MA 02115 USA. [Morley-Fletcher, Alessio] Massachusetts Gen Hosp, Dept Pediat, 55 Fruit St, Boston, MA 02114 USA. [Mehta, Darshan H.] Massachusetts Gen Hosp, Benson Henry Inst Mind Body Med, 151 Merrimac St, Boston, MA 02114 USA. [Lee, Yvonne C.] Brigham & Womens Hosp, Div Rheumatol Immunol & Allergy, 60 Fenwood Rd, Boston, MA 02115 USA. [Cohen, Ezra M.] Boston Childrens Hosp, Dept Rheumatol, 300 Longwood Ave, Boston, MA 02115 USA. RP Cohen, EM (reprint author), Boston Childrens Hosp, Div Immunol, 300 Longwood Ave, Boston, MA 02115 USA.; Cohen, EM (reprint author), Boston Childrens Hosp, Dept Rheumatol, 300 Longwood Ave, Boston, MA 02115 USA. EM ezra.cohen@childrens.harvard.edu FU NIH grant [AR064850] FX No funding was used in the production of this study. Dr. Lee's work was supported by the NIH grant AR064850. NR 38 TC 0 Z9 0 U1 2 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1546-0096 J9 PEDIATR RHEUMATOL JI Pediatr. Rheumatol. PD JAN 17 PY 2017 VL 15 AR 6 DI 10.1186/s12969-016-0133-1 PG 9 WC Pediatrics; Rheumatology SC Pediatrics; Rheumatology GA EJ1TQ UT WOS:000392993500002 PM 28095871 ER PT J AU Micali, N Martini, MG Thomas, JJ Eddy, KT Kothari, R Russell, E Bulik, CM Treasure, J AF Micali, Nadia Martini, Maria G. Thomas, Jennifer J. Eddy, Kamryn T. Kothari, Radha Russell, Ellie Bulik, Cynthia M. Treasure, Janet TI Lifetime and 12-month prevalence of eating disorders amongst women in mid-life: a population-based study of diagnoses and risk factors SO BMC MEDICINE LA English DT Article DE Eating disorders; Anorexia nervosa; Bulimia nervosa; Binge eating disorder; ALSPAC; Women; Mid-life; Prevalence; Risk factors; Childhood ID ANOREXIA-NERVOSA; INTERPERSONAL SENSITIVITY; BULIMIA-NERVOSA; COMMUNITY; CHILDREN; DESIGN; COHORT; METAANALYSIS; COMORBIDITY; MORTALITY AB Background: Eating disorders (EDs) are common amongst women; however, no research has specifically investigated the lifetime/12-month prevalence of eating disorders amongst women in mid-life (i.e., fourth and fifth decade of life) and the relevant longitudinal risk factors. We aimed to investigate the lifetime and 12-month prevalence of EDs and lifetime health service use and to identify childhood, parenting, and personality risk factors. Methods: This is a two-phase prevalence study, nested within an existing longitudinal community-based sample of women in mid-life. A total of 5658 women from the UK Avon Longitudinal Study of Parents and Children (ALSPAC; enrolled 20 years earlier) participated. ED diagnoses were obtained using validated structured interviews. Weighted analyses were carried out accounting for the two-phase methodology to obtain prevalence figures and to carry out risk factor regression analyses. Results: By mid-life, 15.3% (95% confidence intervals, 13.5-17.4%) of women had met criteria for a lifetime ED. The 12-month prevalence of EDs was 3.6%. Childhood sexual abuse was prospectively associated with all binge/purge type disorders and an external locus of control was associated with binge-eating disorder. Better maternal care was protective for bulimia nervosa. Childhood life events and interpersonal sensitivity were associated with all EDs. Conclusions: By mid-life a significant proportion of women will experience an ED, and few women accessed healthcare. Active EDs are common in mid-life, both due to new onset and chronic disorders. Increased awareness of the full spectrum of EDs in this stage of life and adequate service provision is important. This is the first study to investigate childhood and personality risk factors for full threshold and sub-threshold EDs and to identify common predictors for full and sub-threshold EDs. Further research should clarify the role of preventable risk factors on both full and sub-threshold EDs. C1 [Micali, Nadia] Icahn Sch Med Mt Sinai, Dept Psychiat, Eating & Weight Disorders Program, New York, NY 10029 USA. [Micali, Nadia] Icahn Sch Med Mt Sinai, Mindich Child Hlth & Dev Inst, New York, NY 10029 USA. [Micali, Nadia; Martini, Maria G.; Kothari, Radha] UCL, Inst Child Hlth, London, England. [Thomas, Jennifer J.; Eddy, Kamryn T.] Harvard Med Sch, Dept Psychiat, Boston, MA USA. [Thomas, Jennifer J.; Eddy, Kamryn T.] Massachusetts Gen Hosp, Eating Disorders Clin & Res Program, Boston, MA 02114 USA. [Russell, Ellie] Cardiff Univ, Dept Psychol Med, Cardiff, S Glam, Wales. [Bulik, Cynthia M.] Univ N Carolina, Dept Psychiat, Chapel Hill, NC USA. [Bulik, Cynthia M.] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Bulik, Cynthia M.] Univ N Carolina, Dept Nutr, Chapel Hill, NC USA. [Treasure, Janet] Kings Coll London, Inst Psychiat, Eating Disorders Res Unit, Psychol Med, London, England. RP Micali, N (reprint author), Icahn Sch Med Mt Sinai, Dept Psychiat, Eating & Weight Disorders Program, New York, NY 10029 USA.; Micali, N (reprint author), Icahn Sch Med Mt Sinai, Mindich Child Hlth & Dev Inst, New York, NY 10029 USA. EM n.micali@mssm.edu OI Treasure, Janet/0000-0003-0871-4596 FU Wellcome Trust [092731]; National Institute of Health Research, UK; Wellchild FX The UK Medical Research Council and the Wellcome Trust (Grant ref: 092731) and the University of Bristol provide core support for ALSPAC. This publication is the work of the authors and Nadia Micali had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analyses. This specific study was funded by the National Institute of Health Research, UK and Wellchild. Funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. NR 44 TC 1 Z9 1 U1 26 U2 26 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1741-7015 J9 BMC MED JI BMC Med. PD JAN 17 PY 2017 VL 15 AR 12 DI 10.1186/s12916-016-0766-4 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA EI4HT UT WOS:000392454500001 PM 28095833 ER PT J AU Bertrand, PB Schwammenthal, E Levine, RA Vandervoort, PM AF Bertrand, Philippe B. Schwammenthal, Ehud Levine, Robert A. Vandervoort, Pieter M. TI Exercise Dynamics in Secondary Mitral Regurgitation Pathophysiology and Therapeutic Implications SO CIRCULATION LA English DT Article DE exercise capacity; exercise physiology; exercise testing; heart failure; mitral valve regurgitation; mitral valve surgery ID CARDIAC RESYNCHRONIZATION THERAPY; VENTRICULAR SYSTOLIC DYSFUNCTION; CONGESTIVE-HEART-FAILURE; NONISCHEMIC DILATED CARDIOMYOPATHY; PAPILLARY-MUSCLE DYSSYNCHRONY; ACUTE MYOCARDIAL-INFARCTION; CORONARY-ARTERY-DISEASE; ASSOCIATION TASK-FORCE; VALVE ANNULOPLASTY; PULMONARY-HYPERTENSION AB Secondary mitral valve regurgitation (MR) remains a challenging problem in the diagnostic workup and treatment of patients with heart failure. Although secondary MR is characteristically dynamic in nature and sensitive to changes in ventricular geometry and loading, current therapy is mainly focused on resting conditions. An exercise-induced increase in secondary MR, however, is associated with impaired exercise capacity and increased mortality. In an era where a multitude of percutaneous solutions are emerging for the treatment of patients with heart failure, it becomes important to address the dynamic component of secondary MR during exercise as well. A critical reappraisal of the underlying disease mechanisms, in particular the dynamic component during exercise, is of timely importance. This review summarizes the pathophysiological mechanisms involved in the dynamic deterioration of secondary MR during exercise, its functional and prognostic impact, and the way current treatment options affect the dynamic lesion and exercise hemodynamics in general. C1 [Bertrand, Philippe B.; Vandervoort, Pieter M.] Ziekenhuis Oost Limburg, Dept Cardiol, Schiepse Bos 6, B-3600 Genk, Belgium. [Bertrand, Philippe B.; Vandervoort, Pieter M.] Hasselt Univ, Fac Med & Life Sci, Hasselt, Belgium. [Schwammenthal, Ehud] Sheba Med Ctr, Ctr Heart, Tel Hashomer, Israel. [Levine, Robert A.] Harvard Med Sch, Massachusetts Gen Hosp, Cardiac Ultrasound Lab, Boston, MA USA. RP Bertrand, PB (reprint author), Ziekenhuis Oost Limburg, Dept Cardiol, Schiepse Bos 6, B-3600 Genk, Belgium. EM philippe.bertrand@zol.be FU Research Foundation-Flanders [11N7214N]; National Institutes of Health [R01 HL109506]; Leducq Foundation [07CVD04] FX This work was funded, in part, by Research Foundation-Flanders grant 11N7214N (P.B.B.), National Institutes of Health grant R01 HL109506 (R.A.L.), and Leducq Foundation grant 07CVD04. NR 128 TC 0 Z9 0 U1 4 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD JAN 17 PY 2017 VL 135 IS 3 BP 297 EP + DI 10.1161/CIRCULATIONAHA.116.025260 PG 19 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA EI2BJ UT WOS:000392291000013 PM 28093494 ER PT J AU Guo, MH Nandakumar, SK Ulirsch, JC Zekavat, SM Buenrostro, JD Natarajan, P Salem, RM Chiarle, R Mitt, M Kals, M Parn, K Fischer, K Milani, L Magi, R Palta, P Gabriel, SB Metspalu, A Lander, ES Kathiresan, S Hirschhorn, JN Esko, T Sankaran, VG AF Guo, Michael H. Nandakumar, Satish K. Ulirsch, Jacob C. Zekavat, Seyedeh M. Buenrostro, Jason D. Natarajan, Pradeep Salem, Rany M. Chiarle, Roberto Mitt, Mario Kals, Mart Parn, Kalle Fischer, Krista Milani, Lili Magi, Reedik Palta, Priit Gabriel, Stacey B. Metspalu, Andres Lander, Eric S. Kathiresan, Sekar Hirschhorn, Joel N. Esko, Tonu Sankaran, Vijay G. TI Comprehensive population-based genome sequencing provides insight into hematopoietic regulatory mechanisms SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE genome sequencing; GWAS; basophils; hematopoiesis; CEBPA ID INFLAMMATORY-BOWEL-DISEASE; RARE-VARIANT ASSOCIATION; FETAL-HEMOGLOBIN LEVELS; COPY NUMBER VARIATIONS; BLOOD-CELL TRAITS; WIDE ASSOCIATION; MAST-CELL; GENETIC-VARIATION; C/EBP-ALPHA; PARTITIONING HERITABILITY AB Genetic variants affecting hematopoiesis can influence commonly measured blood cell traits. To identify factors that affect hematopoiesis, we performed association studies for blood cell traits in the population-based Estonian Biobank using high-coverage whole-genome sequencing (WGS) in 2,284 samples and SNP genotyping in an additional 14,904 samples. Using up to 7,134 samples with available phenotype data, our analyses identified 17 associations across 14 blood cell traits. Integration of WGS-based fine-mapping and complementary epigenomic datasets provided evidence for causal mechanisms at several loci, including at a previously undiscovered basophil count-associated locus near the master hematopoietic transcription factor CEBPA. The fine-mapped variant at this basophil count association near CEBPA overlapped an enhancer active in common myeloid progenitors and influenced its activity. In situ perturbation of this enhancer by CRISPR/Cas9 mutagenesis in hematopoietic stem and progenitor cells demonstrated that it is necessary for and specifically regulates CEBPA expression during basophil differentiation. We additionally identified basophil count-associated variation at another more pleiotropic myeloid enhancer near GATA2, highlighting regulatory mechanisms for ordered expression of master hematopoietic regulators during lineage specification. Our study illustrates how population-based genetic studies can provide key insights into poorly understood cell differentiation processes of considerable physiologic relevance. C1 [Guo, Michael H.; Nandakumar, Satish K.; Ulirsch, Jacob C.; Zekavat, Seyedeh M.; Buenrostro, Jason D.; Natarajan, Pradeep; Salem, Rany M.; Gabriel, Stacey B.; Lander, Eric S.; Kathiresan, Sekar; Hirschhorn, Joel N.; Esko, Tonu; Sankaran, Vijay G.] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. [Guo, Michael H.; Salem, Rany M.; Hirschhorn, Joel N.; Esko, Tonu] Harvard Med Sch, Boston Childrens Hosp, Div Endocrinol, Boston, MA 02115 USA. [Guo, Michael H.; Salem, Rany M.; Hirschhorn, Joel N.] Harvard Med Sch, Dept Genet, Boston, MA 02115 USA. [Guo, Michael H.; Salem, Rany M.; Hirschhorn, Joel N.; Esko, Tonu] Boston Childrens Hosp, Ctr Basic & Translat Obes Res, Boston, MA 02115 USA. [Nandakumar, Satish K.; Ulirsch, Jacob C.; Sankaran, Vijay G.] Harvard Med Sch, Boston Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USA. [Nandakumar, Satish K.; Ulirsch, Jacob C.; Sankaran, Vijay G.] Harvard Med Sch, Dept Pediat Oncol, Dana Farber Canc Inst, Boston, MA 02115 USA. [Zekavat, Seyedeh M.; Natarajan, Pradeep; Kathiresan, Sekar] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02214 USA. [Zekavat, Seyedeh M.; Natarajan, Pradeep; Kathiresan, Sekar] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02214 USA. [Zekavat, Seyedeh M.; Natarajan, Pradeep; Kathiresan, Sekar] Massachusetts Gen Hosp, Dept Med, Div Cardiol, Boston, MA 02214 USA. [Chiarle, Roberto] Childrens Hosp, Dept Pathol, Boston, MA 02115 USA. [Chiarle, Roberto] Harvard Med Sch, Boston, MA 02115 USA. [Chiarle, Roberto] Univ Torino, Dept Mol Biotechnol & Hlth Sci, I-10126 Turin, Italy. [Mitt, Mario; Kals, Mart; Parn, Kalle; Fischer, Krista; Milani, Lili; Magi, Reedik; Palta, Priit; Metspalu, Andres; Esko, Tonu] Univ Tartu, Estonian Genome Ctr, EE-51010 Tartu, Estonia. [Palta, Priit] Univ Helsinki, Inst Mol Med Finland, FI-00014 Helsinki, Finland. [Lander, Eric S.] MIT, Dept Biol, Cambridge, MA 02139 USA. [Lander, Eric S.] Harvard Med Sch, Dept Syst Biol, Boston, MA 02115 USA. RP Lander, ES; Esko, T; Sankaran, VG (reprint author), Broad Inst MIT & Harvard, Cambridge, MA 02142 USA.; Esko, T (reprint author), Harvard Med Sch, Boston Childrens Hosp, Div Endocrinol, Boston, MA 02115 USA.; Esko, T (reprint author), Boston Childrens Hosp, Ctr Basic & Translat Obes Res, Boston, MA 02115 USA.; Sankaran, VG (reprint author), Harvard Med Sch, Boston Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USA.; Sankaran, VG (reprint author), Harvard Med Sch, Dept Pediat Oncol, Dana Farber Canc Inst, Boston, MA 02115 USA.; Esko, T (reprint author), Univ Tartu, Estonian Genome Ctr, EE-51010 Tartu, Estonia.; Lander, ES (reprint author), MIT, Dept Biol, Cambridge, MA 02139 USA.; Lander, ES (reprint author), Harvard Med Sch, Dept Syst Biol, Boston, MA 02115 USA. EM lander@broadinstitute.org; tesko@broadinstitute.org; sankaran@broadinstitute.org OI Palta, Priit/0000-0001-9320-7008 FU National Institutes of Health [R01 DK103794, R33 HL120791, R01 DK075787]; Nordic Information for Action eScience Center by NordForsk [62721]; Estonian Research Council (PerMed I) [IUT20-60]; European Union [692145, 676550, 654248]; European Union through the European Regional Development Fund (GENTRANSMED) FX We thank members of the V.G.S. and J.N.H. Laboratories, as well as the Estonian Genome Center, and numerous colleagues for valuable comments and discussions. This work was supported by National Institutes of Health Grants R01 DK103794, R33 HL120791 (to V.G.S.), and R01 DK075787 (to J.N.H.). P.P. was funded by the Nordic Information for Action eScience Center by NordForsk (Project 62721). The Estonian Genome Center was supported by the Estonian Research Council (PerMed I; IUT20-60); European Union H2020 Grants 692145, 676550, and 654248; and the European Union through the European Regional Development Fund (GENTRANSMED). NR 105 TC 0 Z9 0 U1 3 U2 3 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JAN 17 PY 2017 VL 114 IS 3 BP E327 EP E336 DI 10.1073/pnas.1619052114 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EH9MQ UT WOS:000392095800009 PM 28031487 ER PT J AU Elnahal, SM Clancy, CM Shulkin, DJ AF Elnahal, Shereef M. Clancy, Carolyn M. Shulkin, David J. TI A Framework for Disseminating Clinical Best Practices in the VA Health System SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material ID CARE-SYSTEM C1 [Elnahal, Shereef M.; Clancy, Carolyn M.; Shulkin, David J.] US Dept Vet Affairs, 810 Vermont Ave NW, Washington, DC 20420 USA. RP Clancy, CM (reprint author), US Dept Vet Affairs, 810 Vermont Ave NW, Washington, DC 20420 USA. EM carolyn.clancy@va.gov NR 8 TC 0 Z9 0 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JAN 17 PY 2017 VL 317 IS 3 BP 255 EP 256 DI 10.1001/jama.2016.18764 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA EH9KC UT WOS:000392089200007 PM 28114562 ER PT J AU Mattison, JA Colman, RJ Beasley, TM Allison, DB Kemnitz, JW Roth, GS Ingram, DK Weindruch, R de Cabo, R Anderson, RM AF Mattison, Julie A. Colman, Ricki J. Beasley, T. Mark Allison, David B. Kemnitz, Joseph W. Roth, George S. Ingram, Donald K. Weindruch, Richard de Cabo, Rafael Anderson, Rozalyn M. TI Caloric restriction improves health and survival of rhesus monkeys SO NATURE COMMUNICATIONS LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; MACAQUES MACACA-MULATTA; DIETARY RESTRICTION; NONHUMAN-PRIMATES; ENERGY-EXPENDITURE; DIABETES-MELLITUS; BODY-COMPOSITION; LIFE-SPAN; AGE; DISEASE AB Caloric restriction (CR) without malnutrition extends lifespan and delays the onset of age-related disorders in most species but its impact in nonhuman primates has been controversial. In the late 1980s two parallel studies were initiated to determine the effect of CR in rhesus monkeys. The University of Wisconsin study reported a significant positive impact of CR on survival, but the National Institute on Aging study detected no significant survival effect. Here we present a direct comparison of longitudinal data from both studies including survival, bodyweight, food intake, fasting glucose levels and age-related morbidity. We describe differences in study design that could contribute to differences in outcomes, and we report species specificity in the impact of CR in terms of optimal onset and diet. Taken together these data confirm that health benefits of CR are conserved in monkeys and suggest that CR mechanisms are likely translatable to human health. C1 [Mattison, Julie A.; de Cabo, Rafael] NIA, Translat Gerontol Branch, Baltimore, MD 21224 USA. [Colman, Ricki J.; Kemnitz, Joseph W.] Univ Wisconsin, Wisconsin Natl Primate Res Ctr, Madison, WI 53715 USA. [Beasley, T. Mark; Allison, David B.] Univ Alabama Birmingham, Dept Biostat, Birmingham, AL 35294 USA. [Beasley, T. Mark] Birmingham Atlanta Vet Adm Hosp, Geriatr Res Educ & Clin Ctr, Birmingham, AL 35233 USA. [Kemnitz, Joseph W.] Univ Wisconsin, Dept Cell & Regenerat Biol, Madison, WI 53792 USA. [Roth, George S.] GeroScience, Pylesville, MD 21323 USA. [Ingram, Donald K.] Pennington Biomed Res Ctr, Baton Rouge, LA 70808 USA. [Weindruch, Richard; Anderson, Rozalyn M.] Univ Wisconsin, Dept Med, Madison, WI 53792 USA. [Weindruch, Richard; Anderson, Rozalyn M.] William S Middleton Mem Vet Adm Med Ctr, Geriatr Res Educ & Clin Ctr, Madison, WI 53705 USA. RP de Cabo, R (reprint author), NIA, Translat Gerontol Branch, Baltimore, MD 21224 USA.; Anderson, RM (reprint author), Univ Wisconsin, Dept Med, Madison, WI 53792 USA.; Anderson, RM (reprint author), William S Middleton Mem Vet Adm Med Ctr, Geriatr Res Educ & Clin Ctr, Madison, WI 53705 USA. EM decabora@grc.nia.nih.gov; rmanderson5@wisc.edu FU NIH [P01AG011915, R01AG040178, R01AG037000]; Department of Medicine, School of Medicine and Public Health UW Madison; NCRR/ORIP grants [P51RR000167/P51OD011106]; NIA [HHSN-263-2013-00026C]; Intramural Research Program of the NIH, National Institute on Aging FX Thanks to animal care and research staff at both facilities including Scott Baum, Julie Adriansjach, Saverio Capuano, Casey Fitz, Heather Simmons at UW, and Rick Herbert, Edward Tilmont, Kelli Vaughan, Mark Szarowicz, Amanda Evans, Danielle Sedlak, Mark Bryant and Matt Starost at NIA for their tireless efforts and stalwart commitment over the years. Funding for the UW study was provided by NIH grants P01AG011915, R01AG040178, R01AG037000, and the Department of Medicine, School of Medicine and Public Health UW Madison. This publication was made possible in part by NCRR/ORIP grants P51RR000167/P51OD011106 to the Wisconsin National Primate Research Center, University of Wisconsin-Madison and the use of resources and facilities at the William S. Middleton Memorial Veterans Hospital, Madison, WI. The internet Primate Aging Database is funded by contract HHSN-263-2013-00026C from the NIA. The NIA study was supported in part by the Intramural Research Program of the NIH, National Institute on Aging. NR 54 TC 1 Z9 1 U1 6 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD JAN 17 PY 2017 VL 8 AR 14063 DI 10.1038/ncomms14063 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EH7GE UT WOS:000391940100001 PM 28094793 ER PT J AU Farris, GR Steinhilber, S AF Farris, Gary Ross Steinhilber, Starr TI An older patient with diabetes and severe foot pain SO CANADIAN MEDICAL ASSOCIATION JOURNAL LA English DT Editorial Material ID DUAL-ENERGY CT; MANAGEMENT; GOUT; HYPERURICEMIA; DIAGNOSIS C1 [Farris, Gary Ross; Steinhilber, Starr] UAB Tinsley Harrison Internal Med Residency Progr, Birmingham, AL 35294 USA. [Steinhilber, Starr] Birmingham Vet Affairs Med Ctr, Birmingham, AL USA. RP Farris, GR (reprint author), UAB Tinsley Harrison Internal Med Residency Progr, Birmingham, AL 35294 USA. EM grfarris1@uabmc.edu NR 10 TC 0 Z9 0 U1 0 U2 0 PU CMA-CANADIAN MEDICAL ASSOC PI OTTAWA PA 1867 ALTA VISTA DR, OTTAWA, ONTARIO K1G 5W8, CANADA SN 0820-3946 EI 1488-2329 J9 CAN MED ASSOC J JI Can. Med. Assoc. J. PD JAN 16 PY 2017 VL 189 IS 2 BP E73 EP E75 DI 10.1503/cmaj.160366 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA EK2UQ UT WOS:000393782600006 ER PT J AU Keliher, EJ Ye, YX Wojtkiewicz, GR Aguirre, AD Tricot, B Senders, ML Groenen, H Fay, F Perez-Medina, C Calcagno, C Carlucci, G Reiner, T Sun, Y Courties, G Iwamoto, Y Kim, HY Wang, CH Chen, JW Swirski, FK Wey, HY Hooker, J Fayad, ZA Mulder, WJM Weissleder, R Nahrendorf, M AF Keliher, Edmund J. Ye, Yu-Xiang Wojtkiewicz, Gregory R. Aguirre, Aaron D. Tricot, Benoit Senders, Max L. Groenen, Hannah Fay, Francois Perez-Medina, Carlos Calcagno, Claudia Carlucci, Giuseppe Reiner, Thomas Sun, Yuan Courties, Gabriel Iwamoto, Yoshiko Kim, Hye-Yeong Wang, Cuihua Chen, John W. Swirski, Filip K. Wey, Hsiao-Ying Hooker, Jacob Fayad, Zahi A. Mulder, Willem J. M. Weissleder, Ralph Nahrendorf, Matthias TI Polyglucose nanoparticles with renal elimination and macrophage avidity facilitate PET imaging in ischaemic heart disease SO NATURE COMMUNICATIONS LA English DT Article ID POSITRON-EMISSION-TOMOGRAPHY; MYOCARDIAL-INFARCTION; ATHEROSCLEROTIC PLAQUES; FDG UPTAKE; INFLAMMATION; BIOMARKER; PET/MRI AB Tissue macrophage numbers vary during health versus disease. Abundant inflammatory macrophages destruct tissues, leading to atherosclerosis, myocardial infarction and heart failure. Emerging therapeutic options create interest in monitoring macrophages in patients. Here we describe positron emission tomography (PET) imaging with F-18-Macroflor, a modified polyglucose nanoparticle with high avidity for macrophages. Due to its small size, Macroflor is excreted renally, a prerequisite for imaging with the isotope flourine-18. The particle's short blood half-life, measured in three species, including a primate, enables macrophage imaging in inflamed cardiovascular tissues. Macroflor enriches in cardiac and plaque macrophages, thereby increasing PET signal in murine infarcts and both mouse and rabbit atherosclerotic plaques. In PET/magnetic resonance imaging (MRI) experiments, Macroflor PET imaging detects changes in macrophage population size while molecular MRI reports on increasing or resolving inflammation. These data suggest that Macroflor PET/MRI could be a clinical tool to non-invasively monitor macrophage biology. C1 [Keliher, Edmund J.; Ye, Yu-Xiang; Wojtkiewicz, Gregory R.; Aguirre, Aaron D.; Tricot, Benoit; Sun, Yuan; Courties, Gabriel; Iwamoto, Yoshiko; Kim, Hye-Yeong; Wang, Cuihua; Chen, John W.; Swirski, Filip K.; Weissleder, Ralph; Nahrendorf, Matthias] Massachusetts Gen Hosp, Ctr Syst Biol, Simches Res Bldg,185 Cambridge St, Boston, MA 02114 USA. [Keliher, Edmund J.; Ye, Yu-Xiang; Wojtkiewicz, Gregory R.; Aguirre, Aaron D.; Tricot, Benoit; Sun, Yuan; Courties, Gabriel; Iwamoto, Yoshiko; Kim, Hye-Yeong; Wang, Cuihua; Chen, John W.; Swirski, Filip K.; Weissleder, Ralph; Nahrendorf, Matthias] Massachusetts Gen Hosp, Dept Imaging, Simches Res Bldg,185 Cambridge St, Boston, MA 02114 USA. [Keliher, Edmund J.; Ye, Yu-Xiang; Wojtkiewicz, Gregory R.; Aguirre, Aaron D.; Tricot, Benoit; Sun, Yuan; Courties, Gabriel; Iwamoto, Yoshiko; Kim, Hye-Yeong; Wang, Cuihua; Chen, John W.; Swirski, Filip K.; Weissleder, Ralph; Nahrendorf, Matthias] Harvard Med Sch, Simches Res Bldg,185 Cambridge St, Boston, MA 02114 USA. [Senders, Max L.; Groenen, Hannah; Fay, Francois; Perez-Medina, Carlos; Calcagno, Claudia; Fayad, Zahi A.; Mulder, Willem J. M.] Icahn Sch Med Mt Sinai, Translat & Mol Imaging Inst, One Gustave L Levy Pl, New York, NY 10029 USA. [Senders, Max L.; Groenen, Hannah; Fay, Francois; Perez-Medina, Carlos; Calcagno, Claudia; Fayad, Zahi A.; Mulder, Willem J. M.] Icahn Sch Med Mt Sinai, Dept Radiol, One Gustave L Levy Pl, New York, NY 10029 USA. [Mulder, Willem J. M.] Acad Med Ctr, Subdiv Expt Vasc Biol, Dept Med Biochem, Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands. [Reiner, Thomas] Mem Sloan Kettering Canc Ctr, Dept Radiol, 1275 York Ave, New York, NY 10065 USA. [Reiner, Thomas] Weill Cornell Med Coll, Dept Radiol, New York, NY 10065 USA. [Wey, Hsiao-Ying; Hooker, Jacob] Harvard Med Sch, Dept Imaging, Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, 149 Thirteenth St, Charlestown, MA 02129 USA. [Weissleder, Ralph] Harvard Med Sch, Dept Syst Biol, 200 Longwood Ave,Alpert 536, Boston, MA 02115 USA. [Nahrendorf, Matthias] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Simches Res Bldg,185 Cambridge St, Boston, MA 02114 USA. RP Weissleder, R; Nahrendorf, M (reprint author), Massachusetts Gen Hosp, Ctr Syst Biol, Simches Res Bldg,185 Cambridge St, Boston, MA 02114 USA.; Weissleder, R; Nahrendorf, M (reprint author), Massachusetts Gen Hosp, Dept Imaging, Simches Res Bldg,185 Cambridge St, Boston, MA 02114 USA.; Weissleder, R; Nahrendorf, M (reprint author), Harvard Med Sch, Simches Res Bldg,185 Cambridge St, Boston, MA 02114 USA.; Weissleder, R (reprint author), Harvard Med Sch, Dept Syst Biol, 200 Longwood Ave,Alpert 536, Boston, MA 02115 USA.; Nahrendorf, M (reprint author), Massachusetts Gen Hosp, Cardiovasc Res Ctr, Simches Res Bldg,185 Cambridge St, Boston, MA 02114 USA. EM rweissleder@mgh.harvard.edu; mnahrendorf@mgh.harvard.edu FU National Institute of Health [HL096576, HL118440, HL114477, HL117829, HL122208, HL125703, EB009638, K25 EB016673]; Deutsche Herzstiftung [S/05/12]; American Heart Association [14FTF20380185]; NWO [Vidi 91713324]; MGH Research Scholar Award; Radiochemistry and Molecular Imaging Probes Core at Memorial Sloan Kettering Cancer Center [P30 CA008748] FX This work was funded by grants from the National Institute of Health HL096576, HL118440, HL114477, HL117829, HL122208, HL125703, EB009638, K25 EB016673, Deutsche Herzstiftung (S/05/12), American Heart Association (14FTF20380185), NWO Vidi 91713324 and the MGH Research Scholar Award. We thank the Radiochemistry and Molecular Imaging Probes Core at Memorial Sloan Kettering Cancer Center for support (P30 CA008748). NR 30 TC 0 Z9 0 U1 13 U2 13 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD JAN 16 PY 2017 VL 8 AR 14064 DI 10.1038/ncomms14064 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EH9LY UT WOS:000392094000001 PM 28091604 ER PT J AU Nowyhed, HN Chandra, S Kiosses, W Marcovecchio, P Andary, F Zhao, M Fitzgerald, ML Kronenberg, M Hedrick, CC AF Nowyhed, Heba N. Chandra, Shilpi Kiosses, William Marcovecchio, Paola Andary, Farah Zhao, Meng Fitzgerald, Michael L. Kronenberg, Mitchell Hedrick, Catherine C. TI ATP Binding Cassette Transporter ABCA7 Regulates NKT Cell Development and Function by Controlling CD1d Expression and Lipid Raft Content SO SCIENTIFIC REPORTS LA English DT Article ID KILLER T-CELLS; ANTIGEN-PRESENTING CELLS; CHOLESTEROL EFFLUX; ALPHA-GALACTOSYLCERAMIDE; HEMATOPOIETIC STEM; DENDRITIC CELLS; MURINE CD1D; INKT CELLS; DISEASE; MICE AB ABCA7 is an ABC transporter expressed on the plasma membrane, and actively exports phospholipid complexes from the cytoplasmic to the exocytoplasmic leaflet of membranes. Invariant NKT (iNKT) cells are a subpopulation of T lymphocytes that recognize glycolipid antigens in the context of CD1dmediated antigen presentation. In this study, we demonstrate that ABCA7 regulates the development of NKT cells in a cell-extrinsic manner. We found that in Abca7-/-mice there is reduced expression of CD1d accompanied by an alteration in lipid raft content on the plasma membrane of thymocytes and antigen presenting cells. Together, these alterations caused by absence of ABCA7 negatively affect NKT cell development and function. C1 [Nowyhed, Heba N.; Chandra, Shilpi; Kiosses, William; Marcovecchio, Paola; Andary, Farah; Zhao, Meng; Kronenberg, Mitchell; Hedrick, Catherine C.] La Jolla Inst Allergy & Immunol, La Jolla, CA 92037 USA. [Fitzgerald, Michael L.] Harvard Med Sch, Massachusetts Gen Hosp, Lipid Metab Unit, Boston, MA USA. [Fitzgerald, Michael L.] Harvard Med Sch, Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Boston, MA USA. RP Hedrick, CC (reprint author), La Jolla Inst Allergy & Immunol, La Jolla, CA 92037 USA. EM Hedrick@lji.org FU NIH [R01 HL118765, R01 HL097368, R01 HL112276, P01 HL055798, F31 HL132538, F32 HL117533] FX We would like to thank Deborah Yoakum for assistance with mouse colonies and the LJI flow cytometry core for technical assistance. This work was supported by funding from NIH R01 HL118765, NIH R01 HL097368, NIH R01 HL112276, and NIH P01 HL055798 (all to C.C.H.), NIH F31 HL132538 (to P.M.), and NIH F32 HL117533 (to H.N.N.). NR 60 TC 0 Z9 0 U1 5 U2 5 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 JAN 16 PY 2017 VL 7 DI 10.1038/srep40273 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EH9NN UT WOS:000392098100001 PM 28091533 ER PT J AU Ahern, TP Hertz, DL Damkier, P Ejlertsen, B Hamilton-Dutoit, SJ Rae, JM Regan, MM Thompson, AM Lash, TL Cronin-Fenton, DP AF Ahern, Thomas P. Hertz, Daniel L. Damkier, Per Ejlertsen, Bent Hamilton-Dutoit, Stephen J. Rae, James M. Regan, Meredith M. Thompson, Alastair M. Lash, Timothy L. Cronin-Fenton, Deirdre P. TI Cytochrome P-450 2D6 (CYP2D6) Genotype and Breast Cancer Recurrence in Tamoxifen-Treated Patients: Evaluating the Importance of Loss of Heterozygosity SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Review DE breast neoplasms; cytochrome P-450 2D6; tamoxifen ID ADJUVANT ENDOCRINE THERAPY; GROUP 1-98 TRIAL; INTERNATIONAL EXPERT CONSENSUS; PATIENTS RECEIVING TAMOXIFEN; POSTMENOPAUSAL WOMEN; GENETIC POLYMORPHISMS; ESTROGEN-RECEPTOR; CLINICAL-PRACTICE; RE CYP2D6; UGT2B7 GENOTYPE AB Tamoxifen therapy for estrogen receptor-positive breast cancer reduces the risk of recurrence by approximately one-half. Cytochrome P-450 2D6, encoded by the polymorphic cytochrome P-450 2D6 gene (CYP2D6), oxidizes tamoxifen to its most active metabolites. Steady-state concentrations of endoxifen (4-hydroxy-Ndesmethyltamoxifen), the most potent antiestrogenic metabolite, are reduced in women whose CYP2D6 genotypes confer poor enzyme function. Thirty-one studies of the association of CYP2D6 genotype with breast cancer survival have yielded heterogeneous results. Some influential studies genotyped DNA from tumorinfiltrated tissues, and their results may have been susceptible to germline genotype misclassification from loss of heterozygosity at the CYP2D6 locus. We systematically reviewed 6 studies of concordance between genotypes obtained from paired nonneoplastic and breast tumor-infiltrated tissues, all of which showed excellent CYP2D6 genotype agreement. We applied these concordance data to a quantitative bias analysis of the subset of the 31 studies that were based on genotypes from tumor-infiltrated tissue to examine whether genotyping errors substantially biased estimates of association. The bias analysis showed negligible bias by discordant genotypes. Summary estimates of association, with or without bias adjustment, indicated no clinically important association between CYP2D6 genotype and breast cancer survival in tamoxifen-treated women. C1 [Ahern, Thomas P.] Univ Vermont, Robert Larner MD Coll Med, Dept Surg, 89 Beaumont Ave,Given D317A, Burlington, VT 05405 USA. [Ahern, Thomas P.] Univ Vermont, Robert Larner MD Coll Med, Dept Biochem, 89 Beaumont Ave,Given D317A, Burlington, VT 05405 USA. [Hertz, Daniel L.] Univ Michigan, Coll Pharm, Dept Clin Pharm, 428 Church St, Ann Arbor, MI 48109 USA. [Damkier, Per] Odense Univ Hosp, Dept Clin Chem & Pharmacol, Odense, Denmark. [Ejlertsen, Bent] Copenhagen Univ Hosp, Rigshosp, Danish Breast Canc Cooperat Grp Secretariat, Copenhagen, Denmark. [Hamilton-Dutoit, Stephen J.] Aarhus Univ Hosp, Inst Pathol, Aarhus, Denmark. [Rae, James M.] Univ Michigan, Med Ctr, Dept Internal Med, Ann Arbor, MI 48109 USA. [Regan, Meredith M.] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Regan, Meredith M.] Harvard Med Sch, Boston, MA USA. [Thompson, Alastair M.] Univ Texas MD Anderson Canc Ctr, Dept Breast Surg Oncol, Houston, TX 77030 USA. [Lash, Timothy L.] Emory Univ, Rollins Sch Publ Hlth, Dept Epidemiol, Atlanta, GA 30322 USA. [Cronin-Fenton, Deirdre P.] Aarhus Univ, Dept Clin Epidemiol, Aarhus, Denmark. RP Ahern, TP (reprint author), Univ Vermont, Robert Larner MD Coll Med, Dept Surg, 89 Beaumont Ave,Given D317A, Burlington, VT 05405 USA.; Ahern, TP (reprint author), Univ Vermont, Robert Larner MD Coll Med, Dept Biochem, 89 Beaumont Ave,Given D317A, Burlington, VT 05405 USA. EM Thomas.Ahern@med.uvm.edu FU National Institutes of Health [R01 CA118708, R01 CA166825, R01GM099143]; Danish Cancer Society [DP06117]; Lundbeck Foundation [R167-2013-15861]; Susan G. Komen for the Cure [CCR13264024, KG080081]; Breast Cancer Research Foundation [N003173]; Breast Cancer Campaign; Tayside Tissue Bank; Mary Kay Foundation [003-14] FX This work was supported by the National Institutes of Health (grants R01 CA118708 and R01 CA166825 to T.L.L. and grant R01GM099143 to J.M.R.); the Danish Cancer Society (grant DP06117 to S.H.D.); the Lundbeck Foundation (grant R167-2013-15861 to D.C.F.); Susan G. Komen for the Cure (grant CCR13264024 to T.P.A. and grant KG080081 to M.M.R.); the Breast Cancer Research Foundation (grant N003173 to J.M.R.); the Breast Cancer Campaign (A.M.T.); the Tayside Tissue Bank (A.M.T.); and the Mary Kay Foundation (grant 003-14 to T.P.A.). NR 90 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 EI 1476-6256 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JAN 15 PY 2017 VL 185 IS 2 BP 75 EP 85 DI 10.1093/aje/kww178 PG 11 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA EP2WM UT WOS:000397244300001 PM 27988492 ER PT J AU Zheng, J Erzurumluoglu, AM Elsworth, BL Kemp, JP Howe, L Haycock, PC Hemani, G Tansey, K Laurin, C St Pourcain, B Warrington, NM Finucane, HK Price, AL Bulik-Sullivan, BK Anttila, V Paternoster, L Gaunt, TR Evans, DM Neale, BM AF Zheng, Jie Erzurumluoglu, A. Mesut Elsworth, Benjamin L. Kemp, John P. Howe, Laurence Haycock, Philip C. Hemani, Gibran Tansey, Katherine Laurin, Charles St Pourcain, Beate Warrington, Nicole M. Finucane, Hilary K. Price, Alkes L. Bulik-Sullivan, Brendan K. Anttila, Verneri Paternoster, Lavinia Gaunt, Tom R. Evans, David M. Neale, Benjamin M. CA Early Genetics Lifecourse TI LD Hub: a centralized database and web interface to perform LD score regression that maximizes the potential of summary level GWAS data for SNP heritability and genetic correlation analysis SO BIOINFORMATICS LA English DT Article ID GENOME-WIDE ASSOCIATION; BODY-MASS INDEX; PARTITIONING HERITABILITY; SUSCEPTIBILITY LOCI; PROVIDES INSIGHTS; COMMON VARIANTS; IDENTIFIES 11; METAANALYSIS; RISK; DISEASES AB Motivation: LD score regression is a reliable and efficient method of using genome-wide association study (GWAS) summary-level results data to estimate the SNP heritability of complex traits and diseases, partition this heritability into functional categories, and estimate the genetic correlation between different phenotypes. Because the method relies on summary level results data, LD score regression is computationally tractable even for very large sample sizes. However, publicly available GWAS summary-level data are typically stored in different databases and have different formats, making it difficult to apply LD score regression to estimate genetic correlations across many different traits simultaneously. Results: In this manuscript, we describe LD Hub -a centralized database of summary-level GWAS results for 173 diseases/traits from different publicly available resources/consortia and a web interface that automates the LD score regression analysis pipeline. To demonstrate functionality and validate our software, we replicated previously reported LD score regression analyses of 49 traits/diseases using LD Hub; and estimated SNP heritability and the genetic correlation across the different phenotypes. We also present new results obtained by uploading a recent atopic dermatitis GWAS meta-analysis to examine the genetic correlation between the condition and other potentially related traits. In response to the growing availability of publicly accessible GWAS summary-level results data, our database and the accompanying web interface will ensure maximal uptake of the LD score regression methodology, provide a useful database for the public dissemination of GWAS results, and provide a method for easily screening hundreds of traits for overlapping genetic aetiologies. C1 [Zheng, Jie; Elsworth, Benjamin L.; Howe, Laurence; Haycock, Philip C.; Hemani, Gibran; Tansey, Katherine; Laurin, Charles; St Pourcain, Beate; Paternoster, Lavinia; Gaunt, Tom R.; Evans, David M.] Univ Bristol, MRC, Integrat Epidemiol Unit, Oakfield House, Bristol, Avon, England. [Erzurumluoglu, A. Mesut] Univ Leicester, Dept Hlth Sci, Genet Epidemiol Grp, Leicester, Leics, England. [Kemp, John P.; Warrington, Nicole M.; Evans, David M.] Univ Queensland, Translat Res Inst, Diamantina Inst, Brisbane, Qld, Australia. [Finucane, Hilary K.; Price, Alkes L.] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Price, Alkes L.; Bulik-Sullivan, Brendan K.; Anttila, Verneri; Neale, Benjamin M.] Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA USA. [Bulik-Sullivan, Brendan K.; Neale, Benjamin M.] Massachusetts Gen Hosp, Dept Med, Analyt & Translat Genet Unit, Boston, MA 02114 USA. [Bulik-Sullivan, Brendan K.; Neale, Benjamin M.] Harvard Med Sch, Boston, MA USA. RP Zheng, J (reprint author), Univ Bristol, MRC, Integrat Epidemiol Unit, Oakfield House, Bristol, Avon, England. EM jie.zheng@bristol.ac.uk OI Erzurumluoglu, A. Mesut/0000-0003-1322-8138 FU Medical Research Council [MC_UU_12013/4, MC_UU_12013/8]; Australian Research Council Future Fellowship [FT130101709]; Cancer Research UK programme [C18281/A19169]; Cancer Research UK Population Research Fellow [C52724/A20138]; [1R01MH101244-02]; [1R01MH107649-01] FX This work was supported by the Medical Research Council (MC_UU_12013/4 and MC_UU_12013/8). This work was also supported by the following grants: 1R01MH101244-02 (Statistical methods for studies of rare variants) and 1R01MH107649-01 (Methods for linking GWAS peaks to function in psychiatric disease) D.M.E. is supported by an Australian Research Council Future Fellowship (FT130101709). This work was in part supported by Cancer Research UK programme grant number C18281/A19169 (the Integrative Cancer Epidemiology Programme). P.H. is a Cancer Research UK Population Research Fellow (grant number C52724/A20138). NR 61 TC 2 Z9 2 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 EI 1460-2059 J9 BIOINFORMATICS JI Bioinformatics PD JAN 15 PY 2017 VL 33 IS 2 BP 272 EP 279 DI 10.1093/bioinformatics/btw613 PG 8 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Computer Science, Interdisciplinary Applications; Mathematical & Computational Biology; Statistics & Probability SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Computer Science; Mathematical & Computational Biology; Mathematics GA EP0RA UT WOS:000397093200017 PM 27663502 ER PT J AU Silterra, J Gillette, MA Lanaspa, M Pelle, KG Valim, C Ahmad, R Acacio, S Almendinger, KD Tan, Y Madrid, L Alonso, PL Carr, SA Wiegand, RC Bassat, Q Mesirov, JP Milner, DA Wirth, DF AF Silterra, Jacob Gillette, Michael A. Lanaspa, Miguel Pelle, Karell G. Valim, Clarissa Ahmad, Rushdy Acacio, Sozinho Almendinger, Katherine D. Tan, Yan Madrid, Lola Alonso, Pedro L. Carr, Steven A. Wiegand, Roger C. Bassat, Quique Mesirov, Jill P. Milner, Danny A., Jr. Wirth, Dyann F. TI Transcriptional Categorization of the Etiology of Pneumonia Syndrome in Pediatric Patients in Malaria-Endemic Areas SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE RNA-Seq; gene expression; biomarkers; machine learning; Pneumonia ID BACTEREMIC PNEUMOCOCCAL PNEUMONIA; STAPHYLOCOCCUS-AUREUS; MYOSIN-X; CHILDREN; DIAGNOSIS; INFECTION; DISEASE; BLOOD; MANAGEMENT; GENOME AB Background. Pediatric acute respiratory distress in tropical settings is very common. Bacterial pneumonia is a major contributor to morbidity and mortality rates and requires adequate diagnosis for correct treatment. A rapid test that could identify bacterial (vs other) infections would have great clinical utility. Methods and Results. We performed RNA sequencing (RNA-seq) and analyzed the transcriptomes of 68 pediatric patients with well-characterized clinical phenotype to identify transcriptional features associated with each disease class. We refined the features to predictive models (support vector machine, elastic net) and validated those models in an independent test set of 37 patients (80%-85% accuracy). Conclusions. We have identified sets of genes that are differentially expressed in pediatric patients with pneumonia syndrome attributable to different infections and requiring different therapeutic interventions. Findings of this study demonstrate that human transcription signatures in infected patients recapitulate the underlying biology and provide models for predicting a bacterial diagnosis to inform treatment. C1 [Silterra, Jacob; Gillette, Michael A.; Pelle, Karell G.; Valim, Clarissa; Ahmad, Rushdy; Almendinger, Katherine D.; Tan, Yan; Carr, Steven A.; Wiegand, Roger C.; Mesirov, Jill P.; Milner, Danny A., Jr.; Wirth, Dyann F.] Broad Inst & MIT Harvard, Cambridge, MA USA. [Gillette, Michael A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Gillette, Michael A.; Milner, Danny A., Jr.] Harvard Med Sch, Boston, MA USA. [Pelle, Karell G.; Valim, Clarissa; Milner, Danny A., Jr.; Wirth, Dyann F.] Harvard TH Chan Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA USA. [Tan, Yan] Boston Univ, Bioinformat Program, Boston, MA 02215 USA. [Milner, Danny A., Jr.] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. [Mesirov, Jill P.] Univ Calif San Diego, Dept Med, San Diego, CA 92103 USA. [Lanaspa, Miguel; Madrid, Lola; Alonso, Pedro L.; Bassat, Quique] Univ Barcelona, Hosp Clin, Barcelona Ctr Int Hlth Res, Barcelona Inst Global Hlth, Barcelona, Spain. [Bassat, Quique] Inst Catalana Recerca & Estudis Avancats, Passeig Lluis Co 23, Barcelona 08010, Spain. [Lanaspa, Miguel; Acacio, Sozinho; Madrid, Lola; Alonso, Pedro L.; Bassat, Quique] Ctr Invest Saude Manhica, Maputo, Mozambique. [Acacio, Sozinho] Minist Hlth, Natl Inst Hlth, Maputo, Mozambique. RP Milner, DA (reprint author), Amer Soc Clin Pathologists, Ctr Global Hlth, 33 W Monroe St,Suite 1600, Chicago, IL 60603 USA. EM dan.milner@ascp.org FU Bill & Melinda Gates Foundation [OPP50092]; program Miguel Servet del Instituto de Salud Carlos III (ISCIII) (Plan Nacional de I+D+I) [CP11/00269]; program Rio Hortega of the ISCIII [CM13/00260] FX This work is supported by the Bill & Melinda Gates Foundation (grant OPP50092). Q. B. has a fellowship from the program Miguel Servet del Instituto de Salud Carlos III (ISCIII) (Plan Nacional de I+D+I 2008-2011; grant CP11/00269). L. M. has a fellowship from the program Rio Hortega of the ISCIII (CM13/00260). NR 41 TC 0 Z9 0 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 JAN 15 PY 2017 VL 215 IS 2 BP 312 EP 320 DI 10.1093/infdis/jiw531 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA EP2HN UT WOS:000397204100019 PM 27837008 ER PT J AU Dillon, ST Vasunilashorn, SM Ngo, L Otu, HH Inouye, SK Jones, RN Alsop, DC Kuchel, GA Metzger, ED Arnold, SE Marcantonio, ER Libermann, TA AF Dillon, Simon T. Vasunilashorn, Sarinnapha M. Ngo, Long Otu, Hasan H. Inouye, Sharon K. Jones, Richard N. Alsop, David C. Kuchel, George A. Metzger, Eran D. Arnold, Steven E. Marcantonio, Edward R. Libermann, Towia A. TI Higher C-Reactive Protein Levels Predict Postoperative Delirium in Older Patients Undergoing Major Elective Surgery: A Longitudinal Nested Case-Control Study SO BIOLOGICAL PSYCHIATRY LA English DT Article DE Case-control study; C-reactive protein; Delirium; Inflammation; Postoperative; Proteomics ID ELDERLY-PATIENTS; INFLAMMATORY MARKERS; RISK; ASSOCIATION AB BACKGROUND: Delirium is a common, morbid, and costly postoperative complication. We aimed to identify blood-based postoperative delirium markers in a nested case-control study of older surgical patients using a proteomics approach followed by enzyme-linked immunosorbent assay (ELISA) validation. METHODS: The Successful Aging after Elective Surgery study enrolled dementia-free adults >= 70 years old undergoing major scheduled noncardiac surgery (N = 566; 24% delirium). Plasma was collected at four time points: preoperative, postanesthesia care unit, postoperative day 2, and 1 month postoperative. Matched pairs were selected for the independent discovery (39 pairs) and replication cohorts (36 pairs), which were subsequently combined into the pooled cohort (75 pairs). Isobaric tags for relative and absolute quantitation-based relative quantitation mass spectrometry proteomics were performed to identify the strongest delirium-related protein, which was selected for ELISA validation. Using the ELISA results, statistical analyses using nonparametric signed rank tests were performed in all cohorts examining the association between the identified protein and delirium. RESULTS: C-reactive protein emerged from the proteomics analysis as the strongest delirium-related protein. Validation by ELISA confirmed that compared with controls, cases had significantly higher C-reactive protein levels in the discovery, replication, and pooled cohorts at the preoperative (median paired difference [MPD] 1.97 mg/L [p .05], 0.29 mg/L, 1.56 mg/L [p,.01]), postanesthesia care unit (MPD 2.83 mg/L, 2.22 mg/L [p,.05], 2.53 mg/L [p,.01]) and postoperative day 2 (MPD 71.97 mg/L [p,.01], 35.18 mg/L [p,.05], 63.76 mg/L [p,.01]) time points, but not 1 month postoperative (MPD 2.72 mg/L, 20.66 mg/L, 1.10 mg/L). CONCLUSIONS: Elevated preoperative and postoperative plasma levels of C-reactive protein were associated with delirium, suggesting that a preinflammatory state and heightened inflammatory response to surgery are potential pathophysiologic mechanisms of delirium. C1 [Dillon, Simon T.; Libermann, Towia A.] Beth Israel Deaconess Med Ctr, Genom Prote Bioinformat & Syst Biol Ctr, Boston, MA 02215 USA. [Dillon, Simon T.; Libermann, Towia A.] Beth Israel Deaconess Med Ctr, Div Interdisciplinary Med & Biotechnol, Boston, MA 02215 USA. [Vasunilashorn, Sarinnapha M.; Ngo, Long; Marcantonio, Edward R.] Beth Israel Deaconess Med Ctr, Div Gen Med & Primary Care, 330 Brookline Ave,CO-212, Boston, MA 02215 USA. [Inouye, Sharon K.; Marcantonio, Edward R.] Beth Israel Deaconess Med Ctr, Div Gerontol, Boston, MA 02215 USA. [Metzger, Eran D.] Beth Israel Deaconess Med Ctr, Dept Psychiat, Boston, MA 02215 USA. [Alsop, David C.] Beth Israel Deaconess Med Ctr, Dept Radiol, Boston, MA 02215 USA. [Dillon, Simon T.; Vasunilashorn, Sarinnapha M.; Ngo, Long; Inouye, Sharon K.; Alsop, David C.; Arnold, Steven E.; Marcantonio, Edward R.; Libermann, Towia A.] Harvard Med Sch, Boston, MA USA. [Vasunilashorn, Sarinnapha M.; Inouye, Sharon K.; Jones, Richard N.; Metzger, Eran D.; Marcantonio, Edward R.] Hebrew SeniorLife, Aging Brain Ctr, Inst Aging Res, Boston, MA USA. [Otu, Hasan H.] Univ Nebraska, Dept Elect & Comp Engn, Lincoln, NE USA. [Jones, Richard N.] Brown Univ, Dept Psychiat & Human Behav, Warren Alpert Med, Providence, RI 02912 USA. [Kuchel, George A.] Univ Connecticut, Ctr Hlth, Ctr Aging, Farmington, CT USA. [Inouye, Sharon K.; Arnold, Steven E.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. RP Vasunilashorn, SM (reprint author), Beth Israel Deaconess Med Ctr, Div Gen Med & Primary Care, 330 Brookline Ave,CO-212, Boston, MA 02215 USA. EM svasunil@bidmc.harvard.edu FU National Institute on Aging [T32AG023480, P01AG031720, K07AG041835, R01AG030618, R01AG051658, K24AG035075]; Charles A. King Trust Postdoctoral Research Fellowship Program, Bank of America, N.A.; Milton and Shirley F. Levy Family Chair FX This work was supported by the National Institute on Aging Grant Nos. T32AG023480, P01AG031720, K07AG041835, R01AG030618, R01AG051658, and K24AG035075; Charles A. King Trust Postdoctoral Research Fellowship Program, Bank of America, N.A., Co-Trustee; and Milton and Shirley F. Levy Family Chair (SKI). NR 39 TC 1 Z9 1 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 EI 1873-2402 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD JAN 15 PY 2017 VL 81 IS 2 BP 145 EP 153 DI 10.1016/j.biopsych.2016.03.2098 PG 9 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA EO2JY UT WOS:000396524000012 PM 27160518 ER PT J AU Durazzo, TC Murray, DE Meyerhoff, DJ AF Durazzo, Timothy C. Murray, Donna E. Meyerhoff, Dieter J. TI Reply to: On the Correction of Effects of Flip Angle in H-1 Magnetic Resonance Spectroscopy Signal Acquired Using Stimulated Echo Acquisition Mode Sequence SO BIOLOGICAL PSYCHIATRY LA English DT Letter C1 [Durazzo, Timothy C.] Stanford Univ, Dept Psychiat & Behav Sci, Sch Med, Stanford, CA USA. [Durazzo, Timothy C.] Vet Affairs Palo Alto Hlth Care Syst, Mental Illness Res & Educ Clin Ctr, Palo Alto, CA USA. [Durazzo, Timothy C.] Vet Affairs Palo Alto Hlth Care Syst, Sierra Pacific War Related Illness & Injury Study, Palo Alto, CA USA. [Murray, Donna E.; Meyerhoff, Dieter J.] Univ Calif San Francisco, Dept Radiol & Biomed Imaging, San Francisco, CA 94143 USA. [Murray, Donna E.; Meyerhoff, Dieter J.] San Francisco VA Med Ctr, Ctr Imaging Neurodegenerat Dis, San Francisco, CA USA. RP Durazzo, TC (reprint author), VA Palo Alto Hlth Care Syst, Mental Illness Res & Educ Clin Ctr, War Related Illness & Injury Study Ctr, 151Y,3801 Miranda Ave, Palo Alto, CA 94304 USA. EM tdurazzo@stanford.edu FU National Institutes of Health [DA24136, AA10788] FX This work was supported by grants from the National Institutes of Health (Grant Nos. DA24136 to TCD and AA10788 to DJM) administered by the Northern California Institute for Research and Education and by the use of resources and facilities at the San Francisco Veterans Administration Medical Center. NR 1 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 EI 1873-2402 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD JAN 15 PY 2017 VL 81 IS 2 BP E17 EP E17 DI 10.1016/j.biopsych.2016.02.025 PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA EO2JY UT WOS:000396524000004 PM 27063070 ER PT J AU Clancy, CJ Nguyen, MH AF Clancy, Cornelius J. Nguyen, M. Hong TI Emergence of Candida auris: An International Call to Arms SO CLINICAL INFECTIOUS DISEASES LA English DT Editorial Material DE Candida auris; emergence; dissemination; outbreak; Centers for Disease Control and Prevention ID CLONAL STRAIN; INDIA; HAEMULONII C1 [Clancy, Cornelius J.; Nguyen, M. Hong] Univ Pittsburgh, Dept Med, Pittsburgh, PA 15260 USA. [Clancy, Cornelius J.] VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. [Nguyen, M. Hong] Univ Pittsburgh, Med Ctr, Pittsburgh, PA 15260 USA. RP Clancy, CJ (reprint author), 3550 Terrace St,Scaife Hall 867, Pittsburgh, PA 15261 USA. EM cjc76@pitt.edu NR 24 TC 0 Z9 0 U1 1 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 EI 1537-6591 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD JAN 15 PY 2017 VL 64 IS 2 BP 141 EP 143 DI 10.1093/cid/ciw696 PG 3 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA EP1GB UT WOS:000397132300012 PM 27989986 ER PT J AU Springelkamp, H Iglesias, AI Mishra, A Hohn, R Wojciechowski, R Khawaja, AP Nag, A Wang, YX Wang, JJ Cuellar-Partida, G Gibson, J Bailey, JNC Vithana, EN Gharahkhani, P Boutin, T Ramdas, WD Zeller, T Luben, RN Yonova-Doing, E Viswanathan, AC Yazar, S Cree, AJ Haines, JL Koh, JY Souzeau, E Wilson, JF Amin, N Muller, C Venturini, C Kearns, LS Kang, JH Tham, YC Zhou, T van Leeuwen, EM Nickels, S Sanfilippo, P Liao, JM van der Linde, H Zhao, WT van Koolwijk, LME Zheng, L Rivadeneira, F Baskaran, M van der Lee, SJ Perera, S de Jong, PTVM Oostra, BA Uitterlinden, AG Fan, Q Hofman, A Tai, ES Vingerling, JR Sim, XL Wolfs, RCW Teo, YY Lemij, HG Khor, CC Willemsen, R Lackner, KJ Aung, T Jansonius, NM Montgomery, G Wild, PS Young, TL Burdon, KP Hysi, PG Pasquale, LR Wong, TY Klaver, CCW Hewitt, AW Jonas, JB Mitchell, P Lotery, AJ Foster, PJ Vitart, V Pfeiffer, N Craig, JE Mackey, DA Hammond, CJ Wiggs, JL Cheng, CY van Duijn, CM MacGregor, S AF Springelkamp, Henriet Iglesias, Adriana I. Mishra, Aniket Hoehn, Rene Wojciechowski, Robert Khawaja, Anthony P. Nag, Abhishek Wang, Ya Xing Wang, Jie Jin Cuellar-Partida, Gabriel Gibson, Jane Bailey, Jessica N. Cooke Vithana, Eranga N. Gharahkhani, Puya Boutin, Thibaud Ramdas, Wishal D. Zeller, Tanja Luben, Robert N. Yonova-Doing, Ekaterina Viswanathan, Ananth C. Yazar, Seyhan Cree, Angela J. Haines, Jonathan L. Koh, Jia Yu Souzeau, Emmanuelle Wilson, James F. Amin, Najaf Mueller, Christian Venturini, Cristina Kearns, Lisa S. Kang, Jae Hee Tham, Yih Chung Zhou, Tiger van Leeuwen, Elisabeth M. Nickels, Stefan Sanfilippo, Paul Liao, Jiemin van der Linde, Herma Zhao, Wanting van Koolwijk, Leonieke M. E. Zheng, Li Rivadeneira, Fernando Baskaran, Mani van der Lee, Sven J. Perera, Shamira de Jong, Paulus T. V. M. Oostra, Ben A. Uitterlinden, Andre G. Fan, Qiao Hofman, Albert Tai, E-Shyong Vingerling, Johannes R. Sim, Xueling Wolfs, Roger C. W. Teo, Yik Ying Lemij, Hans G. Khor, Chiea Chuen Willemsen, Rob Lackner, Karl J. Aung, Tin Jansonius, Nomdo M. Montgomery, Grant Wild, Philipp S. Young, Terri L. Burdon, Kathryn P. Hysi, Pirro G. Pasquale, Louis R. Wong, Tien Yin Klaver, Caroline C. W. Hewitt, Alex W. Jonas, Jost B. Mitchell, Paul Lotery, Andrew J. Foster, Paul J. Vitart, Veronique Pfeiffer, Norbert Craig, Jamie E. Mackey, David A. Hammond, Christopher J. Wiggs, Janey L. Cheng, Ching-Yu van Duijn, Cornelia M. MacGregor, Stuart CA NEIGHBORHOOD Consortium TI New insights into the genetics of primary open-angle glaucoma based on meta-analyses of intraocular pressure and optic disc characteristics SO HUMAN MOLECULAR GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; POPULATION-BASED EPIDEMIOLOGY; SUSCEPTIBILITY LOCI; COMMON VARIANTS; IDENTIFIES 5; RISK; PROSTATE; PROTEIN; CANCER; P53 AB Primary open-angle glaucoma (POAG), the most common optic neuropathy, is a heritable disease. Siblings of POAG cases have a ten-fold increased risk of developing the disease. Intraocular pressure (IOP) and optic nerve head characteristics are used clinically to predict POAG risk. We conducted a genome-wide association meta-analysis of IOP and optic disc parameters and validated our findings in multiple sets of POAG cases and controls. Using imputation to the 1000 genomes (1000G) reference set, we identified 9 new genomic regions associated with vertical cup-disc ratio (VCDR) and 1 new region associated with IOP. Additionally, we found 5 novel loci for optic nerve cup area and 6 for disc area. Previously it was assumed that genetic variation influenced POAG either through IOP or via changes to the optic nerve head; here we present evidence that some genomic regions affect both IOP and the disc parameters. We characterized the effect of the novel loci through pathway analysis and found that pathways involved are not entirely distinct as assumed so far. Further, we identified a novel association between CDKN1A and POAG. Using a zebrafish model we show that six6b (associated with POAG and optic nerve head variation) alters the expression of cdkn1a. In summary, we have identified several novel genes influencing the major clinical risk predictors of POAG and showed that genetic variation in CDKN1A is important in POAG risk. C1 [Springelkamp, Henriet; van Koolwijk, Leonieke M. E.; Rivadeneira, Fernando; van der Lee, Sven J.; Uitterlinden, Andre G.; Hofman, Albert; Klaver, Caroline C. W.] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Springelkamp, Henriet; Ramdas, Wishal D.; Vingerling, Johannes R.; Wolfs, Roger C. W.; Klaver, Caroline C. W.] Erasmus MC, Dept Ophthalmol, Rotterdam, Netherlands. [Iglesias, Adriana I.; Oostra, Ben A.; Willemsen, Rob] Erasmus MC, Dept Clin Sci, Rotterdam, Netherlands. [Mishra, Aniket; Cuellar-Partida, Gabriel; Gharahkhani, Puya; MacGregor, Stuart] Royal Brisbane Hosp, QIMR Berghofer Med Res Inst, Stat Genet, Brisbane, Qld, Australia. [Mishra, Aniket] Vrije Univ Amsterdam, Ctr Neurogenom & Cognit Res, Dept Complex Trait Genet, Amsterdam, Netherlands. [Hoehn, Rene] Univ Bern, Univ Hosp Bern, Inselspital, Dept Ophthalmol, Bern, Switzerland. [Hoehn, Rene; Nickels, Stefan; Pfeiffer, Norbert] Univ Med Ctr Mainz, Dept Ophthalmol, Mainz, Germany. [Wojciechowski, Robert] Natl Human Genome Res Inst NIH, Computat & Stat Genom Branch, Baltimore, MD USA. Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Wojciechowski, Robert] Johns Hopkins Sch Med, Wilmer Eye Inst, Baltimore, MD USA. [Khawaja, Anthony P.; Viswanathan, Ananth C.; Foster, Paul J.] Moorfields Eye Hosp NHS Fdn Trust, NIHR Biomed Res Ctr, London, England. [Khawaja, Anthony P.; Viswanathan, Ananth C.; Foster, Paul J.] UCL, Inst Ophthalmol, London, England. [Nag, Abhishek; Yonova-Doing, Ekaterina; Hammond, Christopher J.] Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England. [Wang, Ya Xing] Capital Med Univ, Beijing Tongren Hosp, Beijing Tongren Eye Ctr, Beijing Inst Ophthalmol, Beijing, Peoples R China. [Wang, Ya Xing] Beijing Ophthalmol & Visual Sci Key Lab, Beijing, Peoples R China. [Wang, Jie Jin; Mitchell, Paul] Univ Sydney, Ctr Vis Res, Dept Ophthalmol, Sydney, NSW, Australia. [Wang, Jie Jin; Mitchell, Paul] Univ Sydney, Westmead Inst Med Res, Sydney, NSW, Australia. [Gibson, Jane] Univ Southampton, Fac Nat & Environm Sci, Ctr Biol Sci, Southampton, Hants, England. [Bailey, Jessica N. Cooke; Haines, Jonathan L.] Case Western Reserve Univ, Dept Epidemiol & Biostat, Cleveland, OH 44106 USA. [Vithana, Eranga N.; Koh, Jia Yu; Tham, Yih Chung; Liao, Jiemin; Zhao, Wanting; Zheng, Li; Baskaran, Mani; Perera, Shamira; Fan, Qiao; Khor, Chiea Chuen; Aung, Tin; Wong, Tien Yin; Cheng, Ching-Yu] Singapore Natl Eye Ctr, Singapore Eye Res Inst, Singapore, Singapore. [Zhao, Wanting; Perera, Shamira; Tai, E-Shyong] Duke Natl Univ Singapore, Grad Sch Med, Singapore, Singapore. [Vithana, Eranga N.; Tham, Yih Chung; Liao, Jiemin; Baskaran, Mani; Aung, Tin; Wong, Tien Yin; Cheng, Ching-Yu] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Ophthalmol, Singapore, Singapore. [Boutin, Thibaud; Wilson, James F.; Vitart, Veronique] Univ Edinburgh, Inst Genet & Mol Med, Med Res Council Human Genet Unit, Edinburgh, Midlothian, Scotland. [Zeller, Tanja; Mueller, Christian] Univ Heart Ctr Hamburg, Clin Gen & Intervent Cardiol, Hamburg, Germany. [Zeller, Tanja; Mueller, Christian] German Ctr Cardiovasc Res DZHK, Partner Site Hamburg, Hamburg, Germany. [Luben, Robert N.] Univ Cambridge, Sch Clin Med, Inst Publ Hlth, Dept Publ Hlth & Primary Care, Cambridge, England. [Yazar, Seyhan; Sanfilippo, Paul; Mackey, David A.] Univ Western Australia, Lions Eye Inst, Ctr Ophthalmol & Visual Sci, Perth, WA, Australia. [Cree, Angela J.; Lotery, Andrew J.] Univ Southampton, Fac Med, Clin & Expt Sci, Southampton, Hants, England. [Souzeau, Emmanuelle; Zhou, Tiger; Craig, Jamie E.] Flinders Univ S Australia, Dept Ophthalmol, Adelaide, SA, Australia. [Wilson, James F.] Univ Edinburgh, Usher Inst Populat Hlth Sci & Informat, Ctr Global Hlth Res, Edinburgh EH8 9YL, Midlothian, Scotland. [Kearns, Lisa S.; Sanfilippo, Paul; Hewitt, Alex W.] Univ Melbourne, Royal Victorian Eye & Ear Hosp, Ctr Eye Res Australia, Melbourne, Vic, Australia. [Kang, Jae Hee; Pasquale, Louis R.] Brigham & Womens Hosp, Dept Med, Div Network Med, Boston, MA USA. [Zheng, Li; Khor, Chiea Chuen] Genome Inst Singapore, Div Human Genet, Singapore, Singapore. [Rivadeneira, Fernando; Uitterlinden, Andre G.] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. [Rivadeneira, Fernando; Uitterlinden, Andre G.; Hofman, Albert] Netherlands Genom Initiat, Netherlands Consortium Healthy Ageing, The Hague, Netherlands. [de Jong, Paulus T. V. M.] Acad Med Ctr, Dept Ophthalmol, Amsterdam, Netherlands. Leiden Univ, Med Ctr, Dept Ophthalmol, Leiden, Netherlands. [de Jong, Paulus T. V. M.] Netherlands Inst Neurosci KNAW, Amsterdam, Netherlands. [Tai, E-Shyong] Natl Univ Singapore, Dept Med, Singapore, Singapore. [Tai, E-Shyong] Natl Univ Hlth Syst, Singapore, Singapore. [Tai, E-Shyong; Sim, Xueling; Teo, Yik Ying] Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore, Singapore. [Tai, E-Shyong; Sim, Xueling; Teo, Yik Ying] Natl Univ Hlth Syst, Singapore, Singapore. [Teo, Yik Ying] Natl Univ Singapore, Dept Stat & Appl Probabil, Singapore, Singapore. [Lemij, Hans G.] Rotterdam Eye Hosp, Glaucoma Serv, Rotterdam, Netherlands. [Khor, Chiea Chuen] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Biochem, Singapore, Singapore. [Lackner, Karl J.] Univ Med Ctr Mainz, Inst Clin Chem, Mainz, Germany. [Lackner, Karl J.] Univ Med Ctr Mainz, Lab Med, Mainz, Germany. [Jansonius, Nomdo M.] Univ Groningen, Univ Med Ctr Groningen, Dept Ophthalmol, Groningen, Netherlands. [Montgomery, Grant] Queensland Inst Med Res, Dept Mol Epidemiol, Brisbane, Qld, Australia. [Wild, Philipp S.] Univ Med Ctr Mainz, Prevent Cardiol & Prevent Med Ctr Cardiol, Mainz, Germany. Univ Med Ctr Mainz, Ctr Thrombosis & Hemostasis, Mainz, Germany. [Wild, Philipp S.] German Ctr Cardiovasc Res DZHK, Partner Site RhineMain, Mainz, Germany. [Young, Terri L.] Univ Wisconsin, Sch Med & Publ Hlth, Dept Ophthalmol & Visual Sci, Madison, WI USA. [Burdon, Kathryn P.; Hewitt, Alex W.; Mackey, David A.] Univ Tasmania, Menzies Res Inst Tasmania, Sch Med, Hobart, Tas, Australia. [Pasquale, Louis R.; Wiggs, Janey L.] Harvard Med Sch, Dept Ophthalmol, Boston, MA USA. [Pasquale, Louis R.; Wiggs, Janey L.] Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. [Jonas, Jost B.] Heidelberg Univ, Med Fac Mannheim, Dept Ophthalmol, Heidelberg, Germany. RP MacGregor, S (reprint author), Royal Brisbane Hosp, QIMR Berghofer Med Res Inst, Stuart MacGregor Stat Genet, Brisbane, Qld, Australia. EM Stuart.MacGregor@qimrberghofer.edu.au RI Mackey, David/H-5340-2014 OI Mackey, David/0000-0001-7914-4709 FU National Institutes of Health/National Eye Institute (NIH/NEI) [1R01EY018246-01]; NIH/NEI [R01 EY014685]; Research to Prevent Blindness, Inc.; University of Wisconsin School of Medicine and Public Health Centennial Scholars Fund; Australian National Health & Medical Research Council (NH&MRC), Canberra Australia [974159, 211069, 457349, 512423, 475604, 529912]; Centre for Clinical Research Excellence (Translational Clinical Research in Major Eye Diseases) [519923]; NH&MRC research fellowships [358702, 632909]; Wellcome Trust, UK as part of Wellcome Trust Case Control Consortium 2 [085475/B/08/Z, 085475/Z/08/Z, 076113]; UK and Eire Glaucoma Society; International Glaucoma Association; Royal College of Ophthalmologists; National Institutes of Health [NIH R01 EY022305]; NEI [K08EY022943]; MRC HGU "QTL in Health and Disease" core programme FX Terri L. Young, MD, MBA is supported by National Institutes of Health/National Eye Institute (NIH/NEI) 1R01EY018246-01, NIH/NEI R01 EY014685, Research to Prevent Blindness, Inc. and The University of Wisconsin School of Medicine and Public Health Centennial Scholars Fund.; Blue Mountains Eye Study was supported by the Australian National Health & Medical Research Council (NH&MRC), Canberra Australia (974159, 211069, 457349, 512423, 475604, 529912); the Centre for Clinical Research Excellence (Translational Clinical Research in Major Eye Diseases, 519923); NH&MRC research fellowships (358702, 632909 to J.J.W); and the Wellcome Trust, UK as part of Wellcome Trust Case Control Consortium 2 (A. Viswanathan, P. McGuffin, P. Mitchell, F. Topouzis, P. Foster) for genotyping costs of the entire BMES population (085475/B/08/Z, 085475/Z/08/Z, 076113).; The Southampton acknowledges funding from the UK and Eire Glaucoma Society and the International Glaucoma Association (in association with the Royal College of Ophthalmologists). EY015473 (LRP) supported generation of the cohort at risk for POAG in Nurses Health Study (NHS, UM1 CA186107) and Health Professionals Followup Study (HPFS, UM1 CA167552).; HG004728 (LRP) supported genotyping in a subset of the Neighborhood consortium, specifically NHS, HPFS and Massachusetts Eye and Ear Infirmary (MEEI) cases and controls. We acknowledge funding from National Institutes of Health NIH R01 EY022305 (JLW) and NEI grant K08EY022943 (RW).; Genetic analyses for the Orkney Complex Disease Study (ORCADES) were supported by the MRC HGU "QTL in Health and Disease" core programme. NR 72 TC 0 Z9 0 U1 0 U2 0 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 JAN 15 PY 2017 VL 26 IS 2 BP 438 EP 453 DI 10.1093/hmg/ddw399 PG 16 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA EP0GX UT WOS:000397066400017 PM 28073927 ER PT J AU Georgopoulos, K AF Georgopoulos, Katia TI In search of the mechanism that shapes the neutrophil's nucleus SO GENES & DEVELOPMENT LA English DT Editorial Material DE genome topology; Lamin B receptor; neutrophils; nucleoli; rDNA ID HUMAN GENOME; PRINCIPLES AB The organization of the genome within the confines of the nuclear compartment is considered a key contributor to transcription and DNA replication, repair, and recombination. A typical higher eukaryotic cell has a spherical nucleus that is similar to 10 mu m in diameter. This is not the case for a neutrophil, a short-lived innate immune cell with an unusual multilobular nuclear structure that may serve purposes outside nuclear functions. In this issue of Genes & Development, Zhu and colleagues (pp. 141-153) investigate the neutrophil's genome organization and the mechanisms that contribute to its unique nuclear shape. C1 [Georgopoulos, Katia] Harvard Med Sch, Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Charlestown, MA 02129 USA. RP Georgopoulos, K (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Charlestown, MA 02129 USA. EM katia.georgopoulos@cbrc2.mgh.harvard.edu FU J. de Gunzburg Massachusetts General Hospital Scholar Award; [5R01CA162092]; [4R01 CA158006]; [5R01CA190964]; [1R21 AI124326]; [1R01 AR069132] FX I thank Dr. T. Yoshida for the artwork on the model presented by Zhu et al (2017). K.G. is supported by 5R01CA162092, 4R01 CA158006, 5R01CA190964, 1R21 AI124326, 1R01 AR069132, and a J. de Gunzburg Massachusetts General Hospital Scholar Award. NR 7 TC 0 Z9 0 U1 2 U2 2 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 0890-9369 EI 1549-5477 J9 GENE DEV JI Genes Dev. PD JAN 15 PY 2017 VL 31 IS 2 BP 85 EP 87 DI 10.1101/gad.296228.117 PG 3 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA EL2LO UT WOS:000394451400001 PM 28202537 ER PT J AU Rajurkar, M Dang, K Fernandez-Barrena, MG Liu, XF Fernandez-Zapico, ME Lewis, BC Mao, JH AF Rajurkar, Mihir Dang, Kyvan Fernandez-Barrena, Maite G. Liu, Xiangfan Fernandez-Zapico, Martin E. Lewis, Brian C. Mao, Junhao TI IKBKE Is Required during KRAS-Induced Pancreatic Tumorigenesis SO CANCER RESEARCH LA English DT Article ID BREAST-CANCER ONCOGENE; B KINASE EPSILON; IKK-EPSILON; DUCTAL ADENOCARCINOMA; CELL-TRANSFORMATION; CYTOKINE NETWORK; TUMOR-SUPPRESSOR; RAS; ACTIVATION; TBK1 AB Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest malignancies lacking effective therapeutic strategies. Here, we show that the noncanonical I kappa B-related kinase, IKBKE, is a critical oncogenic effector during KRAS-induced pancreatic transformation. Loss of IKBKE inhibits the initiation and progression of pancreatic tumors in mice carrying pancreatic-specific KRAS activation. Mechanistically, we demonstrate that this protumoral effect of IKBKE involves the activation of GLI1 and AKT signaling and is independent of the levels of activity of the NF-kappa B pathway. Further analysis reveals that IKBKE regulates GLI1 nuclear translocation and promotes the reactivation of AKT post-inhibition of mTORinPDACcells. Interestingly, combined inhibition of IKBKE and mTOR synergistically blocks pancreatic tumor growth. Together, our findings highlight the functional importance of IKBKE in pancreatic cancer, support the evaluation of IKBKE as a therapeutic target in PDAC, and suggest IKBKE inhibition as a strategy to improve efficacy of mTOR inhibitors in the clinic. (C) 2017 AACR. C1 [Rajurkar, Mihir; Dang, Kyvan; Liu, Xiangfan; Lewis, Brian C.; Mao, Junhao] Univ Massachusetts, Sch Med, Dept Mol Cell & Canc Biol, Worcester, MA USA. [Fernandez-Barrena, Maite G.; Fernandez-Zapico, Martin E.] Mayo Clin, Schulze Ctr Novel Therapeut, Rochester, MN USA. [Rajurkar, Mihir] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02129 USA. [Liu, Xiangfan] Shanghai Jiao Tong Univ, Sch Med, Ruijin Hosp, Dept Lab Med, Shanghai 200025, Peoples R China. RP Mao, JH (reprint author), Univ Massachusetts, Sch Med, 364 Plantat St, Worcester, MA 01605 USA. EM junhao.mao@umassmed.edu FU NIH [R01DK099510, R01CA136526]; American Cancer Society [RSG-11-040-01-DDC]; [R01CA155784] FX J. Mao is supported by NIH grant R01DK099510 and American Cancer Society grant RSG-11-040-01-DDC. M.E. Fernandez-Zapico is supported by NIH grant R01CA136526. B.C. Lewis is supported by grant R01CA155784. NR 39 TC 0 Z9 0 U1 1 U2 1 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 JAN 15 PY 2017 VL 77 IS 2 BP 320 EP 329 DI 10.1158/0008-5472.CAN-15-1684 PG 10 WC Oncology SC Oncology GA EJ4MF UT WOS:000393190600012 PM 28069799 ER PT J AU Hu, DP Ferro, F Yang, F Taylor, AJ Chang, WH Miclau, T Marcucio, RS Bahney, CS AF Hu, Diane P. Ferro, Federico Yang, Frank Taylor, Aaron J. Chang, Wenhan Miclau, Theodore Marcucio, Ralph S. Bahney, Chelsea S. TI Cartilage to bone transformation during fracture healing is coordinated by the invading vasculature and induction of the core pluripotency genes SO DEVELOPMENT LA English DT Article DE Endochondral ossification; Fracture repair; Pluripotency programs; Chondrocyte transformation ID MESENCHYMAL STEM-CELLS; OSTEOBLAST DIFFERENTIATION; GROWTH-PLATE; HYPERTROPHIC CHONDROCYTES; ENDOCHONDRAL OSSIFICATION; SELF-RENEWAL; IN-VIVO; SIGNALING CENTER; OCT4 EXPRESSION; CRE ACTIVITY AB Fractures heal predominantly through the process of endochondral ossification. The classic model of endochondral ossification holds that chondrocytes mature to hypertrophy, undergo apoptosis and new bone forms by invading osteoprogenitors. However, recent data demonstrate that chondrocytes transdifferentiate to osteoblasts in the growth plate and during regeneration, yet the mechanism(s) regulating this process remain unknown. Here, we show a spatially-dependent phenotypic overlap between hypertrophic chondrocytes and osteoblasts at the chondro-osseous border in the fracture callus, in a region we define as the transition zone (TZ). Hypertrophic chondrocytes in the TZ activate expression of the pluripotency factors [Sox2, Oct4 (Pou5f1), Nanog], and conditional knock-out of Sox2 during fracture healing results in reduction of the fracture callus and a delay in conversion of cartilage to bone. The signal(s) triggering expression of the pluripotency genes are unknown, but we demonstrate that endothelial cell conditioned medium upregulates these genes in ex vivo fracture cultures, supporting histological evidence that transdifferentiation occurs adjacent to the vasculature. Elucidating the cellular and molecular mechanisms underlying fracture repair is important for understanding why some fractures fail to heal and for developing novel therapeutic interventions. C1 [Hu, Diane P.; Ferro, Federico; Yang, Frank; Taylor, Aaron J.; Miclau, Theodore; Marcucio, Ralph S.; Bahney, Chelsea S.] Univ Calif San Francisco, 2550 23rd St,Bldg 9,3rd Floor, San Francisco, CA 94110 USA. [Hu, Diane P.; Ferro, Federico; Yang, Frank; Taylor, Aaron J.; Miclau, Theodore; Marcucio, Ralph S.; Bahney, Chelsea S.] San Francisco Gen Hosp, Orthopaed Trauma Inst, Dept Orthopaed Surg, 2550 23rd St,Bldg 9,3rd Floor, San Francisco, CA 94110 USA. [Chang, Wenhan] Univ Calif San Francisco, 1700 Owens St,4th Floor, San Francisco, CA 94158 USA. [Chang, Wenhan] San Francisco VA Med Ctr, Dept Med, 1700 Owens St,4th Floor, San Francisco, CA 94158 USA. RP Marcucio, RS; Bahney, CS (reprint author), Univ Calif San Francisco, 2550 23rd St,Bldg 9,3rd Floor, San Francisco, CA 94110 USA.; Marcucio, RS; Bahney, CS (reprint author), San Francisco Gen Hosp, Orthopaed Trauma Inst, Dept Orthopaed Surg, 2550 23rd St,Bldg 9,3rd Floor, San Francisco, CA 94110 USA. EM Ralph.Marcucio@UCSF.edu; Chelsea.Bahney@UCSF.edu FU National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) of the National Institutes of Health (NIH) [5F32AR062469, AR053645, AR057344, AR067291]; Musculoskeletal Transplant Foundation (MTF Junior Investigator Award); AO Foundation (Career Development Award) [S-14-114B]; UCSF Clinical and Translational Science Institute [UL1TR000004]; UCSF Core Center for Musculoskeletal Biology and Medicine [P30AR066262]; US Bone and Joint Initiative Young Investigator Program; Department of Veterans Affairs Program Project Award [IPIBX001599] FX Research reported in this publication was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) of the National Institutes of Health (NIH) (5F32AR062469 to C.S.B.; AR053645 and AR057344 to T.M.; and AR067291 to W.C.). Additional research support was provided by the Musculoskeletal Transplant Foundation (MTF Junior Investigator Award to C.S.B.), the AO Foundation (Career Development Award, S-14-114B to C.S.B.), the UCSF Clinical and Translational Science Institute (UL1TR000004 to C.S.B.), UCSF Core Center for Musculoskeletal Biology and Medicine (P30AR066262 to C.S.B.), the US Bone and Joint Initiative Young Investigator Program (to C.S.B.) and Department of Veterans Affairs Program Project Award (IPIBX001599 to W.C.). Deposited in PMC for release after 12 months. NR 71 TC 0 Z9 0 U1 4 U2 4 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0950-1991 EI 1477-9129 J9 DEVELOPMENT JI Development PD JAN 15 PY 2017 VL 144 IS 2 BP 221 EP 234 DI 10.1242/dev.130807 PG 14 WC Developmental Biology SC Developmental Biology GA EJ8DR UT WOS:000393455700005 PM 28096214 ER PT J AU Charidimou, A Schmitt, A Wilson, D Yakushiji, Y Gregoire, SM Fox, Z Jager, HR Werring, DJ AF Charidimou, Andreas Schmitt, Anne Wilson, Duncan Yakushiji, Yusuke Gregoire, Simone M. Fox, Zoe Jager, Hans R. Werring, David J. TI The Cerebral Haemorrhage Anatomical RaTing inStrument (CHARTS): Development and assessment of reliability SO JOURNAL OF THE NEUROLOGICAL SCIENCES LA English DT Article DE Stroke; Intracerebral haemorrhage; CT; MRI; Cerebral amyloid angiopathy ID SMALL VESSEL DISEASE; INTRACEREBRAL HEMORRHAGE; AMYLOID ANGIOPATHY; AGREEMENT; STROKE; GUIDELINES; MAP AB Purpose: The causes, risk factors and prognosis of spontaneous intracerebral haemorrhage (ICH) are partly determined by anatomical location (specifically, lobar vs. non-lobar (deep and infratentorial) regions). We systematically developed a rating instrument to reliably classify ICH location. Methods: We used a two-stage iterative Delphi-style method for instrument development. The resultant Cerebral Haemorrhage Anatomical RaTing inStrument (CHARTS) was validated on CT and MRI scans from a cohort of consecutive patients with acute spontaneous symptomatic ICH by three independent raters. We tested interrater and intrarater reliability using kappa statistics. Results: Our validation cohort included 227 patients (58% male; median age: 72.4 (IQR: 67.1-74.6)). The interrater reliability for the main analyses (i.e. including any lobar ICH; all deep and infratentorial anatomical categories (lentiform, caudate thalamus; brainstem; cerebellum); and uncertain location) was excellent (all kappa values > 0.80) both in pair-wise between-rater comparisons and across all raters. The intrarater reliability was substantial to almost perfect (k = 0.83; 95%CI: 0.77-0.88 and k = 0.95; 95%CI: 0.92-0.96 respectively). All kappa statistics remained consistent for individual cerebral lobar regions. Conclusions: The CHARTS instrument can be used to reliably and comprehensively map the anatomical location of spontaneous ICH, and may be helpful for studying important questions regarding causes, risk factors, prognosis, and for stratification in clinical trials. (C) 2016 Elsevier B.V. All rights reserved. C1 [Charidimou, Andreas; Wilson, Duncan; Yakushiji, Yusuke; Gregoire, Simone M.; Jager, Hans R.; Werring, David J.] UCL Inst Neurol, UCL Stroke Res Ctr, Queen Sq, London WC1N 3BG, England. [Charidimou, Andreas; Schmitt, Anne; Wilson, Duncan; Yakushiji, Yusuke; Gregoire, Simone M.; Jager, Hans R.; Werring, David J.] Natl Hosp Neurol & Neurosurg, Queen Sq, London WC1N 3BG, England. [Schmitt, Anne; Jager, Hans R.] UCL Inst Neurol, Lysholm Dept Neuroradiol, London, England. [Fox, Zoe] UCL Inst Neurol, Educ Unit, Biomed Res Ctr, Queen Sq, London WC1N 3BG, England. [Charidimou, Andreas; Fox, Zoe] Massachusetts Gen Hosp, Harvard Med Sch, Hemorrhag Stroke Res Grp, Boston, MA 02114 USA. RP Werring, DJ (reprint author), UCL Inst Neurol, 10-12 Russell Sq, London WC1B 5EH, England.; Werring, DJ (reprint author), Natl Hosp Neurol & Neurosurg, UCL Stroke Res Ctr, 10-12 Russell Sq, London WC1B 5EH, England. EM d.werring@ucl.ac.uk FU Greek State Scholarship Foundation; Stroke Association; British Heart Foundation [TSA BHF 2009/01]; Rosetrees Trust; Department of Health's NIHR Biomedical Research Centres; British Heart Foundation FX Dr. Charidimou received research support from the Greek State Scholarship Foundation, the Stroke Association and the British Heart Foundation. Prof. Werring receives research support from the Stroke Association, British Heart Foundation TSA BHF 2009/01, and the Rosetrees Trust. This work was partly undertaken at UCLH/UCL who received a proportion of funding from the Department of Health's NIHR Biomedical Research Centres funding scheme. NR 23 TC 0 Z9 0 U1 0 U2 0 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 JAN 15 PY 2017 VL 372 BP 178 EP 183 DI 10.1016/j.jns.2016.11.021 PG 6 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA EJ1WZ UT WOS:000393002500035 PM 28017207 ER PT J AU Tromp, J ter Maaten, JM Damman, K O'Connor, CM Metra, M Dittrich, HC Ponikowski, P Teerlink, JR Cotter, G Davison, B Cleland, JGF Givertz, MM Bloomfield, DM van der Wal, MHL Jaarsma, T van Veldhuisen, DJ Hillege, HL Voors, AA van der Meer, P AF Tromp, Jasper ter Maaten, Jozine M. Damman, Kevin O'Connor, Christopher M. Metra, Marco Dittrich, Howard C. Ponikowski, Piot Teerlink, John R. Cotter, Gad Davison, Beth Cleland, John G. F. Givertz, Michael M. Bloomfield, Daniel M. van der Wal, Martje H. L. Jaarsma, Tiny van Veldhuisen, Dirk J. Hillege, Hans L. Voors, Adriaan A. van der Meer, Peter TI Serum Potassium Levels and Outcome in Acute Heart Failure (Data from the PROTECT and COACH Trials) SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID REDUCED EJECTION FRACTION; DIURETIC RESPONSE; RENAL-FUNCTION; HOSPITALIZATION; HYPERKALEMIA; MORTALITY; ROLOFYLLINE; PREDICTORS; ANTAGONIST; SURVIVAL AB Serum potassium is routinely measured at admission for acute heart failure (AHF), but information on association with clinical variables and prognosis is limited. Potassium measurements at admission were available in 1,867 patients with AHF in the original cohort of 2,033 patients included in the Patients Hospitalized with acute heart failure and Volume Overload to Assess Treatment Effect on Congestion and Renal FuncTion trial. Patients were grouped according to low potassium (<3.5 mEq/l), normal potassium (3.5 to 5.0 mEq/l), and high potassium (>5.0 mEq/l) levels. Results were verified in a validation cohort of 1,023 patients. Mean age of patients was 71 +/- 11 years, and 66% were men. Low potassium was present in 115 patients (6%), normal potassium in 1,576 (84%), and high potassium in 176 (9%). Potassium levels increased during hospitalization (0.18 +/- 0.69 mEq/l). Patients with high potassium more often used angiotensin-converting enzyme inhibitors and mineralocorticoid receptor antagonists before admission, had impaired baseline renal function and a better diuretic response (p = 0.005), independent of mineralocorticoid receptor antagonist usage. During 180-day follow-up, a total of 330 patients (18%) died. Potassium levels at admission showed a univariate linear association with mortality (hazard ratio [log] 2.36, 95% confidence interval 1.07 to 5.23; p = 0.034) but not after multivariate adjustment. Changes of potassium levels during hospitalization or potassium levels at discharge were not associated with outcome after multivariate analysis. Results in the validation cohort were similar to the index cohort. In conclusion, high potassium levels at admission are associated with an impaired renal function but a better diuretic response. Changes in potassium levels are common, and overall levels increase during hospitalization. In conclusion, potassium levels at admission or its change during hospitalization are not associated with mortality after multivariate adjustment. (C) 2016 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativeconunons.org/licenses/by/4.0/). C1 [Tromp, Jasper; ter Maaten, Jozine M.; Damman, Kevin; van der Wal, Martje H. L.; van Veldhuisen, Dirk J.; Hillege, Hans L.; Voors, Adriaan A.; van der Meer, Peter] Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, Groningen, Netherlands. [Hillege, Hans L.] Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, Groningen, Netherlands. [O'Connor, Christopher M.] Inova Heart & Vasc Inst, Falls Church, VA USA. [Metra, Marco] Univ Brescia, Dept Cardiol, Brescia, Italy. [Dittrich, Howard C.] Univ Iowa, Cardiovasc Res Ctr, Carver Coll Med, Iowa City, IA USA. [Ponikowski, Piot] Med Univ, Dept Heart Dis, Clin Mil Hosp, Wroclaw, Poland. [Teerlink, John R.] Univ Calif San Francisco, Dept Cardiol, San Francisco, CA 94143 USA. [Teerlink, John R.] San Francisco VA Med Ctr, San Francisco, CA USA. [Cotter, Gad; Davison, Beth] Momentum Res, Durham, NC USA. [Cleland, John G. F.] Univ Hull, Dept Cardiol, Kingston Upon Hull, Yorks, England. [Givertz, Michael M.] Harvard Med Sch, Div Cardiovasc, Brigham & Womens Hosp, Boston, MA USA. [Bloomfield, Daniel M.] Merck & Co Inc, Kenilworth, NJ USA. [van der Wal, Martje H. L.; Jaarsma, Tiny] Linkoping Univ, Fac Hlth & Med Sci, Linkoping, Sweden. RP van der Meer, P (reprint author), Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, Groningen, Netherlands. EM p.van.der.meer@umcg.nl FU NovaCardia; Merck Co., Inc. FX Dr. Cleland was, on the Steering Committee for the PROTECT trial, served on the advisory board for MSD, and received payments for both. Dr. O'Connor is a consultant to Merck & Co., Inc. Dr. Ponikowski has received honoraria from Merck & Co., Inc. Drs. Davison and Cotter are employees of Momentum Research Inc., which was contracted to perform work on the project by Merck & Co., Inc. Dr. Metra has received honoraria and reimbursements from NovaCardia, sponsors of the study, and Merck & Co., Inc. Dr. Givertz has received institutional research support and served on a scientific advisory board for Merck & Co., Inc. Dr. Teerlink has received research funds and consulting fees from Merck & Co., Inc. Dr. Bloomfield is an employee of Merck & Co., Inc. Dr. Dittrich served as a consultant to Merck & Co., Inc. Dr. Voors has received speaker and consultancy fees from Merck & Co., Inc. All other authors have reported that they have no conflict of interest to declare. NR 29 TC 0 Z9 0 U1 2 U2 2 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 JAN 15 PY 2017 VL 119 IS 2 BP 290 EP 296 DI 10.1016/j.amjcard.2016.09.038 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EJ0KI UT WOS:000392896900020 PM 27823598 ER PT J AU Murray, MJ DeBlock, HF Erstad, BL Gray, AW Jacobi, J Jordan, CJ McGee, WT McManus, C Meade, MO Nix, SA Patterson, AJ Sands, K Pino, RM Tescher, AN Arbour, R Rochwerg, B Murray, CF Mehta, S AF Murray, Michael J. DeBlock, Heidi F. Erstad, Brian L. Gray, Anthony W., Jr. Jacobi, Judith Jordan, Che J. McGee, William T. McManus, Claire Meade, Maureen O. Nix, Sean A. Patterson, Andrew J. Sands, Karen Pino, Richard M. Tescher, Ann N. Arbour, Richard Rochwerg, Bram Murray, Catherine Friederich Mehta, Sangeeta TI Clinical practice guidelines for sustained neuromuscular blockade in the adult critically ill patient: 2016 update-executive summary SO AMERICAN JOURNAL OF HEALTH-SYSTEM PHARMACY LA English DT Article ID RESPIRATORY-DISTRESS-SYNDROME; INTENSIVE-CARE-UNIT; MYASTHENIA-GRAVIS; INSULIN THERAPY; BLOCKING-AGENTS; CARDIAC-ARREST; EYE CARE; VECURONIUM; ATRACURIUM; PARALYSIS C1 [Murray, Michael J.] Geisinger Med Ctr, Div Anesthesiol, Dept Crit Care Med, Danville, PA 17822 USA. [DeBlock, Heidi F.] Albany Med Ctr, Albany, NY USA. [Erstad, Brian L.] Univ Arizona, Coll Pharm, Dept Pharm Practice & Sci, Tucson, AZ 85721 USA. [Gray, Anthony W., Jr.] Tufts Univ, Sch Med, Boston, MA 02111 USA. [Gray, Anthony W., Jr.] Lahey Hosp & Med Ctr, Burlington, MA USA. [Jacobi, Judith] Indiana Univ, Hlth Methodist Hosp, Indianapolis, IN 46204 USA. [Jordan, Che J.] Grand Strand Med Ctr, Myrtle Beach, SC USA. [McGee, William T.] Tufts Univ, Sch Med, Pulm & Crit Care Div, Boston, MA 02111 USA. [McManus, Claire] Steward St Elizabeths Med Ctr, Boston, MA USA. [Meade, Maureen O.] McMaster Univ, Dept Med, Hamilton, ON, Canada. [Nix, Sean A.] Riverside Reg Med Ctr, Newport News, VA USA. [Nix, Sean A.] Edward Via Coll Osteopath Med, Dept Surg, Blacksburg, VA USA. [Patterson, Andrew J.] Univ Nebraska Med Ctr, Dept Anesthesiol, Omaha, NE USA. [Sands, Karen] Novant Hlth Forsyth Med Ctr, Winston Salem, NC USA. [Pino, Richard M.] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. [Tescher, Ann N.] Mayo Clin, Dept Nursing, Rochester, MN USA. [Arbour, Richard] Lancaster Gen Hlth Penn Med, Lancaster, PA USA. [Rochwerg, Bram] McMaster Univ, Dept Med, Hamilton, ON, Canada. [Rochwerg, Bram] McMaster Univ, Dept Clin Epidemiol & Biostat, Hamilton, ON, Canada. [Murray, Catherine Friederich] Morpheus Commun Inc, Scottsdale, AZ USA. [Mehta, Sangeeta] Mt Sinai Hosp, Dept Med, Toronto, ON, Canada. [Mehta, Sangeeta] Univ Toronto, Interdept Div Crit Care Med, Toronto, ON, Canada. RP Murray, MJ (reprint author), Geisinger Med Ctr, Div Anesthesiol, Dept Crit Care Med, Danville, PA 17822 USA. EM mmurray1@geisinger.edu NR 43 TC 0 Z9 0 U1 1 U2 1 PU AMER SOC HEALTH-SYSTEM PHARMACISTS PI BETHESDA PA 7272 WISCONSIN AVE, BETHESDA, MD 20814 USA SN 1079-2082 EI 1535-2900 J9 AM J HEALTH-SYST PH JI Am. J. Health-Syst. Pharm. PD JAN 15 PY 2017 VL 74 IS 2 BP 76 EP 78 DI 10.2146/ajhp160803 PG 3 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EI4LO UT WOS:000392465400019 PM 28069681 ER PT J AU Freire, MO Dalli, J Serhan, CN Van Dyke, TE AF Freire, Marcelo O. Dalli, Jesmond Serhan, Charles N. Van Dyke, Thomas E. TI Neutrophil Resolvin E1 Receptor Expression and Function in Type 2 Diabetes SO JOURNAL OF IMMUNOLOGY LA English DT Article ID ALLERGIC AIRWAY INFLAMMATION; LIPID MEDIATOR; ANTIINFLAMMATORY ACTIONS; ANTI-INFLAMMATION; INDUCED COLITIS; HUMAN BLOOD; RESOLUTION; ACID; CHEMR23; BIOSYNTHESIS AB Unresolved inflammation is key in linking metabolic dysregulation and the immune system in type 2 diabetes. Successful regulation of acute inflammation requires biosynthesis of specialized proresolving lipid mediators, such as E-series resolvin (RvE) 1, and activation of cognate G protein-coupled receptors. RvE1 binds to leukotriene B4 (BLT-1) on neutrophils and to ERV-1/ChemR23 on monocyte/macrophages. We show novel actions of RvE1 and expression patterns of neutrophil receptors in type 2 diabetes. Neutrophils from healthy subjects express functional BLT-1, low levels of minimally functional ERV-1, and inversed coexpression when compared to neutrophils from type 2 diabetes subjects. Stimulation with TNF-alpha or LPS increased the expression of ERV-1 by healthy and diabetic neutrophils. RvE1 counteracted LPS and TNF-alpha induction of ERV-1 overexpression and endogenous diabetic overexpression, activating phagocytosis and resolution signals. Functional ERV-1 was determined by phosphorylation of the signaling protein ribosomal S6. Receptor-antagonism experiments revealed that the increase in phosphorylation of ribosomal S6 was mediated by BLT-1 in healthy subject neutrophils and by ERV-1 in diabetes. Metabololipidomics reveal a proinflammatory profile in diabetic serum. Cell phagocytosis is impaired in type 2 diabetes and requires RvE1 for activation. The dose of RvE1 required to activate resolution signals in type 2 diabetic neutrophils was significantly higher than in healthy controls. RvE1 rescues the dysregulation seen on neutrophil receptor profile and, following a therapeutic dosage, activates phagocytosis and resolution signals in type 2 diabetes. These findings reveal the importance of resolution receptors in health, disease, and dysregulation of inflammation in type 2 diabetes. C1 [Freire, Marcelo O.; Van Dyke, Thomas E.] Forsyth Inst, Ctr Periodontol, Dept Appl Oral Sci, 245 First St, Cambridge, MA 02142 USA. [Freire, Marcelo O.; Van Dyke, Thomas E.] Harvard Sch Dent Med, Dept Infect & Immun, Boston, MA 02115 USA. [Dalli, Jesmond; Serhan, Charles N.] Brigham & Womens Hosp, Harvard Inst Med, Ctr Expt Therapeut & Reperfus Injury, Dept Anesthesiol Perioperat & Pain Med, Boston, MA 02115 USA. [Dalli, Jesmond; Serhan, Charles N.] Harvard Med Sch, Boston, MA 02115 USA. RP Van Dyke, TE (reprint author), Forsyth Inst, Ctr Periodontol, Dept Appl Oral Sci, 245 First St, Cambridge, MA 02142 USA. EM tvandyke@forsyth.org OI Dalli, Jesmond/0000-0001-6328-3640; Van Dyke, Thomas/0000-0003-0568-124X; Freire, Marcelo/0000-0003-4906-7698 FU U.S. Public Health Service from the National Institutes of Health/National Institutes of Dental and Craniofacial Research/Department of Health and Human Services [K99/R00 DE 0235804, R01 DE025020, DE025383]; National Institutes of Health [P01GM095467] FX This work was supported by U.S. Public Health Service Grants K99/R00 DE 0235804 (to M.O.F.), R01 DE025020, and DE025383 (both to T.E.V.D.) from the National Institutes of Health/National Institutes of Dental and Craniofacial Research/Department of Health and Human Services and by National Institutes of Health Grant P01GM095467 (to C.N.S.). NR 56 TC 0 Z9 0 U1 3 U2 3 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD JAN 15 PY 2017 VL 198 IS 2 BP 718 EP 728 DI 10.4049/jimmunol.1601543 PG 11 WC Immunology SC Immunology GA EI3PZ UT WOS:000392405000021 PM 27994073 ER PT J AU Satyam, A Kannan, L Matsumoto, N Geha, M Lapchak, PH Bosse, R Shi, GP Lucca, JJD Tsokos, MG Tsokos, GC AF Satyam, Abhigyan Kannan, Lakshmi Matsumoto, Naoya Geha, Mayya Lapchak, Peter H. Bosse, Robin Shi, Guo-Ping Lucca, Jurandir J. Dalle Tsokos, Maria G. Tsokos, George C. TI Intracellular Activation of Complement 3 Is Responsible for Intestinal Tissue Damage during Mesenteric Ischemia SO JOURNAL OF IMMUNOLOGY LA English DT Article ID TUBULAR EPITHELIAL-CELLS; REPERFUSION INJURY; NATURAL ANTIBODIES; ORGAN INJURY; FACTOR-B; MICE; C3; EXPRESSION; DIFFERENTIATION; INSUFFICIENCY AB Intestinal ischemia followed by reperfusion leads to local and remote organ injury attributed to inflammatory response during the reperfusion phase. The extent to which ischemia contributes to ischemia/reperfusion injury has not been thoroughly studied. After careful evaluation of intestinal tissue following 30 min of ischemia, we noticed significant local mucosal injury in wild-type mice. This injury was drastically reduced in C3-deficient mice, suggesting C3 involvement. Depletion of circulating complement with cobra venom factor eliminated, as expected, injury recorded at the end of the reperfusion phase but failed to eliminate injury that occurred during the ischemic phase. Immunohistochemical studies showed that tissue damage during ischemia was associated with increased expression of C3/C3 fragments primarily in the intestinal epithelial cells, suggesting local involvement of complement. In vitro studies using Caco2 intestinal epithelial cells showed that in the presence of LPS or exposure to hypoxic conditions the cells produce higher C3 mRNA as well as C3a fragment. Caco2 cells were also noted to produce cathepsins B and L, and inhibition of cathepsins suppressed the release of C3a. Finally, we found that mice treated with a cathepsin inhibitor and cathepsin B-deficient mice suffer limited intestinal injury during the ischemic phase. To our knowledge, our findings demonstrate for the first time that significant intestinal injury occurs during ischemia prior to reperfusion and that this is due to activation of C3 within the intestinal epithelial cells in a cathepsin-dependent manner. Modulation of cathepsin activity may prevent injury of organs exposed to ischemia. C1 [Satyam, Abhigyan; Kannan, Lakshmi; Matsumoto, Naoya; Geha, Mayya; Lapchak, Peter H.; Bosse, Robin; Tsokos, Maria G.; Tsokos, George C.] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Dept Med, 330 Brookline Ave,CLS-937, Boston, MA 02215 USA. [Geha, Mayya] Harvard Med Sch, Massachusetts Gen Hosp, Dept Pediat, Boston, MA 02115 USA. [Shi, Guo-Ping] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Shi, Guo-Ping] Harvard Med Sch, Boston, MA 02115 USA. [Lucca, Jurandir J. Dalle] Def Threat Reduct Agcy, Dept Chem & Biol Technol, Translat Med Div, Ft Belvoir, VA 22060 USA. RP Tsokos, GC (reprint author), Harvard Med Sch, Beth Israel Deaconess Med Ctr, Dept Med, 330 Brookline Ave,CLS-937, Boston, MA 02215 USA. EM gtsokos@bidmc.harvard.edu FU U.S. Department of the Army Medical Research and Materiel Command [W81XWH-09-1-0530, W81XWH-09-1-0536] FX This work was supported by U.S. Department of the Army Medical Research and Materiel Command Grants W81XWH-09-1-0530 and W81XWH-09-1-0536. NR 39 TC 0 Z9 0 U1 2 U2 2 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD JAN 15 PY 2017 VL 198 IS 2 BP 788 EP 797 DI 10.4049/jimmunol.1502287 PG 10 WC Immunology SC Immunology GA EI3PZ UT WOS:000392405000028 PM 27913632 ER PT J AU Rodriguez, RM Suarez-Alvarez, B Lavin, JL Mosen-Ansorena, D Raneros, AB Marquez-Kisinousky, L Aransay, AM Lopez-Larrea, C AF Rodriguez, Ramon M. Suarez-Alvarez, Beatriz Lavin, Jose L. Mosen-Ansorena, David Baragano Raneros, Aroa Marquez-Kisinousky, Leonardo Aransay, Ana M. Lopez-Larrea, Carlos TI Epigenetic Networks Regulate the Transcriptional Program in Memory and Terminally Differentiated CD8(+) T Cells SO JOURNAL OF IMMUNOLOGY LA English DT Article ID GLOBAL DNA METHYLATION; HISTONE ACETYLATION; VIRAL-INFECTION; GENE-EXPRESSION; FACTOR-I; EFFECTOR; PROMOTES; ANTIGEN; ROBUST; BET AB Epigenetic mechanisms play a critical role during differentiation of T cells by contributing to the formation of stable and heritable transcriptional patterns. To better understand the mechanisms of memory maintenance in CD8(+) T cells, we performed genome-wide analysis of DNA methylation, histone marking (acetylated lysine 9 in histone H3 and trimethylated lysine 9 in histone), and gene-expression profiles in naive, effector memory (EM), and terminally differentiated EM (TEMRA) cells. Our results indicate that DNA demethylation and histone acetylation are coordinated to generate the transcriptional program associated with memory cells. Conversely, EM and TEMRA cells share a very similar epigenetic landscape. Nonetheless, the TEMRA transcriptional program predicts an innate immunity phenotype associated with genes never reported in these cells, including several mediators of NK cell activation (VAV3 and LYN) and a large array of NK receptors (e.g., KIR2DL3, KIR2DL4, KIR2DL1, KIR3DL1, KIR2DS5). In addition, we identified up to 161 genes that encode transcriptional regulators, some of unknown function in CD8(+) T cells, and that were differentially expressed in the course of differentiation. Overall, these results provide new insights into the regulatory networks involved in memory CD8(+) T cell maintenance and T cell terminal differentiation. C1 [Rodriguez, Ramon M.; Suarez-Alvarez, Beatriz; Baragano Raneros, Aroa; Marquez-Kisinousky, Leonardo; Lopez-Larrea, Carlos] Cent Univ Hosp Asturias, Dept Immunol, Oviedo 33011, Spain. [Lavin, Jose L.; Aransay, Ana M.] CIC bioGUNE, Genome Anal Platform, Derio 48160, Spain. [Lavin, Jose L.; Aransay, Ana M.] CIBERehd Technol Pk Bizkaia, Derio 48160, Spain. [Mosen-Ansorena, David] Dana Farber Canc Inst, Biostat & Computat Biol, Boston, MA 02215 USA. [Mosen-Ansorena, David] Harvard Sch Publ Hlth, Boston, MA 02215 USA. [Lopez-Larrea, Carlos] Fdn Renal Inigo Alvarez Toledo, Madrid 28003, Spain. RP Lopez-Larrea, C (reprint author), Cent Univ Hosp Asturias, Dept Immunol, Oviedo 33011, Spain. EM inmuno@hca.es OI Lavin, Jose Luis/0000-0003-0914-3211 FU Plan Nacional de I+D+I; European Union Fondos Feder, Instituto de Salud Carlos III [PI12/02587, PI16/01318]; Red Espanola de Investigacion Renal [RD12/0021/0018, RD12/0021/0021, RD16/0009/0020]; Plan de Ciencia, Tecnologia e Innovacion del Principado de Asturias [GRUPIN-14-030]; Department of Industry, Tourism and Trade of the Government of the Autonomous Community of the Basque Country (Etortek Research Programs); Innovation Technology Department of Bizkaia County; CIBER (Biomedical Research Networking Centre) program at Instituto de Salud Carlos III FX This work was supported by the Plan Nacional de I+D+I 2008-2011 and the European Union Fondos Feder, Instituto de Salud Carlos III (Grants PI12/02587 and PI16/01318), Red Espanola de Investigacion Renal (Grants RD12/0021/0018, RD12/0021/0021, and RD16/0009/0020), and Plan de Ciencia, Tecnologia e Innovacion 2013-2017 del Principado de Asturias (GRUPIN-14-030). CIC bioGUNE support was provided by The Department of Industry, Tourism and Trade of the Government of the Autonomous Community of the Basque Country (Etortek Research Programs 2007-2015), the Innovation Technology Department of Bizkaia County, and the CIBER (Biomedical Research Networking Centre) program at Instituto de Salud Carlos III. NR 46 TC 0 Z9 0 U1 4 U2 4 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD JAN 15 PY 2017 VL 198 IS 2 BP 937 EP 949 DI 10.4049/jimmunol.1601102 PG 13 WC Immunology SC Immunology GA EI3PZ UT WOS:000392405000042 PM 27974453 ER PT J AU Ling, ITC Rochard, L Liao, EC AF Ling, Irving T. C. Rochard, Lucie Liao, Eric C. TI Distinct requirements of wls, wnt9a, wnt5b and gpc4 in regulating chondrocyte maturation and timing of endochondral ossification SO DEVELOPMENTAL BIOLOGY LA English DT Article DE Wnt; Chondrocyte; Osteoblast; Zebrafish; Meckel's cartilage; Endochondral ossification ID ZEBRAFISH CRANIOFACIAL DEVELOPMENT; SYNOVIAL JOINT FORMATION; INDIAN-HEDGEHOG; CARTILAGE MORPHOGENESIS; SKELETAL MORPHOGENESIS; CONVERGENT EXTENSION; CELL-PROLIFERATION; MUSCLE-CONTRACTION; MECKELS CARTILAGE; BONE-FORMATION AB Formation of the mandible requires progressive morphologic change, proliferation, differentiation and organization of chondrocytes preceding osteogenesis. The Wnt signaling pathway is involved in regulating bone development and maintenance. Chondrocytes that are fated to become bone require Wnt to polarize and orientate appropriately to initiate the endochondral ossification program. Although the canonical Wnt signaling has been well studied in the context of bone development, the effects of non-canonical Wnt signaling in regulating the timing of cartilage maturation and subsequent bone formation in shaping ventral craniofacial structure is not fully understood.. Here we examined the role of the non-canonical Wnt signaling pathway (wls, gpc4, wnt5b and wnt9a) in regulating zebrafish Meckel's cartilage maturation to the onset of osteogenic differentiation. We found that disruption of wls resulted in a significant loss of craniofacial bone, whereas lack of gpc4, wnt5b and wnt9a resulted in severely delayed endochondral ossification. This study demonstrates the importance of the non canonical Wnt pathway in regulating coordinated ventral cartilage morphogenesis and ossification. C1 [Ling, Irving T. C.; Rochard, Lucie; Liao, Eric C.] Harvard Med Sch, Shriners Hosp Children, Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA. [Liao, Eric C.] Massachusetts Gen Hosp, Div Plast & Reconstruct Surg, Boston, MA 02114 USA. [Ling, Irving T. C.] Univ Glasgow, Sch Med Vet & Life Sci, Glasgow G12 8QQ, Lanark, Scotland. RP Liao, EC (reprint author), Harvard Med Sch, Shriners Hosp Children, Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA. EM cliao@partners.org FU National Institute of Dental and Craniofacial Research Grant [R03DE024490]; Shriners Hospital for Children FX This work was supported by National Institute of Dental and Craniofacial Research Grant R03DE024490 and by a grant from Shriners Hospital for Children to ECL. NR 72 TC 0 Z9 0 U1 3 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 EI 1095-564X J9 DEV BIOL JI Dev. Biol. PD JAN 15 PY 2017 VL 421 IS 2 BP 219 EP 232 DI 10.1016/j.ydbio.2016.11.016 PG 14 WC Developmental Biology SC Developmental Biology GA EH6UM UT WOS:000391909400015 PM 27908786 ER PT J AU Wojtowicz, M Iverson, GL Silverberg, ND Mannix, R Zafonte, R Maxwell, B Berkner, PD AF Wojtowicz, Magdalena Iverson, Grant L. Silverberg, Noah D. Mannix, Rebekah Zafonte, Ross Maxwell, Bruce Berkner, Paul D. TI Consistency of Self-Reported Concussion History in Adolescent Athletes SO JOURNAL OF NEUROTRAUMA LA English DT Article DE assessment tools; head trauma; pediatric brain injury ID SPORT-RELATED CONCUSSIONS; STATES HIGH-SCHOOL; YOUTH ICE HOCKEY; FOOTBALL PLAYERS; NEUROCOGNITIVE PERFORMANCE; SYMPTOMS; MANAGEMENT; EPIDEMIOLOGY; DIAGNOSIS; CHILDREN AB Relying on self-reported concussion injury history is common in both clinical care and research. However, young athletes may not provide consistent medical information. To date, little is known about the reliability of self-reported concussion history in high school students. This study examined whether student athletes reported their lifetime history of concussions consistently over time. Self-reported concussion history was examined in 4792 student athletes (ages 13-18) from Maine who completed a preseason health survey on two occasions (median re-test interval = 23.7 months; standard deviation = 7.3; interquartile range = 12.4-24.5). Consistency of self-reported concussion history was determined by differences in the number of concussions reported during the second survey. Inconsistent concussion history was defined primarily by a decrease in the number of lifetime concussions reported at the second testing, compared with at the first testing. The majority of the sample (80.3%) reported no change in the number of concussions between the two baseline assessments. A minority (15.9%; n = 763) reported more concussions during the second assessment. Only 3.8% (n = 181) of student athletes provided inconsistent concussion histories, defined as fewer concussions at the second assessment. Boys provided inconsistent concussion histories a little more frequently, compared with girls (5.3% and 2.0%, respectively; p < 0.001). Similarly, athletes with self-reported attention-deficit hyperactivity disorder (ADHD) provided inconsistent concussion histories somewhat more frequently, compared with those without ADHD (7.8% and 3.5%, respectively; p < 0.001). Of the athletes with inconsistent concussion histories, greater degree of inconsistency was associated with a greater number of concussions initially reported at baseline (r(s) = 0.54; p < 0.001). Only a small proportion of student athletes provided inconsistent concussion histories. Male gender, ADHD, and greater number of baseline concussions were significantly associated with inconsistency in reporting. Overall, these findings suggest that student athletes are quite consistent when reporting their concussion history when surveyed twice during high school. C1 [Wojtowicz, Magdalena] Harvard Med Sch, Dept Psychiat, Boston, MA USA. [Wojtowicz, Magdalena; Iverson, Grant L.; Zafonte, Ross] Harvard Med Sch, Dept Phys Med & Rehabil, 101 Merrimac 250, Boston, MA 02124 USA. [Wojtowicz, Magdalena; Iverson, Grant L.; Zafonte, Ross] MassGeneral Hosp Children Sports Concuss Program, Boston, MA USA. [Wojtowicz, Magdalena; Iverson, Grant L.; Silverberg, Noah D.; Zafonte, Ross] Red Sox Fdn, Boston, MA USA. [Wojtowicz, Magdalena; Iverson, Grant L.; Silverberg, Noah D.; Zafonte, Ross] Massachusetts Gen Hosp Home Base Program, Boston, MA USA. [Iverson, Grant L.; Silverberg, Noah D.; Zafonte, Ross] Spaulding Rehabil Hosp, Dept Phys Med & Rehabil, Boston, MA USA. [Silverberg, Noah D.] Univ British Columbia, Div Phys Med & Rehabil, Vancouver, BC, Canada. [Silverberg, Noah D.] GF Strong Rehabil Ctr, Vancouver, BC, Canada. [Mannix, Rebekah] Boston Childrens Hosp, Div Emergency Med, Boston, MA USA. [Zafonte, Ross] Massachusetts Gen Hosp, Dept Phys Med & Rehabil, Boston, MA 02114 USA. [Zafonte, Ross] Brigham & Womens Hosp, Dept Phys Med & Rehabil, 75 Francis St, Boston, MA 02115 USA. [Maxwell, Bruce] Colby Coll, Dept Comp Sci, Waterville, ME 04901 USA. [Berkner, Paul D.] Colby Coll, Hlth Serv, Waterville, ME 04901 USA. [Berkner, Paul D.] Colby Coll, Dept Biol, Waterville, ME 04901 USA. RP Wojtowicz, M (reprint author), Harvard Med Sch, Dept Phys Med & Rehabil, 101 Merrimac 250, Boston, MA 02124 USA. EM mwojtowicz@mgh.harvard.edu FU Goldfarb Center for Public Policy and Civic Engagement/Colby College; Bill and Joan Alfond Foundation; NICHD [T32 HD40128-11A1]; Harvard Integrated Program to Protect and Improve the Health of National Football League Players Association Members; Mooney-Reed Charitable Foundation FX Funding source: Goldfarb Center for Public Policy and Civic Engagement/Colby College and the Bill and Joan Alfond Foundation. RM is funded by NICHD T32 HD40128-11A1. RZ was supported in part by the Harvard Integrated Program to Protect and Improve the Health of National Football League Players Association Members. The research program at MassGeneral Hospital for Children Sport Concussion Program acknowledges funding support from the Mooney-Reed Charitable Foundation. NR 30 TC 0 Z9 0 U1 18 U2 18 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0897-7151 EI 1557-9042 J9 J NEUROTRAUM JI J. Neurotrauma PD JAN 15 PY 2017 VL 34 IS 2 BP 322 EP 327 DI 10.1089/neu.2016.4412 PG 6 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA EH4QD UT WOS:000391754800007 PM 27349296 ER PT J AU Montenigro, PH Alosco, ML Martin, BM Daneshvar, DH Mez, J Chaisson, CE Nowinski, CJ Au, R Mckee, AC Cantu, RC McClean, MD Stern, RA Tripodis, Y AF Montenigro, Philip H. Alosco, Michael L. Martin, Brett M. Daneshvar, Daniel H. Mez, Jesse Chaisson, Christine E. Nowinski, Christopher J. Au, Rhoda Mckee, Ann C. Cantu, Robert C. McClean, Michael D. Stern, Robert A. Tripodis, Yorghos TI Cumulative Head Impact Exposure Predicts Later-Life Depression, Apathy, Executive Dysfunction, and Cognitive Impairment in Former High School and College Football Players SO JOURNAL OF NEUROTRAUMA LA English DT Article DE behavior; cognition; concussion; football; long-term impairment; subconcussive impacts ID CHRONIC TRAUMATIC ENCEPHALOPATHY; INSTRUMENTAL VARIABLE ANALYSIS; BEHAVIOR RATING INVENTORY; SPORT-RELATED CONCUSSION; FIGHTERS BRAIN HEALTH; RECURRENT CONCUSSION; LONG-TERM; AMERICAN FOOTBALL; EVALUATION SCALE; ADULT COGNITION AB The term "repetitive head impacts'' (RHI) refers to the cumulative exposure to concussive and subconcussive events. Although RHI are believed to increase risk for later-life neurological consequences (including chronic traumatic encephalopathy), quantitative analysis of this relationship has not yet been examined because of the lack of validated tools to quantify lifetime RHI exposure. The objectives of this study were: 1) to develop a metric to quantify cumulative RHI exposure from football, which we term the "cumulative head impact index'' (CHII); 2) to use the CHII to examine the association between RHI exposure and long-term clinical outcomes; and 3) to evaluate its predictive properties relative to other exposure metrics (i.e., duration of play, age of first exposure, concussion history). Participants included 93 former high school and collegiate football players who completed objective cognitive and self-reported behavioral/mood tests as part of a larger ongoing longitudinal study. Using established cutoff scores, we transformed continuous outcomes into dichotomous variables (normal vs. impaired). The CHII was computed for each participant and derived from a combination of self-reported athletic history (i.e., number of seasons, position[s], levels played), and impact frequencies reported in helmet accelerometer studies. A bivariate probit, instrumental variable model revealed a threshold dose-response relationship between the CHII and risk for later-life cognitive impairment (p < 0.0001), self-reported executive dysfunction (p < 0.0001), depression (p < 0.0001), apathy (p = 0.0161), and behavioral dysregulation (p < 0.0001). Ultimately, the CHII demonstrated greater predictive validity than other individual exposure metrics. C1 [Montenigro, Philip H.; Alosco, Michael L.; Daneshvar, Daniel H.; Mez, Jesse; Chaisson, Christine E.; Nowinski, Christopher J.; Mckee, Ann C.; Cantu, Robert C.; Stern, Robert A.; Tripodis, Yorghos] Boston Univ, Sch Med, Alzheimers Dis & CTE Ctr, Boston, MA 02118 USA. [Montenigro, Philip H.; Stern, Robert A.] Boston Univ, Sch Med, Dept Anat & Neurobiol, Boston, MA 02118 USA. [Mez, Jesse; Au, Rhoda; Mckee, Ann C.; Stern, Robert A.] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Au, Rhoda] Boston Univ, Sch Med, Framingham Heart Study, Boston, MA 02118 USA. [Mckee, Ann C.] Boston Univ, Sch Med, Dept Pathol, Boston, MA 02118 USA. [Cantu, Robert C.; Stern, Robert A.] Boston Univ, Sch Med, Dept Neurosurg, Boston, MA 02118 USA. [Martin, Brett M.; Chaisson, Christine E.] Boston Univ, Sch Publ Hlth, Data Coordinating Ctr, Boston, MA USA. [Chaisson, Christine E.; Tripodis, Yorghos] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [McClean, Michael D.] Boston Univ, Sch Publ Hlth, Dept Environm Hlth, Boston, MA USA. [Nowinski, Christopher J.; Cantu, Robert C.] Concuss Legacy Fdn, Waltham, MA USA. [Mckee, Ann C.] VA Boston Healthcare Syst, Boston, MA USA. [Cantu, Robert C.] Emerson Hosp, Dept Neurosurg, Concord, MA USA. RP Stern, RA (reprint author), 72 E Concord St,Suite B7800, Boston, MA 02118 USA. EM bobstern@bu.edu FU Concussion Legacy Foundation; National Institutes of Health (NIH) [U01NS093334]; Boston University School of Medicine Medical Student Summer Research Program Scholarship; Graduate Medical Sciences Student Organization Community Service Award; [T32-AG06697] FX This study was funded in part by a grant from the Concussion Legacy Foundation, as well as National Institutes of Health (NIH) grant U01NS093334. Dr. Montenigro received partial support for this study from a Boston University School of Medicine Medical Student Summer Research Program Scholarship and from a Graduate Medical Sciences Student Organization Community Service Award. Dr. Alosco is supported by the T32-AG06697 post-doctoral fellowship. The authors thank the following individuals: Sarah Fairfield, Dr. Brandon Gavett, Kaitlin Perry, David Riley, Clifford Robbins, and members of the Boston University Alzheimer's Disease and CTE Center. The authors also extend their gratitude and appreciation to all the participants who made this study possible. NR 119 TC 2 Z9 2 U1 31 U2 31 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0897-7151 EI 1557-9042 J9 J NEUROTRAUM JI J. Neurotrauma PD JAN 15 PY 2017 VL 34 IS 2 BP 328 EP + DI 10.1089/neu.2016.4413 PG 14 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA EH4QD UT WOS:000391754800008 PM 27029716 ER PT J AU Silverberg, ND Crane, PK Dams-O'Connor, K Holdnack, J Ivins, BJ Lange, RT Manley, GT McCrea, M Iverson, GL AF Silverberg, Noah D. Crane, Paul K. Dams-O'Connor, Kristen Holdnack, James Ivins, Brian J. Lange, Rael T. Manley, Geoffrey T. McCrea, Michael Iverson, Grant L. TI Developing a Cognition Endpoint for Traumatic Brain Injury Clinical Trials SO JOURNAL OF NEUROTRAUMA LA English DT Article DE clinical trials; cognition; craniocerebral trauma; neuropsychological tests; outcome assessment; psychometrics ID NEUROPSYCHOLOGICAL TEST-PERFORMANCE; NEUROIMAGING INITIATIVE ADNI; PATIENT-REPORTED OUTCOMES; MINOR HEAD-INJURY; PREDICTIVE-VALIDITY; RANDOMIZED-TRIAL; COMPOSITE SCORE; NIH TOOLBOX; MILD; REHABILITATION AB Cognitive impairment is a core clinical feature of traumatic brain injury (TBI). After TBI, cognition is a key determinant of post-injury productivity, outcome, and quality of life. As a final common pathway of diverse molecular and microstructural TBI mechanisms, cognition is an ideal endpoint in clinical trials involving many candidate drugs and nonpharmacological interventions. Cognition can be reliably measured with performance-based neuropsychological tests that have greater granularity than crude rating scales, such as the Glasgow Outcome Scale-Extended, which remain the standard for clinical trials. Remarkably, however, there is no well-defined, widely accepted, and validated cognition endpoint for TBI clinical trials. A single cognition endpoint that has excellent measurement precision across a wide functional range and is sensitive to the detection of small improvements (and declines) in cognitive functioning would enhance the power and precision of TBI clinical trials and accelerate drug development research. We outline methodologies for deriving a cognition composite score and a research program for validation. Finally, we discuss regulatory issues and the limitations of a cognition endpoint. C1 [Silverberg, Noah D.] Univ British Columbia, Div Phys Med & Rehabil, Dept Med, Vancouver, BC, Canada. [Silverberg, Noah D.] GF Strong Rehab Ctr, Vancouver, BC, Canada. [Silverberg, Noah D.] Harvard Med Sch, Dept Phys Med & Rehabil, Boston, MA USA. [Silverberg, Noah D.; Iverson, Grant L.] Red Sox Fdn, Boston, MA USA. [Silverberg, Noah D.; Iverson, Grant L.] Massachusetts Gen Hosp, Home Base Program, Boston, MA 02114 USA. [Crane, Paul K.] Univ Washington, Dept Med, Seattle, WA USA. [Dams-O'Connor, Kristen] Icahn Sch Med Mt Sinai, Dept Rehabil Med, New York, NY 10029 USA. [Holdnack, James] Univ Delaware, Dept Phys Therapy, Newark, DE USA. [Ivins, Brian J.] DVBIC, Silver Spring, MD USA. [Lange, Rael T.] Walter Reed Natl Mil Med Ctr, DVBIC, Bethesda, MD USA. [Lange, Rael T.] Natl Intrepid Ctr Excellence, Bethesda, MD USA. [Manley, Geoffrey T.] Univ Calif San Francisco, Dept Neurol Surg, San Francisco, CA USA. [McCrea, Michael] Med Coll Wisconsin, Dept Neurosurg, Milwaukee, WI 53226 USA. [Iverson, Grant L.] Harvard Med Sch, Spaulding Rehabil Hosp, MassGen Hosp Children, Sports Concuss Program,Dept Phys Med & Rehabil, Boston, MA USA. [Iverson, Grant L.] Natl Intrepid Ctr Excellence, Def & Vet Brain Injury Ctr, Bethesda, MD USA. RP Silverberg, ND (reprint author), Rehabil Res Program, 4255 Laurel St, Vancouver, BC V5Z 2G9, Canada. EM noah.silverberg@vch.ca FU Vancouver Coastal Health Research Institute Clinician-Scientist Career Development Award; INTRuST Posttraumatic Stress Disorder and Traumatic Brain Injury Clinical Consortium - Department of Defense Psychological Health/Traumatic Brain Injury Research Program [X81XWH-07-CC-CSDoD]; Harvard Integrated Program to Protect and Improve the Health of NFLPA Members; Mooney-Reed Charitable Foundation; NIH [U01 NS086090-01]; DOD USAMRAA [W81XWH-13-1-0441]; DOD [W81XWH-14-2-0176]; One Mind FX NDS receives salary support from a Vancouver Coastal Health Research Institute Clinician-Scientist Career Development Award. GLI acknowledges support from the INTRuST Posttraumatic Stress Disorder and Traumatic Brain Injury Clinical Consortium funded by the Department of Defense Psychological Health/Traumatic Brain Injury Research Program (X81XWH-07-CC-CSDoD), Harvard Integrated Program to Protect and Improve the Health of NFLPA Members, and the Mooney-Reed Charitable Foundation. GTM acknowledges support from NIH U01 NS086090-01, DOD USAMRAA W81XWH-13-1-0441, DOD W81XWH-14-2-0176, and One Mind. This work is related to the TBI Endpoints Development Initiative and a grant entitled Development and Validation of a Cognition Endpoint for Traumatic Brain Injury Clinical Trials. NR 92 TC 2 Z9 2 U1 6 U2 6 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0897-7151 EI 1557-9042 J9 J NEUROTRAUM JI J. Neurotrauma PD JAN 15 PY 2017 VL 34 IS 2 BP 363 EP 371 DI 10.1089/neu.2016.4443 PG 9 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA EH4QD UT WOS:000391754800011 PM 27188248 ER PT J AU Harmon, JL Gibbs, WS Whitaker, RM Schnellmann, RG Adkins, DL AF Harmon, Jennifer L. Gibbs, Whitney S. Whitaker, Ryan M. Schnellmann, Rick G. Adkins, DeAnna L. TI Striatal Mitochondrial Disruption following Severe Traumatic Brain Injury SO JOURNAL OF NEUROTRAUMA LA English DT Article DE controlled cortical impact; mitochondria; oxidative stress; traumatic brain injury ID INFLAMMATION; MICRORNA-21; DYSFUNCTION; BIOGENESIS; CORTEX; DAMAGE; RAT; HIPPOCAMPUS; CIRCUIT; IMPACT AB Traumatic brain injury (TBI) results in oxidative stress and calcium dysregulation in mitochondria. However, little work has examined perturbations of mitochondrial homeostasis in peri-injury tissue. We examined mitochondrial homeostasis after a unilateral controlled cortical impact over the sensorimotor cortex in adult male rats. There was a significant reduction in peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1 alpha) messenger RNA (mRNA) at post-injury days 3 and 6 and a transient reduction in mitochondrial DNA copy number at 3 days post-injury that recovered by 6 days in the ipsi-injury striatum. In ipsilateral cortex, PGC-1a mRNA was reduced only at 6 days post-injury. Additionally, expression of mitochondrial-encoded mRNAs, cytochrome c oxidase subunit 1 and NADH dehydrogenase subunit 1, was decreased at 3 and 6 days post-injury in ipsilesional striatum and at 6 days post-injury in ipsilesional cortex. There was no observable decrease in nuclear-encoded mRNAs mitochondrial transcription factor A or NADH dehydrogenase (ubiquinone) Fe-S protein 1. We detected an acute increase in superoxide dismutase 2 mRNA expression, as well as an induction of microRNA (miR)-21 and miR-155, which have been previously demonstrated to disrupt mitochondrial homeostasis. Behaviorally, rats with TBI exhibited marked error rates in contrainjury forelimb performance on the ladder test. These findings reveal that there may be differential susceptibilities of various peri-injury brain structures to mitochondrial dysfunction and associated behavioral deficits, and that molecular pathways demonstrated to interfere with mitochondrial homeostasis and function are activated subacutely post-TBI. C1 [Harmon, Jennifer L.; Gibbs, Whitney S.; Whitaker, Ryan M.; Schnellmann, Rick G.] Med Univ South Carolina, Dept Drug Discovery & Biomed Sci, Charleston, SC 29425 USA. [Schnellmann, Rick G.] Ralph H Johnson Vet Adm Med Ctr, Charleston, SC USA. [Adkins, DeAnna L.] Med Univ South Carolina, Dept Neurosci, 173 Ashley Ave,404D MSC510, Charleston, SC 29425 USA. [Adkins, DeAnna L.] Med Univ South Carolina, Dept Hlth Sci & Res, Charleston, SC 29425 USA. [Adkins, DeAnna L.] Med Univ South Carolina, Ctr Biomed Imaging, Charleston, SC 29425 USA. RP Adkins, DL (reprint author), Med Univ South Carolina, Dept Neurosci, 173 Ashley Ave,404D MSC510, Charleston, SC 29425 USA. EM adkinsdl@musc.edu FU National Institute of Neurological Disorders and Stroke [R01 NS065866]; National Institute of Diabetes and Digestive and Kidney Diseases [F30 DK091107, T32 DK083262]; National Institute of General Medical Sciences [GM084147, P20GM103542]; National Center for Research Resources [UL1-RR029882, C06-RR015455]; Biomedical Laboratory Research and Development Program of the Department of Veterans Affairs [5I01 BX-000851]; South Carolina Clinical and Translational Research Institute at the Medical University of South Carolina FX This work was supported, in part, by the National Institute of Neurological Disorders and Stroke (R01 NS065866; to D.L.A.), National Institute of Diabetes and Digestive and Kidney Diseases (F30 DK091107 and T32 DK083262; to J.L.H.), and National Institute of General Medical Sciences (GM084147 [to R.G.S.] and P20GM103542 [to South Carolina COBRE in Oxidants, Redox Balance, and Stress Signaling]); National Center for Research Resources (UL1-RR029882); the Biomedical Laboratory Research and Development Program of the Department of Veterans Affairs (5I01 BX-000851; to R.G.S.); and the South Carolina Clinical and Translational Research Institute at the Medical University of South Carolina. Animal facilities were funded by the National Center for Research Resources (C06-RR015455). NR 38 TC 0 Z9 0 U1 2 U2 2 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0897-7151 EI 1557-9042 J9 J NEUROTRAUM JI J. Neurotrauma PD JAN 15 PY 2017 VL 34 IS 2 BP 487 EP + DI 10.1089/neu.2015.4395 PG 9 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA EH4QD UT WOS:000391754800024 PM 27321815 ER PT J AU Duval, T Levy, S Stikov, N Campbell, J Mezer, A Witzel, T Keil, B Smith, V Wald, LL Klawiter, E Cohen-Adad, J AF Duval, T. Levy, S. Stikov, N. Campbell, J. Mezer, A. Witzel, T. Keil, B. Smith, V. Wald, L. L. Klawiter, E. Cohen-Adad, J. TI g-Ratio weighted imaging of the human spinal cord in vivo SO NEUROIMAGE LA English DT Article DE g-Ratio; MRI; Diffusion; Axcaliber; Myelin mapping; Spinal cord ID NEURITE ORIENTATION DISPERSION; AXON DIAMETER DISTRIBUTION; TIME-DEPENDENT DIFFUSION; HUMAN WHITE-MATTER; MYELIN G-RATIO; MULTIPLE-SCLEROSIS; MAGNETIC-RESONANCE; RADIOFREQUENCY FIELD; HUMAN BRAIN; 300 MT/M AB The fiber g-ratio is defined as the ratio of the inner to the outer diameter of the myelin sheath. This ratio provides a measure of the myelin thickness that complements axon morphology (diameter and density) for assessment of demyelination in diseases such as multiple sclerosis. Previous work has shown that an aggregate g-ratio map can be computed using a formula that combines axon and myelin density measured with quantitative MM. In this work, we computed g-ratio weighted maps in the cervical spinal cord of nine healthy subjects. We utilized the 300 mT/m gradients from the CONNECTOM scanner to estimate the fraction of restricted water (fr) with high accuracy, using the CHARMED model. Myelin density was estimated using the lipid and macromolecular tissue volume (MTV) method, derived from normalized proton density (PD) mapping. The variability across spinal level, laterality and subject were assessed using a three-way ANOVA. The average g-ratio value obtained in the white matter was 0.76+/-0.03, consistent with previous histology work. Coefficients of variation of fr and MTV were respectively 4.3% and 13.7%. fr and myelin density were significantly different across spinal tracts (p=3x10(-7) and 0.004 respectively) and were positively correlated in the white matter (r=0.42), suggesting shared microstructural information. The aggregate g-ratio did not show significant differences across tracts (p=0.6). This study suggests that fr and myelin density can be measured in vivo with high precision and that they can be combined to produce a g-ratio-weighted map robust to free water pool contamination from cerebrospinal fluid or veins. Potential applications include the study of early demyelination in multiple sclerosis, and the quantitative assessment of remyelination drugs. C1 [Duval, T.; Levy, S.; Stikov, N.; Cohen-Adad, J.] Polytech Montreal, NeuroPoly Lab, Inst Biomed Engn, Montreal, PQ, Canada. [Stikov, N.] Montreal Heart Inst, Montreal, PQ, Canada. [Campbell, J.] McGill Univ, Montreal Neurol Inst, Montreal, PQ, Canada. [Mezer, A.] Hebrew Univ Jerusalem, Edmond & Lily Safra Ctr Brain Sci ELSC, Jerusalem, Israel. [Witzel, T.; Keil, B.; Smith, V.; Wald, L. L.; Klawiter, E.] Harvard Med Sch, Massachusetts Gen Hosp, AA Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Cohen-Adad, J.] Univ Montreal, Funct Neuroimaging Unit, CRIUGM, Montreal, PQ, Canada. RP Cohen-Adad, J (reprint author), Polytech Montreal, Inst Biomed Engn, 2900 Edouard Montpetit Blvd, Montreal, PQ H3T 1J4, Canada. EM jcohen@polymtl.ca FU NIH Blueprint Initiative for Neuroscience Research Grant [U01MH093765]; National Institutes of Health [P41EB015896] FX We would like to thank the participants of this study and M. Brun-Cosme-Bruny and M. De Leener for their help with the processing of the data. We also thank the anonymous reviewers for their valuable comments. This study was founded by the National Institutes of Health, the NIH Blueprint Initiative for Neuroscience Research Grant U01MH093765, the National Institutes of Health Grant P41EB015896, the MS Society of Canada [EGID 2370], the Canada Research Chair in Quantitative Magnetic Resonance Imaging (JCA), the Canadian Institute of Health Research [CIHR FDN-143263], the Fonds de Recherche du Quebec - Sante [28826], the Fonds de Recherche du Quebec - Nature et Technologies [2015-PR-182754], the Natural Sciences and Engineering Research Council of Canada [435897-2013] [2016-06774] and the Quebec BioImaging Network. NR 97 TC 2 Z9 2 U1 9 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 JAN 15 PY 2017 VL 145 BP 11 EP 23 DI 10.1016/j.neuroimage.2016.09.018 PN A PG 13 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA EG7QF UT WOS:000391243200002 PM 27664830 ER PT J AU Thompson, PM Andreassen, OA Arias-Vasquez, A Bearden, CE Boedhoe, PS Brouwer, RM Buckner, RL Buitelaar, JK Bulayeva, KB Cannon, DM Cohen, RA Conrod, PJ Dale, AM Deary, IJ Dennis, EL de Reus, MA Desrivieres, S Dima, D Donohoe, G Fisher, SE Fouche, JP Francks, C Frangou, S Franke, B Ganjgahi, H Garavan, H Glahn, DC Grabe, HJ Guadalupe, T Gutman, BA Hashimoto, R Hibar, DP Holland, D Hoogman, M Pol, HEH Hosten, N Jahanshad, N Kelly, S Kochunov, P Kremen, WS Lee, PH Mackey, S Martin, NG Mazoyer, B McDonald, C Medland, SE Morey, RA Nichols, TE Paus, T Pausova, Z Schmaal, L Schumann, G Shen, L Sisodiya, SM Smit, DJA Smoller, JW Stein, DJ Stein, JL Toro, R Turner, JA van den Heuvel, MP van den Heuvel, OL van Erp, TGM van Rooij, D Veltman, DJ Walter, H Wang, YL Wardlaw, JM Whelan, CD Wright, MJ Ye, JP AF Thompson, Paul M. Andreassen, Ole A. Arias-Vasquez, Alejandro Bearden, Carrie E. Boedhoe, Premika S. Brouwer, Rachel M. Buckner, Randy L. Buitelaar, Jan K. Bulayeva, Kazima B. Cannon, Dara M. Cohen, Ronald A. Conrod, Patricia J. Dale, Anders M. Deary, Ian J. Dennis, Emily L. de Reus, Marcel A. Desrivieres, Sylvane Dima, Danai Donohoe, Gary Fisher, Simon E. Fouche, Jean-Paul Francks, Clyde Frangou, Sophia Franke, Barbara Ganjgahi, Habib Garavan, Hugh Glahn, David C. Grabe, Hans J. Guadalupe, Tulio Gutman, Boris A. Hashimoto, Ryota Hibar, Derrek P. Holland, Dominic Hoogman, Martine Pol, Hilleke E. Hulshoff Hosten, Norbert Jahanshad, Neda Kelly, Sinead Kochunov, Peter Kremen, William S. Lee, Phil H. Mackey, Scott Martin, Nicholas G. Mazoyer, Bernard McDonald, Colm Medland, Sarah E. Morey, Rajendra A. Nichols, Thomas E. Paus, Tomas Pausova, Zdenka Schmaal, Lianne Schumann, Gunter Shen, Li Sisodiya, Sanjay M. Smit, Dirk J. A. Smoller, Jordan W. Stein, Dan J. Stein, Jason L. Toro, Roberto Turner, Jessica A. van den Heuvel, Martijn P. van den Heuvel, Odile L. van Erp, Theo G. M. van Rooij, Daan Veltman, Dick J. Walter, Henrik Wang, Yalin Wardlaw, Joanna M. Whelan, Christopher D. Wright, Margaret J. Ye, Jieping CA ENIGMA Consortium TI ENIGMA and the individual: Predicting factors that affect the brain in 35 countries worldwide SO NEUROIMAGE LA English DT Article ID GENOME-WIDE ASSOCIATION; 22Q11.2 DELETION SYNDROME; CORTICAL SURFACE-AREA; ALZHEIMERS-DISEASE; WHITE-MATTER; CHRONIC-SCHIZOPHRENIA; HERITABILITY ANALYSIS; GENETIC ASSOCIATIONS; SUSCEPTIBILITY LOCI; CANDIDATE GENES AB In this review, we discuss recent work by the ENIGMA Consortium (http://enigma.ini.usc.edu) - a global alliance of over 500 scientists spread across 200 institutions in 35 countries collectively analyzing brain imaging, clinical, and genetic data. Initially formed to detect genetic influences on brain measures, ENIGMA has grown to over 30 working groups studying 12 major brain diseases by pooling and comparing brain data. In some of the largest neuroimaging studies to date - of schizophrenia and major depression - ENIGMA has found replicable disease effects on the brain that are consistent worldwide, as well as factors that modulate disease effects. In partnership with other consortia including ADNI, CHARGE, IMAGEN and others(1), ENIGMA's genomic screens - now numbering over 30,000 MRI scans - have revealed at least 8 genetic loci that affect brain volumes. Downstream of gene findings, ENIGMA has revealed how these individual variants and genetic variants in general - may affect both the brain and risk for a range of diseases. The ENIGMA consortium is discovering factors that consistently affect brain structure and function that will serve as future predictors linking individual brain scans and genomic data. It is generating vast pools of normative data on brain measures - from tens of thousands of people - that may help detect deviations from normal development or aging in specific groups of subjects. We discuss challenges and opportunities in applying these predictors to individual subjects and new cohorts, as well as lessons we have learned in ENIGMA's efforts so far. (C) 2015 The Authors. Published by Elsevier Inc. C1 [Thompson, Paul M.; Dennis, Emily L.; Gutman, Boris A.; Hibar, Derrek P.; Jahanshad, Neda; Kelly, Sinead; Stein, Jason L.; Whelan, Christopher D.] Univ Southern Calif, Keck Sch Med, Mark & Mary Stevens Inst Neuroimaging & Informat, Imaging Genet Ctr, Marina Del Rey, CA 90292 USA. [Andreassen, Ole A.] Univ Oslo, Inst Clin Med, NORMENT KG Jebsen Ctr, N-0315 Oslo, Norway. [Andreassen, Ole A.] Oslo Univ Hosp, Div Mental Hlth & Addict, NORMENT KG Jebsen Ctr, N-0315 Oslo, Norway. [Arias-Vasquez, Alejandro] Radboud Univ Nijmegen, Med Ctr, Dept Psychiat, Donders Ctr Cognit Neurosci, NL-6525 Nijmegen, Netherlands. [Arias-Vasquez, Alejandro] Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, Donders Ctr Cognit Neurosci, NL-6525 Nijmegen, Netherlands. [Arias-Vasquez, Alejandro] Radboud Univ Nijmegen, Med Ctr, Dept Cognit Neurosci, Donders Ctr Cognit Neurosci, NL-6525 Nijmegen, Netherlands. [Bearden, Carrie E.] Univ Calif Los Angeles, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90095 USA. [Bearden, Carrie E.] Univ Calif Los Angeles, Dept Psychol, Los Angeles, CA 90095 USA. [Bearden, Carrie E.] Univ Calif Los Angeles, Brain Res Inst, Los Angeles, CA 90095 USA. [Boedhoe, Premika S.; van den Heuvel, Odile L.; Veltman, Dick J.] Vrije Univ Amsterdam, Med Ctr, Dept Anat & Neurosci, Amsterdam, Netherlands. [Brouwer, Rachel M.; de Reus, Marcel A.; Pol, Hilleke E. Hulshoff; van den Heuvel, Martijn P.] UMC Utrecht, Dept Psychiat, Brain Ctr Rudolf Magnus, NL-3584 CX Utrecht, Netherlands. [Buckner, Randy L.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Buitelaar, Jan K.; Fisher, Simon E.; Francks, Clyde; Franke, Barbara; Hoogman, Martine; van Rooij, Daan] Radboud Univ Nijmegen, Med Ctr, Donders Inst Brain Cognit & Behav, NL-6500 HB Nijmegen, Netherlands. [Buitelaar, Jan K.] Harvard Univ, Dept Psychol, Ctr Brain Sci, 33 Kirkland St, Cambridge, MA 02138 USA. [Bulayeva, Kazima B.] Russian Acad Sci, NI Vavilov Inst Gen Genet, Gubkin Str 3, Moscow 119991, Russia. [Cannon, Dara M.] NIMH, Intramural Res Program, Bethesda, MD 20892 USA. [Cannon, Dara M.; McDonald, Colm] Natl Univ Ireland Galway, Coll Med Nursing & Hlth Sci, NCBES Galway Neurosci Ctr, Neuroimaging & Cognit Genom Ctr NICOG,Clin Neuroi, Galway H91 TK33, Ireland. [Cohen, Ronald A.] Univ Florida, Inst Aging, Gainesville, FL 32611 USA. [Conrod, Patricia J.] Univ London, Kings Coll London, Sect Addict, Dept Psychol Med & Psychiat, London, England. [Dale, Anders M.; Holland, Dominic] Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA. [Dale, Anders M.; Holland, Dominic] Univ Calif San Diego, Dept Radiol, La Jolla, CA 92093 USA. [Dale, Anders M.; Holland, Dominic; Kremen, William S.] Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA. [Dale, Anders M.; Holland, Dominic] Univ Calif San Diego, Dept Cognit Sci, La Jolla, CA 92093 USA. [Thompson, Paul M.] Univ Calif San Diego, Dept Neurosci, San Diego, CA 92093 USA. [Thompson, Paul M.] Univ Calif San Diego, Dept Radiol, San Diego, CA 92093 USA. [Thompson, Paul M.] Univ Calif San Diego, Dept Psychiat, San Diego, CA 92093 USA. [Thompson, Paul M.] Univ Calif San Diego, Dept Cognit Sci, San Diego, CA 92093 USA. [Deary, Ian J.; Wardlaw, Joanna M.] Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol Psychol, Edinburgh EH8 9JZ, Midlothian, Scotland. [Desrivieres, Sylvane; Schumann, Gunter] Kings Coll London, Inst Psychiat, MRC SGDP Ctr, London SE5 8AF, England. [Dima, Danai] Kings Coll London, Inst Psychiat Psychol & Neurosci, London, England. [Dima, Danai; Frangou, Sophia] Icahn Sch Med Mt Sinai, Dept Psychiat, Clin Neurosci Studies CNS Ctr, New York, NY 10029 USA. [Donohoe, Gary] Natl Univ Ireland, Sch Psychol, Neuroimaging & Cognit Genom Ctr NICOG, Galway, Ireland. [Fisher, Simon E.; Francks, Clyde; Guadalupe, Tulio] Max Planck Inst Psycholinguist, Language & Genet Dept, NL-6525 XD Nijmegen, Netherlands. [Fouche, Jean-Paul; Stein, Dan J.] Univ Cape Town, Dept Psychiat & Mental Hlth, Cape Town, South Africa. [Franke, Barbara; Hoogman, Martine] Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, NL-6525 Nijmegen, Netherlands. [Franke, Barbara] Radboud Univ Nijmegen, Med Ctr, Dept Psychiat, NL-6525 Nijmegen, Netherlands. [Ganjgahi, Habib] Univ Warwick, Dept Stat, Coventry, W Midlands, England. [Garavan, Hugh; Mackey, Scott] Univ Vermont, Dept Psychiat, Burlington, VT 05401 USA. [Glahn, David C.] Yale Univ, Dept Psychiat, New Haven, CT 06511 USA. [Glahn, David C.] Olin Neuropsychiat Res Ctr, Hartford, CT 06114 USA. [Grabe, Hans J.] Univ Med Greifswald, Dept Psychiat, D-17489 Greifswald, Germany. [Grabe, Hans J.] HELIOS Hosp, Dept Psychiat & Psychotherapy, D-18435 Stralsund, Germany. [Guadalupe, Tulio] Int Max Planck Res Sch Language Sci, NL-6525 XD Nijmegen, Netherlands. [Hashimoto, Ryota] Osaka Univ, United Grad Sch Child Dev, Mol Res Ctr Childrens Mental Dev, Suita, Osaka, Japan. [Hosten, Norbert] Univ Med Greifswald, Dept Radiol, D-17475 Greifswald, Germany. [Kochunov, Peter] Univ Maryland, Sch Med, Dept Psychiat, Baltimore, MD 21201 USA. [Lee, Phil H.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Lee, Phil H.] Harvard Med Sch, Dept Psychiat, Boston, MA USA. [Lee, Phil H.] Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Cambridge, MA USA. [Mazoyer, Bernard] Univ Bordeaux, CEA, CNRS, UMR5296,Grp Imagerie Neurofonct, Bordeaux, France. [Martin, Nicholas G.; Medland, Sarah E.] QIMR Berghofer Med Res Inst, Brisbane, Qld 4006, Australia. [Morey, Rajendra A.] Duke Univ, Duke Inst Brain Sci, Durham, NC 27710 USA. [Nichols, Thomas E.] Univ Warwick, Dept Stat, Coventry CV4 7AL, W Midlands, England. [Nichols, Thomas E.] Univ Warwick, WMG, Coventry CV4 7AL, W Midlands, England. [Nichols, Thomas E.] Univ Oxford, FMRIB Ctr, Oxford OX3 9DU, England. [Paus, Tomas] Baycrest, Rotman Res Inst, Toronto, ON, Canada. [Paus, Tomas] Univ Toronto, Dept Psychol, Toronto, ON, Canada. [Paus, Tomas] Univ Toronto, Dept Psychiat, Toronto, ON, Canada. [Paus, Tomas] Child Mind Inst, New York, NY USA. [Pausova, Zdenka] Univ Toronto, Hosp Sick Children, Toronto, ON, Canada. [Pausova, Zdenka] Univ Toronto, Dept Physiol, Toronto, ON, Canada. [Pausova, Zdenka] Univ Toronto, Dept Nutr Sci, Toronto, ON, Canada. [Shen, Li] Indiana Univ Sch Med, Dept Radiol & Imaging Sci, Ctr Neuroimaging, 355 W 16th St,Suite 4100, Indianapolis, IN 46202 USA. [Shen, Li] Indiana Univ Sch Med, Ctr Computat Biol & Bioinformat, 355 W 16th St,Suite 4100, Indianapolis, IN 46202 USA. [Sisodiya, Sanjay M.] UCL Inst Neurol, Dept Clin & Expt Epilepsy, London WC1N 3BG, England. [Sisodiya, Sanjay M.] Epilepsy Soc, Gerrards Cross, Bucks, England. [Smit, Dirk J. A.] Vrije Univ Amsterdam, Dept Biol Psychol, Amsterdam, Netherlands. [Smoller, Jordan W.] Massachusetts Gen Hosp, Ctr Human Genet Res, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA. [Stein, Dan J.] MRC Res Unit Anxiety & Stress Disorders, Stellenbosch, South Africa. [Stein, Jason L.] UCLA Sch Med, Dept Neurol, Neurogenet Program, Los Angeles, CA 90095 USA. [Toro, Roberto] Inst Pasteur, F-75015 Paris, France. [Turner, Jessica A.] Georgia State Univ, Dept Psychol, Atlanta, GA 30302 USA. [Turner, Jessica A.] Georgia State Univ, Dept Neurosci, Atlanta, GA 30302 USA. [Boedhoe, Premika S.; Schmaal, Lianne; van den Heuvel, Odile L.; Veltman, Dick J.] Vrije Univ Amsterdam Med Ctr, Dept Psychiat, Amsterdam, Netherlands. [Boedhoe, Premika S.; Schmaal, Lianne; Smit, Dirk J. A.; van den Heuvel, Odile L.; Veltman, Dick J.] VU VUMC, Neurosci Campus Amsterdam, Amsterdam, Netherlands. [van Erp, Theo G. M.] Univ Calif Irvine, Dept Psychiat & Human Behav, Irvine, CA 92617 USA. [Walter, Henrik] Charite, CCM, Dept Psychiat & Psychotherapy, D-10117 Berlin, Germany. [Wang, Yalin] Arizona State Univ, Sch Comp Informat & Decis Syst Engn, Tempe, AZ 85281 USA. [Wardlaw, Joanna M.] Univ Edinburgh, Brain Res Imaging Ctr, Edinburgh EH4 2XU, Midlothian, Scotland. [Wardlaw, Joanna M.] Univ Edinburgh, Ctr Clin Brain Sci, Edinburgh EH4 2XU, Midlothian, Scotland. [Wright, Margaret J.] Univ Queensland, Queensland Brain Inst, Brisbane, Qld 4072, Australia. [Ye, Jieping] Univ Michigan, Dept Computat Med & Bioinformat, Ann Arbor, MI 48109 USA. [Ye, Jieping] Univ Michigan, Dept Elect Engn & Comp Sci, Ann Arbor, MI 48109 USA. RP Thompson, PM (reprint author), Univ Southern Calif, Keck Sch Med, Mark & Mary Stevens Inst Neuroimaging & Informat, Imaging Genet Ctr, Marina Del Rey, CA 90292 USA.; Thompson, PM (reprint author), Univ Calif San Diego, Dept Neurosci, San Diego, CA 92093 USA.; Thompson, PM (reprint author), Univ Calif San Diego, Dept Radiol, San Diego, CA 92093 USA.; Thompson, PM (reprint author), Univ Calif San Diego, Dept Psychiat, San Diego, CA 92093 USA.; Thompson, PM (reprint author), Univ Calif San Diego, Dept Cognit Sci, San Diego, CA 92093 USA. RI McDonald, Colm/C-1430-2009; Franke, Barbara/D-4836-2009; OI Franke, Barbara/0000-0003-4375-6572; Donohoe, Gary/0000-0003-3037-7426; Wright, Margaret/0000-0001-7133-4970; Shen, Li/0000-0002-5443-0503; Medland, Sarah/0000-0003-1382-380X FU NIH Institutes [U54 EB 020403]; NIBIB FX This work was supported in part by a Consortium grant (U54 EB 020403) from the NIH Institutes contributing to the Big Data to Knowledge (BD2K) Initiative, including the NIBIB. Funding for individual consortium authors is listed in Hibar et al., Nature, 2015 and in other papers cited here. This paper was collaboratively written on Google Docs by all authors, over a period of several weeks. We thank Josh Faskowitz for making Fig. 3, the ENIGMA "roadmap". NR 123 TC 2 Z9 3 U1 8 U2 8 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 EI 1095-9572 J9 NEUROIMAGE JI Neuroimage PD JAN 15 PY 2017 VL 145 SI SI BP 389 EP 408 DI 10.1016/j.neuroimage.2015.11.057 PN B PG 20 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA EG3WU UT WOS:000390976200022 PM 26658930 ER PT J AU Taylor, AE Martin, RM Geybels, MS Stanford, JL Shui, I Eeles, R Easton, D Kote-Jarai, Z Al Olama, AA Benlloch, S Muir, K Giles, GG Wiklund, F Gronberg, H Haiman, CA Schleutker, J Nordestgaard, BG Travis, RC Neal, D Pashayan, N Khaw, KT Blot, W Thibodeau, S Maier, C Kibel, AS Cybulski, C Cannon-Albright, L Brenner, H Park, J Kaneva, R Batra, J Teixeira, MR Pandha, H Donovan, J Munafo, MR AF Taylor, Amy E. Martin, Richard M. Geybels, Milan S. Stanford, Janet L. Shui, Irene Eeles, Rosalind Easton, Doug Kote-Jarai, Zsofia Al Olama, Ali Amin Benlloch, Sara Muir, Kenneth Giles, Graham G. Wiklund, Fredrik Gronberg, Henrik Haiman, Christopher A. Schleutker, Johanna Nordestgaard, Borge G. Travis, Ruth C. Neal, David Pashayan, Nora Khaw, Kay-Tee Blot, William Thibodeau, Stephen Maier, Christiane Kibel, Adam S. Cybulski, Cezary Cannon-Albright, Lisa Brenner, Hermann Park, Jong Kaneva, Radka Batra, Jyotsna Teixeira, Manuel R. Pandha, Hardev Donovan, Jenny Munafo, Marcus R. CA PRACTICAL Consortium TI Investigating the possible causal role of coffee consumption with prostate cancer risk and progression using Mendelian randomization analysis SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE prostate cancer; coffee; Mendelian randomization ID PRACTICAL CONSORTIUM; METAANALYSIS; MORTALITY; ASSOCIATION; DRINKING; COHORT; HEALTH AB Coffee consumption has been shown in some studies to be associated with lower risk of prostate cancer. However, it is unclear if this association is causal or due to confounding or reverse causality. We conducted a Mendelian randomisation analysis to investigate the causal effects of coffee consumption on prostate cancer risk and progression. We used two genetic variants robustly associated with caffeine intake (rs4410790 and rs2472297) as proxies for coffee consumption in a sample of 46,687 men of European ancestry from 25 studies in the PRACTICAL consortium. Associations between genetic variants and prostate cancer case status, stage and grade were assessed by logistic regression and with all-cause and prostate cancer-specific mortality using Cox proportional hazards regression. There was no clear evidence that a genetic risk score combining rs4410790 and rs2472297 was associated with prostate cancer risk (OR per additional coffee increasing allele: 1.01, 95% CI: 0.98,1.03) or having high-grade compared to low-grade disease (OR: 1.01, 95% CI: 0.97,1.04). There was some evidence that the genetic risk score was associated with higher odds of having nonlocalised compared to localised stage disease (OR: 1.03, 95% CI: 1.01, 1.06). Amongst men with prostate cancer, there was no clear association between the genetic risk score and all-cause mortality (HR: 1.00, 95% CI: 0.97,1.04) or prostate cancer-specific mortality (HR: 1.03, 95% CI: 0.98,1.08). These results, which should have less bias from confounding than observational estimates, are not consistent with a substantial effect of coffee consumption on reducing prostate cancer incidence or progression. C1 [Taylor, Amy E.; Martin, Richard M.; Munafo, Marcus R.] Univ Bristol, MRC Integrat Epidemiol Unit IEU, Bristol, Avon, England. [Taylor, Amy E.; Munafo, Marcus R.] Univ Bristol, Sch Expt Psychol, 12a Priory Rd, Bristol, Avon, England. [Taylor, Amy E.; Munafo, Marcus R.] Univ Bristol, UK Ctr Tobacco & Alcohol Studies, Bristol, Avon, England. [Martin, Richard M.; Donovan, Jenny] Univ Bristol, Sch Social & Community Med, Bristol, Avon, England. [Martin, Richard M.] Univ Hosp Bristol NHS Fdn Trust, NIHR Bristol Nutr Biomed Res Unit, Bristol, Avon, England. [Martin, Richard M.] Univ Bristol, Bristol BS8 1TH, Avon, England. [Geybels, Milan S.; Stanford, Janet L.; Shui, Irene] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA. [Stanford, Janet L.] Univ Washington, Sch Publ Hlth, Dept Epidemiol, Seattle, WA 98195 USA. [Eeles, Rosalind; Kote-Jarai, Zsofia] Inst Canc Res, Sutton SM2 5NG, Surrey, England. [Eeles, Rosalind] Royal Marsden NHS Fdn Trust, London SW3 6JJ, England. [Easton, Doug; Al Olama, Ali Amin; Benlloch, Sara] Univ Cambridge, Dept Publ Hlth & Primary Care, Strangeways Lab, Ctr Canc Genet Epidemiol, Worts Causeway, Cambridge, England. [Muir, Kenneth] Univ Manchester, Inst Populat Hlth, Manchester, Lancs, England. [Giles, Graham G.] Canc Council Victoria, Canc Epidemiol Ctr, 615 St Kilda Rd, Melbourne, Vic, Australia. [Giles, Graham G.] Univ Melbourne, Melbourne Sch Populat & Global Hlth, Ctr Epidemiol & Biostat, Melbourne, Vic, Australia. [Wiklund, Fredrik; Gronberg, Henrik] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Haiman, Christopher A.] Univ Southern Calif, Kenneth Norris Jr Comprehens Canc Ctr, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Schleutker, Johanna] Univ Turku, Dept Med Biochem & Genet, Turku, Finland. [Schleutker, Johanna] Univ Tampere, Inst Biomed Technol BioMediTech, Tampere, Finland. [Schleutker, Johanna] FimLab Labs, Tampere, Finland. [Nordestgaard, Borge G.] Copenhagen Univ Hosp, Herlev Hosp, Dept Clin Biochem, Herlev Ringvej 75, DK-2730 Herlev, Denmark. [Travis, Ruth C.] Univ Oxford, Nuffield Dept Clin Med, Canc Epidemiol Unit, Oxford, England. [Neal, David] Univ Cambridge, Addenbrookes Hosp, Surg Oncol Urooncology S4, Hills Rd,Box 279, Cambridge, England. [Pashayan, Nora] UCL, Dept Appl Hlth Res, 1-19 Torrington Pl, London WC1E 7HB, England. [Khaw, Kay-Tee] Univ Cambridge, Cambridge Inst Publ Hlth, Forvie Site,Robinson Way, Cambridge CB2 0SR, England. [Blot, William] Int Epidemiol Inst, 1455 Res Blvd,Suite 550, Rockville, MD USA. [Thibodeau, Stephen] Mayo Clin, Rochester, MN USA. [Maier, Christiane] Univ Hosp Ulm, Dept Urol, Ulm, Germany. [Maier, Christiane] Univ Hosp Ulm, Inst Human Genet, Ulm, Germany. [Kibel, Adam S.] Brigham & Womens Hosp, Dana Farber Canc Inst, Francis St ASB II 3, Boston, MA USA. [Kibel, Adam S.] Washington Univ, Sch Med, St Louis, MO USA. [Cybulski, Cezary] Pomeranian Med Univ, Dept Genet & Pathol, Int Hereditary Canc Ctr, Szczecin, Poland. [Cannon-Albright, Lisa] Univ Utah, Sch Med, Dept Med, Div Genet Epidemiol, Salt Lake City, UT USA. [Brenner, Hermann] German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany. [Brenner, Hermann] German Canc Res Ctr, Div Prevent Oncol, Heidelberg, Germany. [Brenner, Hermann] German Canc Res Ctr, German Canc Consortium DKTK, Heidelberg, Germany. [Park, Jong] H Lee Moffitt Canc Ctr & Res Inst, Div Canc Prevent & Control, 12902 Magnolia Dr, Tampa, FL USA. [Kaneva, Radka] Med Univ Sofia, Mol Med Ctr, 2 Zdrave St, Sofia 1431, Bulgaria. [Kaneva, Radka] Med Univ Sofia, Dept Med Chem & Biochem, 2 Zdrave St, Sofia 1431, Bulgaria. [Batra, Jyotsna] Queensland Univ Technol, Australian Prostate Canc Res Centre Qld, Inst Hlth & Biomed Innovat, Brisbane, Qld, Australia. [Batra, Jyotsna] Queensland Univ Technol, Sch Biomed Sci, Brisbane, Qld, Australia. [Teixeira, Manuel R.] Portuguese Oncol Inst, Dept Genet, Oporto, Portugal. [Teixeira, Manuel R.] Univ Porto, Biomed Sci Inst ICBAS, Oporto, Portugal. [Pandha, Hardev] Univ Surrey, Fac Hlth & Med Sci, Guildford GU2 7XH, Surrey, England. RP Taylor, AE (reprint author), Univ Bristol, Sch Expt Psychol, 12a Priory Rd, Bristol, Avon, England. EM amy.taylor@bristol.ac.uk RI Brenner, Hermann/B-4627-2017 OI Brenner, Hermann/0000-0002-6129-1572 FU UK Centre for Tobacco and Alcohol Studies, a UKCRC Public Health Research: Centre of Excellence; British Heart Foundation; Cancer Research UK [C5047/A7357, C5047/A3354, C16913/A6135, C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692]; Economic and Social Research Council; Medical Research Council; National Institute for Health Research, under UK Clinical Research Collaboration; Canadian Institutes of Health Research; CRUK study; PRACTICAL consortium; European Commission [223175 (HEALTH-F2-2009-223175)]; National Institute of Health (NIH) Cancer Post-Cancer GWAS initiative (the GAME-ON initiative) [1 U19 CA 148537-01]; European Community's Seventh Framework Programme (iCOGS infrastructure) [223175 (HEALTH-F2-2009-223175) (iCOGS)]; National Institutes of Health [CA128978]; Post-Cancer GWAS initiative [1U19 CA148537, 1U19 CA148065, 1U19 CA148112]; Department of Defence [W81XWH-10-1-0341]; Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer; Komen Foundation for the Cure; Breast Cancer Research Foundation; Ovarian Cancer Research Fund; VicHealth and Cancer Council Victoria (MCCS cohort recruitment); Australian NHMRC [209057, 251553, 504711]; Victorian Cancer Registry (VCR); Australian Institute of Health and Welfare (AIHW); National Death Index; Australian Cancer Database; U.K. Health Technology Assessment (HTA) Programme of the NIH Research (ProtecT study) [HTA 96/20/99, ISRCTN20141297]; National Cancer Research Institute (NCRI); ProMPT (Prostate Mechanisms of Progression and Treatment) [G0500966/75466]; NIHR Biomedical Research Centre at The Institute of Cancer Research; NIHR Biomedical Research Centre at The Institute of Cancer Research and Royal Marsden NHS Foundation Trust; National Institute for Health Research Bristol Nutrition Biomedical Research Unit based at University Hospitals Bristol NHS Foundation Trust; University of Bristol; NIHR; MRC; University of Bristol (Integrative Epidemiology Unit) [G0600705, MC_UU_12013/6]; [C18281/A19169] FX Grant sponsor: UK Centre for Tobacco and Alcohol Studies, a UKCRC Public Health Research: Centre of Excellence (to A.E.T. and M.R.M.); British Heart Foundation, Cancer Research UK, Economic and Social Research Council, Medical Research Council, and the National Institute for Health Research, under the auspices of the UK Clinical Research Collaboration; Grant sponsor: Cancer Research UK (to R.M.M. and Caroline Relton (Integrative Cancer Epidemiology Programme)); Grant number: C18281/A19169; Grant sponsor: Canadian Institutes of Health Research; (CRUK study and the PRACTICAL consortium); Grant sponsor: European Commission's Seventh Framework Programme; Grant number: 223175 (HEALTH-F2-2009-223175); Grant sponsor: Cancer Research UK; Grant numbers: C5047/A7357, C1287/A10118, C5047/A3354, C5047/A10692, C16913/A6135; Grant sponsor: National Institute of Health (NIH) Cancer Post-Cancer GWAS initiative (the GAME-ON initiative); Grant number: 1 U19 CA 148537-01; Grant sponsor: European Community's Seventh Framework Programme (iCOGS infrastructure); Grant number: 223175 (HEALTH-F2-2009-223175) (iCOGS); Grant sponsor: Cancer Research UK; Grant numbers: C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692; Grant sponsor: National Institutes of Health; Grant number: CA128978; Grant sponsor: Post-Cancer GWAS initiative; Grant numbers: 1U19 CA148537, 1U19 CA148065 and 1U19 CA148112 (GAME-ON initiative); Grant sponsor: Department of Defence; Grant number: W81XWH-10-1-0341; Grant sponsor: Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund; Grant sponsor: VicHealth and Cancer Council Victoria (MCCS cohort recruitment); Grant sponsor: Australian NHMRC; Grant numbers: 209057, 251553 and 504711; Grant sponsor: Victorian Cancer Registry (VCR) and Australian Institute of Health and Welfare (AIHW), including the National Death Index and the Australian Cancer Database; Grant sponsor: U.K. Health Technology Assessment (HTA) Programme of the NIH Research (ProtecT study); Grant numbers: HTA 96/20/99; ISRCTN20141297; Grant sponsor: National Cancer Research Institute (NCRI) formed by the Department of Health, the Medical Research Council and Cancer Research UK [NHS R&D Directorate supported Prodigal study and the ProMPT (Prostate Mechanisms of Progression and Treatment)]; Grant number: G0500966/75466; Grant sponsor: Cancer Research UK (to R.A.E. and Z.K.J.); Grant number: C5047/A7357; Grant sponsor: NIHR Biomedical Research Centre at The Institute of Cancer Research and Royal Marsden NHS Foundation Trust (to RAE and ZKJ); Grant sponsors: National Institute for Health Research Bristol Nutrition Biomedical Research Unit based at University Hospitals Bristol NHS Foundation Trust and the University of Bristol (to R.M.M.); Grant sponsor: NIHR Senior Investigators (to F.C.H., D.E.N. and J.L.D.); Grant sponsors: MRC and the University of Bristol (Integrative Epidemiology Unit); Grant numbers: G0600705, MC_UU_12013/6 NR 25 TC 0 Z9 0 U1 9 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 EI 1097-0215 J9 INT J CANCER JI Int. J. Cancer PD JAN 15 PY 2017 VL 140 IS 2 BP 322 EP 328 DI 10.1002/ijc.30462 PG 7 WC Oncology SC Oncology GA EG0EI UT WOS:000390703600008 PM 27741566 ER PT J AU Sharma, A Helft, G Garg, A Agrawal, S Chatterjee, S Lavie, CJ Goel, S Mukherjee, D Marmur, JD AF Sharma, Abhishek Helft, Gerard Garg, Aakash Agrawal, Sahil Chatterjee, Saurav Lavie, Carl J. Goel, Sunny Mukherjee, Debabrata Marmur, Jonathan D. TI Safety and efficacy of vorapaxar in secondary prevention of atherosclerotic disease: A meta-analysis of randomized control trials SO INTERNATIONAL JOURNAL OF CARDIOLOGY LA English DT Article DE Vorapaxar; Atherosclerotic vascular disease ID PERCUTANEOUS CORONARY INTERVENTION; PROTEASE-ACTIVATED RECEPTOR-1; DUAL ANTIPLATELET THERAPY; 2-DEGREES-P-TIMI 50 TRIAL; ELUTING STENT IMPLANTATION; MYOCARDIAL-INFARCTION; ARTERY-DISEASE; ATHEROTHROMBOTIC EVENTS; ANTAGONIST VORAPAXAR; SCH 530348 AB Objective To study the cumulative evidence for vorapaxar use in patients with atherosclerotic cardiovascular disease. Methods A systematic review of randomized control trials in MEDLINE, EMBASE, EBSCO, CINAHL, Web of Science and Cochrane databases comparing vorapaxar with placebo was performed. Pre-specified efficacy endpoints were all-cause mortality, CV mortality, myocardial infarction (MI), ischemic stroke and repeat revascularization. The pre-specified safety endpoint was intracranial hemorrhage (ICH) and a composite of TIMI major and minor bleeding. Risk ratios were used as the metric of choice by applying random effects models. Results Five randomized controlled trials with 40,630 patients were included in final analysis. Compared with placebo, vorapaxar led to a statistically non-significant reduction in risk of MI [RR 0.86; 95% CI 0.80-0.93, p = 0.427] and ischemic stroke [RR 0.84; 95% CI 0.72-0.97, p = 0.920]. No differences were observed between vorapaxar and placebo with respect to all-cause mortality [RR 0.99; 95% CI 0.90-1.08, p = 0.620], cardiovascular mortality [RR 0.94; 95% CI 0.83-1.06, p = 0.351], repeat revascularization [RR 0.97; 95% CI 0.82-1.15, p = 0.236], and TIMI bleeding [RR 1.29; 95% CI 0.98-1.69, p = 0.126]. Vorapaxar was associated with a statistically non-significant higher risk of ICH [RR 2.36; 95% CI 1.40-3.96, p = 0.137] compared with placebo. Conclusion Addition of Vorapaxar to standard medical therapy in in patients with atherosclerotic disease led to a statistically non-significant reduction in the risk of MI and ischemic stroke at the cost of statistically non-significant increase in risk of ICH. (C) 2016 Elsevier Ireland Ltd. All rights reserved. C1 [Sharma, Abhishek; Marmur, Jonathan D.] Suny Downstate Med Ctr, Div Cardiovasc Med, New York, NY USA. [Helft, Gerard] Univ Paris 06, Hop Pitie Salpetriere, AP HP, Inst Cardiol, Blvd Hop, Paris, France. [Helft, Gerard] Hop La Pitie Salpetriere, Inst Cardiometab & Nutr, Paris, France. [Garg, Aakash] Mt Sinai Sch Med, James J Peters VA Med Ctr, Dept Med, New York, NY USA. [Agrawal, Sahil] St Lukes Univ Hlth Network, Div Cardiol, Bethlehem, PA USA. [Chatterjee, Saurav] Mt Sinai Hlth Syst, St Lukes Roosevelt Hosp Ctr, Div Cardiovasc Dis, New York, NY USA. [Lavie, Carl J.] Univ Queensland, Sch Med, John Ochsner Heart end Vasc Inst, Dept Cardiovasc Dis,Ochsner Clin Sch, New Orleans, LA USA. [Goel, Sunny] Maimonides Hosp, Dept Cardiol, New York, NY USA. [Mukherjee, Debabrata] Texas Tech Univ, Div Cardiol, El Paso, TX USA. [Sharma, Abhishek] Inst Cardiovasc Res & Technol, Brooklyn, NY USA. RP Sharma, A (reprint author), Suny Downstate Med Ctr, Div Cardiol, Brooklyn, NY 11203 USA. EM abhisheksharma4mamc@gmail.com NR 33 TC 1 Z9 1 U1 3 U2 3 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0167-5273 EI 1874-1754 J9 INT J CARDIOL JI Int. J. Cardiol. PD JAN 15 PY 2017 VL 227 BP 617 EP 624 DI 10.1016/j.ijcard.2016.10.088 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EF6ZU UT WOS:000390480700105 PM 27810296 ER PT J AU Mischoulon, D Hyek, L Yeung, AS Clain, AJ Baer, L Cusin, C Ionescu, DF Alpert, JE Soskinl, DP Faval, M AF Mischoulon, David Hyek, Lindsay Yeung, Albert S. Clain, Alisabet J. Baer, Lee Cusin, Cristina Ionescu, Dawn Flosnik Alpert, Jonathan E. Soskinl, David P. Faval, Maurizio TI Randomized, proof-of-concept trial of low dose naltrexone for patients with breakthrough symptoms of major depressive disorder on antidepressants SO JOURNAL OF AFFECTIVE DISORDERS LA English DT Article DE Naltrexone; LDN; Depression; Relapse; Breakthrough ID MOOD-DISORDERS; FOLLOW-UP; DOPAMINE RELEASE; INTERFERON-ALPHA; QUESTIONNAIRE; SCALE; RECEPTORS; REMISSION; RELAPSE; DISEASE AB Background: Given the proposed dopaminergic mechanism of low-dose naltrexone (LDN), we examined its efficacy as augmentation for depressive breakthrough on pro-dopaminergic antidepressant regimens. Methods: 12 adults (67% female, mean age = 45 +/- 12) with recurrent DSM-W major depressive disorder (MDD) on dopaminergic antidepressant regimens (stimulants, dopamine agonists, bupropion [>= 300 mg/day], aripiprazole [<= 2.5 mg/day], or sertraline [>= 150 mg/day]) were randomized to naltrexone 1 mg b.i.d. (n=6) or placebo (n=6) augmentation for 3 weeks. Results: All subjects completed the trial. Hamilton Depression Rating Scale (HAM-D-17) scores (primary outcome measure) decreased from 21.2 +/- 2.0 to 11.7 +/- 7.7 for LDN, from 23.7 +/- 2.3 to 17.8 +/- 5.9 for placebo (Cohen's d=0.62; p=0.3 between treatment groups). HAM-D-28 scores decreased from 26.2 +/- 4.0 to 12.0 +/- 9.8 for LDN, from 26.3 +/- 2.6 to 19.8 +/- 6.6 for placebo (d=1.15; p=0.097). Montgomery-Asberg Depression Rating Scale (MADRS-10 item) scores decreased from 30.4 +/- 4.9 to 12.2 +/- 8.4 for LDN, from 30.7 +/- 4.3 to 22.8 +/- 8.5) for placebo (d=1.45; p=0.035). MADRS-15 item scores decreased from 36.6 +/- 6.2 to 13.2 +/- 8.8 for LDN, from 36.7 +/- 4.2 to 26.0 +/- 10.0 for placebo (d=1.49; p=0.035). Clinical Global Improvement Scale-Severity (CGI-S) scores decreased from 4.3 +/- 0.5 to 3.0 +/- 1.1 for LDN, from 4.3 +/- 0.5 to 4.0 +/- 0.6 for placebo (d=1.22; p=0.064). Limitations: Small study; restrictions on allowed antidepressants. Conclusion: LDN augmentation showed some benefit for MDD relapse on dopaminergic agents. Confirmation in larger studies is needed. C1 [Mischoulon, David; Hyek, Lindsay; Yeung, Albert S.; Clain, Alisabet J.; Baer, Lee; Cusin, Cristina; Ionescu, Dawn Flosnik; Alpert, Jonathan E.; Soskinl, David P.; Faval, Maurizio] Harvard Med Sch, Massachusetts Gen Hosp, Dept Psychiat, Depress Clin & Res Program, Boston, MA USA. RP Mischoulon, D (reprint author), Massachusetts Gen Hosp, One Bowdoin Sq,6th Floor, Boston, MA 02114 USA. EM dmischoulon@partners.org FU PharmoRx Therapeutics FX The study was sponsored by PharmoRx Therapeutics, who provided funding, drug, and placebo. Only the authors were responsible for the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, and approval of the manuscript for submission. The sponsors played no role in any of the above. NR 47 TC 0 Z9 0 U1 3 U2 3 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 JAN 15 PY 2017 VL 208 BP 6 EP 14 DI 10.1016/j.jad.2016.08.029 PG 9 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA EG0OR UT WOS:000390732600002 PM 27736689 ER PT J AU Poindexter, EK Nazem, S Forster, JE AF Poindexter, Erin K. Nazem, Sarra Forster, Jeri E. TI Painful and provocative events scale and fearlessness about death among Veterans: Exploratory factor analysis SO JOURNAL OF AFFECTIVE DISORDERS LA English DT Article DE Painful and provocative events; Fearlessness about death; Acquired capability ID INTERPERSONAL-PSYCHOLOGICAL THEORY; ACQUIRED CAPABILITY; PSYCHOMETRIC PROPERTIES; CONSTRUCT-VALIDITY; MILITARY PERSONNEL; SUICIDAL-BEHAVIOR; RISK; EXPERIENCES; TOLERANCE; SAMPLE AB Background: The interpersonal theory of suicide suggests three proximal risk factors for suicide: perceived burdensomeness, thwarted belongingness, and acquired capability. Previous literature indicates that repetitive exposure to painful and provocative events is related to increased acquired capability for suicide. Despite this, research related to the assessment of painful and provocative events has been insufficient. Research has inconsistently administered the Painful and Provocative Events Scale (PPES; a painful and provocative events assessment), and no study has examined the factor structure of the English PPES. This study explored the factor structure of the PPES and the relation between factors and fearlessness about death. Methods: The sample was a cross-sectional, self-report study comprised of 119 Veterans (Mage = 46.5, SD = 13.5). Results: Findings from an exploratory factor analysis indicated a four-factor solution for the PPES; however, no factor from the PPES significantly related to fearlessness about death (measured by the Acquired Capability for Suicide Scale Fearlessness About Death Scale; all p > .21). Limitations: Cross-sectional, small Veteran sample. Conclusions: Findings suggest that the PPES lacks the psychometric properties necessary to reliably investigate painful and provocative factors. Consequently, this measure may not reliably capture and explain how painful and provocative events relate to fearlessness about death, which is a barrier to improving suicide risk assessment and prediction. Recommendations for the construction of a new PPES are offered. C1 [Poindexter, Erin K.; Nazem, Sarra; Forster, Jeri E.] Rocky Mt Mental Illness Res Educ & Clin Ctr MIREC, Denver, CO USA. [Poindexter, Erin K.] Texas Tech Univ, Lubbock, TX 79409 USA. [Nazem, Sarra; Forster, Jeri E.] Univ Colorado, Anschutz Med Campus, Aurora, CO USA. RP Nazem, S (reprint author), Denver VAMC, Rocky Mt MIRECC, 1055 Clermont St, Denver, CO 80220 USA. EM Sarra.Nazem@va.gov FU Rocky Mountain MIRECC FX This work was supported by Rocky Mountain MIRECC pilot funding. NR 31 TC 0 Z9 0 U1 3 U2 3 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 JAN 15 PY 2017 VL 208 BP 528 EP 534 DI 10.1016/j.jad.2016.10.030 PG 7 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA EG0OR UT WOS:000390732600076 PM 27817911 ER PT J AU Lamkin, J Lavner, JA Shaffer, A AF Lamkin, Joanna Lavner, Justin A. Shaffer, Anne TI Narcissism and observed communication in couples SO PERSONALITY AND INDIVIDUAL DIFFERENCES LA English DT Article DE Narcissism; Communication; Observational; Couples; Dyadic ID PERSONALITY-INVENTORY; GENDER-DIFFERENCES; RELATIONSHIP SATISFACTION; ROMANTIC RELATIONSHIPS; SELF-ESTEEM; MODEL; LOVE; AGGRESSION; MARRIAGE; ANGER AB Narcissism is associated with dysfunction in interpersonal relationships. Empirically, limited information is available about how narcissism affects observed interactions in romantic relationships. In this study, we employed dyadic data analyses to investigate the effects of narcissism on relationship functioning. Young adult couples (N = 54 couples) participated in a neutral discussion task, and their communication behaviors (hostility, anger, and positive affect) were coded by observers. We also assessed self-reported relationship satisfaction and narcissism. Results of multilevel models revealed that women with higher levels of narcissism demonstrated significantly higher levels of hostility, as did their male partners. Men also displayed more anger if their female partner had higher levels of narcissism. Narcissism was not associated with observed positive affect in any of the analyses. Results are consistent with previous research on couples in highlighting that women's narcissism is associated with more difficulties in romantic relationships for women and their male partners. Findings are discussed with attention to better understanding the behaviors that lead to dissatisfaction and dysfunction in romantic relationships where narcissism is present. Published by Elsevier Ltd. C1 [Lamkin, Joanna; Lavner, Justin A.; Shaffer, Anne] Univ Georgia, Athens, GA 30602 USA. [Lamkin, Joanna] Baylor Coll Med, South Cent Mental Illness Res Educ & Clin Ctr MIR, VA HSR&D Ctr Innovat Qual Effectiveness & Safety, Michael E DeBakey Vet Affairs Med Ctr, Houston, TX 77030 USA. RP Lamkin, J (reprint author), 2002 Holcombe Blvd,MC 152, Houston, TX 77030 USA.; Lamkin, J (reprint author), Baylor Coll Med, South Cent Mental Illness Res Educ & Clin Ctr MIR, VA HSR&D Ctr Innovat Qual Effectiveness & Safety, Michael E DeBakey Vet Affairs Med Ctr, Houston, TX 77030 USA. EM joannalamkin@bcm.edu NR 33 TC 0 Z9 0 U1 19 U2 19 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0191-8869 J9 PERS INDIV DIFFER JI Pers. Individ. Differ. PD JAN 15 PY 2017 VL 105 BP 224 EP 228 DI 10.1016/j.paid.2016.09.046 PG 5 WC Psychology, Social SC Psychology GA ED3YF UT WOS:000388783700035 ER PT J AU Frodermann, V Nahrendorf, M AF Frodermann, Vanessa Nahrendorf, Matthias TI Neutrophil-macrophage cross-talk in acute myocardial infarction SO EUROPEAN HEART JOURNAL LA English DT Editorial Material ID ATHEROSCLEROSIS; INFLAMMATION; RESOLUTION; MONOCYTES; MICE C1 [Frodermann, Vanessa; Nahrendorf, Matthias] Harvard Med Sch, Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. RP Nahrendorf, M (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. EM mnahrendorf@mgh.harvard.edu FU Netherlands Organisation for Scientific Research (NWO) [835.15.014]; National Institutes of Health [R01HL117829] FX This work was supported by a fellowship from the Netherlands Organisation for Scientific Research (NWO, Rubicon Grant: 835.15.014) and from the National Institutes of Health (R01HL117829). The figure was made using Servier Medical Art. NR 12 TC 1 Z9 1 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0195-668X EI 1522-9645 J9 EUR HEART J JI Eur. Heart J. PD JAN 14 PY 2017 VL 38 IS 3 BP 198 EP 200 DI 10.1093/eurheartj/ehw085 PG 3 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EK6BD UT WOS:000394009100018 PM 28158564 ER PT J AU Vigano, S Negron, JJ Tse, S Chowdhury, FZ Lichterfeld, M Yu, XG AF Vigano, Selena Negron, Jordi J. Tse, Samantha Chowdhury, Fatema Z. Lichterfeld, Mathias Yu, Xu G. TI HLA-G(+) HIV-1-specific CD8(+) T cells are associated with HIV-1 immune control SO AIDS LA English DT Article DE antiviral mechanisms; CD8(+) T cells; chemokines; controllers; HIV-1; HLA-G ID REPLICATION AB Objective(s): To assess the frequency and function of HIV-1-specific HLA-G(+) (histocompatibility antigen class I, G) CD8(+) T cells in HIV-1 controllers and progressors. Design: We performed an observational cross-sectional cohort analysis in untreated (n = 47) and treated (n = 17) HIV-1 patients with different rates of disease progression and n = 14 healthy individuals. Methods: We evaluated the frequency, the proportion and the function of total and virus-specific HLA-G(+) CD8(+) T cells by tetramer or intracellular cytokine staining, followed by flow cytometric analysis. Cytokine secretion of sorted CD8(+) T-cell subsets was evaluated by Luminex assays. Results: The proportion and the absolute frequency of HLA-G(+) HIV-1-specific CD8(+) T cells were directly associated with CD4(+) T-cell counts and inversely correlated with viral loads, whereas total or HLA-G-negative HIV-1-specific CD8(+) T cells were not. In functional assays, HLA-G(+) CD8(+) T cells from HIV-1-negative individuals had higher abilities to produce the antiviral (C-C chemokine receptor type 5) ligands MIP-1 beta (macrophage inflammatory protein-1 beta), MIP-1 alpha and Rantes. Conclusion: HLA-G(+) HIV-1-specific CD8(+) T cells may represent a previously unrecognized correlate of HIV-1 immune control. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved. C1 [Vigano, Selena; Negron, Jordi J.; Tse, Samantha; Chowdhury, Fatema Z.; Yu, Xu G.] Ragon Inst MGH MIT & Harvard, Boston, MA USA. [Lichterfeld, Mathias] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Lichterfeld, Mathias] Brigham & Womens Hosp, Div Infect Dis, 75 Francis St, Boston, MA 02115 USA. RP Yu, XG (reprint author), Massachusetts Gen Hosp, Ragon Inst MGH MIT & Harvard, Med, Boston, MA 02114 USA. EM xyu@mgh.harvard.edu FU US National Institutes of Health [R01 AI078799, R56 AI098484, R01 AI089339]; Bill and Melinda Gates Foundation; Mark and Lisa Swartz Foundation; Ragon Institute of MGH, MEI; Harvard and the international HIV Controller Consortium; Harvard University Center of AIDS research (HU CFAR NIH/NIAIS fund) [5P30AI060354-10] FX This work was supported by the US National Institutes of Health (grants R01 AI078799, R56 AI098484 and R01 AI089339 to X.G.Y.). PBMC sample collection was supported by the Bill and Melinda Gates Foundation, the Mark and Lisa Swartz Foundation, the Ragon Institute of MGH, MEI and Harvard and the international HIV Controller Consortium. Ragon Institute Imaging Core is supported by the Harvard University Center of AIDS research (HU CFAR NIH/NIAIS fund 5P30AI060354-10). NR 17 TC 0 Z9 0 U1 2 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0269-9370 EI 1473-5571 J9 AIDS JI Aids PD JAN 14 PY 2017 VL 31 IS 2 BP 207 EP 212 DI 10.1097/QAD.0000000000001326 PG 6 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA EF6PK UT WOS:000390452800006 PM 27835619 ER PT J AU Powis, KM Slogrove, AL Mofenson, L AF Powis, Kathleen M. Slogrove, Amy L. Mofenson, Lynne TI Protecting the health of our AIDS-free generation: beyond prevention of mother-to-child HIV transmission SO AIDS LA English DT Letter ID EXPOSED UNINFECTED INFANTS; INFECTED WOMEN; INCREASED RISK; MORTALITY; BOTSWANA; MORBIDITY C1 [Powis, Kathleen M.] Harvard TH Chan Sch Publ Hlth, Div Immunol & Infect Dis, Boston, MA USA. [Powis, Kathleen M.] Massachusetts Gen Hosp, Dept Internal Med & Pediat, Boston, MA 02114 USA. [Powis, Kathleen M.] Botswana Harvard AIDS Inst Partnership, Gaborone, Botswana. [Slogrove, Amy L.] Univ Cape Town, Ctr Infect Dis & Epidemiol Res, Sch Publ Hlth & Med, Cape Town, South Africa. [Mofenson, Lynne] Elizabeth Glaser Pediat AIDS Fdn, Washington, DC USA. RP Powis, KM (reprint author), Massachusetts Gen Hosp, Dept Internal Med & Pediat, Boston, MA 02114 USA. EM kpowis@mgh.harvard.edu FU NICHD NIH HHS [K23 HD070774] NR 25 TC 0 Z9 0 U1 9 U2 9 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0269-9370 EI 1473-5571 J9 AIDS JI Aids PD JAN 14 PY 2017 VL 31 IS 2 BP 315 EP 316 DI 10.1097/QAD.0000000000001315 PG 2 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA EF6PK UT WOS:000390452800019 PM 28002087 ER PT J AU Acharya, B Maru, D Schwarz, R Citrin, D Tenpa, J Hirachan, S Basnet, M Thapa, P Swar, S Halliday, S Kohrt, B Luitel, NP Hung, E Gauchan, B Pokharel, R Ekstrand, M AF Acharya, Bibhav Maru, Duncan Schwarz, Ryan Citrin, David Tenpa, Jasmine Hirachan, Soniya Basnet, Madhur Thapa, Poshan Swar, Sikhar Halliday, Scott Kohrt, Brandon Luitel, Nagendra P. Hung, Erick Gauchan, Bikash Pokharel, Rajeev Ekstrand, Maria TI Partnerships in mental healthcare service delivery in low-lresource settings: developing an innovative network in rural Nepal SO GLOBALIZATION AND HEALTH LA English DT Article DE Mental health; Global health; Nepal; Partnerships; Low- and middle-income countries ID RANDOMIZED CONTROLLED-TRIAL; HUMAN-RIGHTS; DEPRESSION; INTERVENTION; DISORDERS; THERAPY; ILLNESS; ANXIETY; PEOPLE; WOMEN AB Background: Mental illnesses are the largest contributors to the global burden of non-communicable diseases. However, there is extremely limited access to high quality, culturally-sensitive, and contextually-appropriate mental healthcare services. This situation persists despite the availability of interventions with proven efficacy to improve patient outcomes. A partnerships network is necessary for successful program adaptation and implementation. Partnerships network: We describe our partnerships network as a case example that addresses challenges in delivering mental healthcare and which can serve as a model for similar settings. Our perspectives are informed from integrating mental healthcare services within a rural public hospital in Nepal. Our approach includes training and supervising generalist health workers by off-site psychiatrists. This is made possible by complementing the strengths and weaknesses of the various groups involved: the public sector, a non-profit organization that provides general healthcare services and one that specializes in mental health, a community advisory board, academic centers in high- and low-income countries, and bicultural professionals from the diaspora community. Conclusions: We propose a partnerships model to assist implementation of promising programs to expand access to mental healthcare in low- resource settings. We describe the success and limitations of our current partners in a mental health program in rural Nepal. C1 [Acharya, Bibhav; Maru, Duncan; Schwarz, Ryan; Citrin, David; Tenpa, Jasmine; Thapa, Poshan; Swar, Sikhar; Halliday, Scott; Gauchan, Bikash] Bayalpata Hosp, Sanfebagar 10, Achham, Nepal. [Acharya, Bibhav; Hung, Erick] Univ Calif San Francisco, Dept Psychiat, 401 Parnassus Ave, San Francisco, CA 94143 USA. [Acharya, Bibhav; Hirachan, Soniya; Basnet, Madhur] Shared Minds, Boston, MA USA. [Maru, Duncan; Schwarz, Ryan] Brigham & Womens Hosp, Dept Med, Div Global Hlth Equity, Boston, MA USA. [Maru, Duncan] Boston Childrens Hosp, Dept Med, Div Gen Pediat, Boston, MA USA. [Maru, Duncan; Schwarz, Ryan] Harvard Med Sch, Dept Med, Boston, MA USA. [Schwarz, Ryan] Massachusetts Gen Hosp, Dept Med, Div Gen Internal Med, Boston, MA USA. [Citrin, David] Univ Washington, Dept Anthropol, Seattle, WA USA. [Citrin, David] Univ Washington, Dept Global Hlth, Seattle, WA USA. [Citrin, David; Halliday, Scott] Univ Washington, Henry M Jackson Sch Int Studies, Seattle, WA USA. [Hirachan, Soniya] Univ Minnesota, Dept Psychiat, Minneapolis, MN USA. [Basnet, Madhur] B P Koirala Inst Hlth Sci, Fac Med, Dept Psychiat, Sunsari, Nepal. [Swar, Sikhar] Kathmandu Med Coll, Dept Psychiat, Kathmandu, Nepal. [Kohrt, Brandon; Luitel, Nagendra P.] Transcultural Psychosocial Org Nepal, Res Dept, Kathmandu, Nepal. [Kohrt, Brandon] Duke Univ, Sch Med, Dept Psychiat & Behav Sci, Durham, NC USA. [Kohrt, Brandon] Duke Univ, Global Hlth Inst, Durham, NC USA. [Kohrt, Brandon] Duke Univ, Dept Cultural Anthropol, Durham, NC USA. [Pokharel, Rajeev] Policy Planning Int Cooperat Div, Minist Hlth, Kathmandu, Nepal. [Ekstrand, Maria] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. RP Acharya, B (reprint author), Bayalpata Hosp, Sanfebagar 10, Achham, Nepal.; Acharya, B (reprint author), Univ Calif San Francisco, Dept Psychiat, 401 Parnassus Ave, San Francisco, CA 94143 USA.; Acharya, B (reprint author), Shared Minds, Boston, MA USA. EM Bibhav.Acharya@ucsf.edu FU National Institute of Mental Health (NIMH) [R25MH060482-14]; Harvard Medical School Center for Global Health Delivery-Dubai [027562-746845-0201] FX Bibhav Acharya, MD was supported by National Institute of Mental Health (NIMH) grant R25MH060482-14. NIMH played no role in the design, analysis, or publication of the study.; The mental health services program is supported by Harvard Medical School Center for Global Health Delivery-Dubai (027562-746845-0201). NR 52 TC 0 Z9 0 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1744-8603 J9 GLOBALIZATION HEALTH JI Global. Health PD JAN 13 PY 2017 VL 13 AR 2 DI 10.1186/s12992-016-0226-0 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA EO8FH UT WOS:000396924000001 PM 28086925 ER PT J AU Ewald, CY Hourihan, JM Bland, MS Obieglo, C Katic, I Mazzeo, LEM Alcedo, J Blackwell, TK Hynes, NE AF Ewald, Collin Yves Hourihan, John M. Bland, Monet S. Obieglo, Carolin Katic, Iskra Mazzeo, Lorenza E. Moronetti Alcedo, Joy Blackwell, T. Keith Hynes, Nancy E. TI NADPH oxidase-mediated redox signaling promotes oxidative stress resistance and longevity through memo-1 in C. elegans SO ELIFE LA English DT Article ID NEMATODE CAENORHABDITIS-ELEGANS; CHRONOLOGICAL LIFE-SPAN; REACTIVE OXYGEN; CELL-MIGRATION; IN-VIVO; CALORIC RESTRICTION; EXPRESSION ANALYSIS; MITOCHONDRIAL ROS; RNA INTERFERENCE; FREE-RADICALS AB Transient increases in mitochondrially-derived reactive oxygen species (ROS) activate an adaptive stress response to promote longevity. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases produce ROS locally in response to various stimuli, and thereby regulate many cellular processes, but their role in aging remains unexplored. Here, we identified the C. elegans orthologue of mammalian mediator of ErbB2-driven cell motility, MEMO-1, as a protein that inhibits BLI-3/NADPH oxidase. MEMO-1 is complexed with RHO-1/RhoA/GTPase and loss of memo-1 results in an enhanced interaction of RHO-1 with BLI-3/NADPH oxidase, thereby stimulating ROS production that signal via p38 MAP kinase to the transcription factor SKN-1/NRF1,2,3 to promote stress resistance and longevity. Either loss of memo-1 or increasing BLI-3/NADPH oxidase activity by overexpression is sufficient to increase lifespan. Together, these findings demonstrate that NADPH oxidase-induced redox signaling initiates a transcriptional response that protects the cell and organism, and can promote both stress resistance and longevity. C1 [Ewald, Collin Yves] ETH, Dept Hlth Sci & Technol, Zurich, Switzerland. [Ewald, Collin Yves; Katic, Iskra; Alcedo, Joy; Hynes, Nancy E.] Univ Basel, Friedrich Miescher Inst Biomed Res, Basel, Switzerland. [Ewald, Collin Yves; Hourihan, John M.; Bland, Monet S.; Obieglo, Carolin; Mazzeo, Lorenza E. Moronetti; Blackwell, T. Keith] Harvard Med Sch, Dept Genet, Boston, MA 02115 USA. [Ewald, Collin Yves; Hourihan, John M.; Bland, Monet S.; Obieglo, Carolin; Mazzeo, Lorenza E. Moronetti; Blackwell, T. Keith] Joslin Diabet Ctr, Boston, MA 02215 USA. [Ewald, Collin Yves; Hourihan, John M.; Bland, Monet S.; Obieglo, Carolin; Mazzeo, Lorenza E. Moronetti; Blackwell, T. Keith] Harvard Stem Cell Inst, Cambridge, MA 02138 USA. [Alcedo, Joy] Wayne State Univ, Dept Biol Sci, Detroit, MI 48202 USA. RP Ewald, CY (reprint author), ETH, Dept Hlth Sci & Technol, Zurich, Switzerland.; Ewald, CY; Hynes, NE (reprint author), Univ Basel, Friedrich Miescher Inst Biomed Res, Basel, Switzerland.; Ewald, CY; Blackwell, TK (reprint author), Harvard Med Sch, Dept Genet, Boston, MA 02115 USA.; Ewald, CY; Blackwell, TK (reprint author), Joslin Diabet Ctr, Boston, MA 02215 USA.; Ewald, CY; Blackwell, TK (reprint author), Harvard Stem Cell Inst, Cambridge, MA 02138 USA. EM collin-ewald@ethz.ch; keith.blackwell@joslin.harvard.edu; nancy.hynes@fmi.ch OI Ewald, Collin/0000-0003-1166-4171 FU Schweizerischer National fonds zur Forderungder Wiss enschaftlichen Forschung [PBSKP3_140135, P300P3_154633, 310030A-121574, 310030B-138674, P00P3_163898]; Novartis Stiftung fur Medizinisch-Biologische Forschung; National Institutes of Health [GM062891, GM094398] FX Schweizerischer Nationalfonds zur Forderung der Wissenschaftlichen Forschung PBSKP3_140135 Collin Yves Ewald; Novartis Stiftung fur Medizinisch-Biologische Forschung Nancy E Hynes; National Institutes of Health GM062891 T Keith Blackwell; Schweizerischer Nationalfonds zur Forderung der Wissenschaftlichen Forschung P300P3_154633 Collin Yves Ewald; Schweizerischer Nationalfonds zur Forderung der Wissenschaftlichen Forschung 310030A-121574 Nancy E Hynes; Schweizerischer Nationalfonds zur Forderung der Wissenschaftlichen Forschung 310030B-138674 Nancy E Hynes; National Institutes of Health GM094398 T Keith Blackwell; Schweizerischer National fonds zur Forderungder Wiss enschaftlichen Forschung P00P3_163898 Collin Yves Ewald; The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. NR 103 TC 0 Z9 0 U1 3 U2 3 PU ELIFE SCIENCES PUBLICATIONS LTD PI CAMBRIDGE PA SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND SN 2050-084X J9 ELIFE JI eLife PD JAN 13 PY 2017 VL 6 AR e19493 DI 10.7554/eLife.19493 PG 23 WC Biology SC Life Sciences & Biomedicine - Other Topics GA EJ7EQ UT WOS:000393384800001 ER PT J AU Sarmento, OF Svingen, PA Xiong, YN Sun, ZF Bamidele, AO Mathison, AJ Smyrk, TC Nair, AA Gonzalez, MM Sagstetter, MR Baheti, S McGovern, DPB Friton, JJ Papadakis, KA Gautam, G Xavier, RJ Urrutia, RA Faubion, WA AF Sarmento, Olga F. Svingen, Phyllis A. Xiong, Yuning Sun, Zhifu Bamidele, Adebowale O. Mathison, Angela J. Smyrk, Thomas C. Nair, Asha A. Gonzalez, Michelle M. Sagstetter, Mary R. Baheti, Saurabh McGovern, Dermot P. B. Friton, Jessica J. Papadakis, Konstantinos A. Gautam, Goel Xavier, Ramnik J. Urrutia, Raul A. Faubion, William A. TI The Role of the Histone Methyltransferase Enhancer of Zeste Homolog 2 (EZH2) in the Pathobiological Mechanisms Underlying Inflammatory Bowel Disease (IBD) SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID REGULATORY T-CELLS; GENE-EXPRESSION; HELPER-CELLS; RNA-SEQ; FOXP3; DIFFERENTIATION; CANCER; PHOSPHORYLATION; TRANSCRIPTION; METHYLATION AB Regulatory T (Treg) cells expressing the transcription factor FOXP3 play a pivotal role in maintaining immunologic self-tolerance. We and others have shown previously that EZH2 is recruited to the FOXP3 promoter and its targets in Treg cells. To further address the role for EZH2 in Treg cellular function, we have now generated mice that lack EZH2 specifically in Treg cells (EZH2(Delta/Delta) FOXP3(+)). We find that EZH2 deficiency in FOXP3(+) T cells results in lethal multiorgan autoimmunity. We further demonstrate that EZH2(Delta/Delta)FOXP3(+) T cells lack a regulatory phenotype in vitro and secrete proinflammatory cytokines. Of special interest, EZH2(Delta/Delta)FOXP3(+) mice develop spontaneous inflammatory bowel disease. Guided by these results, we assessed the FOXP3 and EZH2 gene networks by RNA sequencing in isolated intestinal CD4(+) T cells from patients with Crohn's disease. Gene network analysis demonstrates that these CD4(+) T cells display a Th1/Th17-like phenotype with an enrichment of gene targets shared by FOXP3 and EZH2. Combined, these results suggest that the inflammatory milieu found in Crohn's disease could lead to or result from deregulation of FOXP3/EZH2-enforced T cell gene networks contributing to the underlying intestinal inflammation. C1 [Sarmento, Olga F.; Svingen, Phyllis A.; Xiong, Yuning; Bamidele, Adebowale O.; Mathison, Angela J.; Gonzalez, Michelle M.; Sagstetter, Mary R.; Friton, Jessica J.; Papadakis, Konstantinos A.; Urrutia, Raul A.; Faubion, William A.] Mayo Clin, Div Gastroenterol & Hepatol, Epigenet & Chromatin Dynam Lab, Rochester, MN 55905 USA. [Sarmento, Olga F.; Svingen, Phyllis A.; Xiong, Yuning; Bamidele, Adebowale O.; Mathison, Angela J.; Gonzalez, Michelle M.; Sagstetter, Mary R.; Friton, Jessica J.; Papadakis, Konstantinos A.; Urrutia, Raul A.; Faubion, William A.] Mayo Clin, Translat Epigen Program, Ctr Individualized Med, Rochester, MN 55905 USA. [Sun, Zhifu; Nair, Asha A.; Baheti, Saurabh] Mayo Clin, Div Biomed Stat & Informat, Rochester, MN 55905 USA. [Smyrk, Thomas C.] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN 55905 USA. [McGovern, Dermot P. B.] Cedars Sinai Med Ctr, F Widjaja Fdn, Inflammatory Bowel & Immunobiol Res Inst, Los Angeles, CA 90048 USA. [Gautam, Goel; Xavier, Ramnik J.] Harvard Med Sch, Gastrointestinal Unit, Boston, MA 02114 USA. [Gautam, Goel; Xavier, Ramnik J.] Harvard Med Sch, Massachusetts Gen Hosp, Ctr Study Inflammatory Bowel Dis, Boston, MA 02114 USA. [Gautam, Goel; Xavier, Ramnik J.] Broad Inst MIT & Harvard, Ctr Computat & Integrat Biol, Cambridge, MA 02142 USA. RP Faubion, WA (reprint author), 200 First St SW, Rochester, MN 55905 USA. EM Faubion.william@mayo.edu FU Crohn's and Colitis Foundation of America [271332, 401661]; Mayo Clinic Foundation; National Institutes of Health [RO1DK52913]; Career Developmental Award Mayo Clinic SPORE in Pancreatic Cancer; Career Developmental Award Mayo Clinic Center for Cell Signaling in Gastroenterology; NIAID, National Institutes of Health [RO1 AI089714]; Leona Helmsley Charitable Trust FX This work was supported by Crohn's and Colitis Foundation of America Fellowship award 271332 and Career Development Award 401661 (to O. F. S.); the Mayo Clinic Foundation (to K. A. P.); National Institutes of Health Grant RO1DK52913 (to R. A. U.); Career Developmental Award Mayo Clinic SPORE in Pancreatic Cancer and Career Developmental Award Mayo Clinic Center for Cell Signaling in Gastroenterology (to G. A. L.); and NIAID, National Institutes of Health Grant RO1 AI089714 and the Leona Helmsley Charitable Trust (to W. A. F.). The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 60 TC 0 Z9 0 U1 1 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD JAN 13 PY 2017 VL 292 IS 2 BP 706 EP 722 DI 10.1074/jbc.M116.749663 PG 17 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EI2KN UT WOS:000392316100025 PM 27909059 ER PT J AU Abu Zaid, M Wu, J Wu, C Logan, BR Yu, J Cutler, C Antin, JH Paczesny, S Choi, SW AF Abu Zaid, Mohammad Wu, Juan Wu, Cindy Logan, Brent R. Yu, Jeffrey Cutler, Corey Antin, Joseph H. Paczesny, Sophie Choi, Sung Won TI Plasma biomarkers of risk for death in a multicenter phase 3 trial with uniform transplant characteristics post-allogeneic HCT SO BLOOD LA English DT Article ID VERSUS-HOST-DISEASE; STEM-CELL TRANSPLANTATION; ACUTE GVHD; T-CELLS; CXCL10; MORTALITY; PATHOGENESIS; PROPHYLAXIS; EXPRESSION; DIAGNOSIS AB A phase 3 clinical trial (BMT CTN 0402) comparing tacrolimus/sirolimus (Tac/Sir) vs tacrolimus/methotrexate (Tac/Mtx) as graft-versus-host disease (GVHD) prophylaxis after matched-related allogeneic hematopoietic cell transplantation (HCT) recently showed no difference between study arms in acute GVHD-free survival. Within this setting of a prospective, multicenter study with uniform GVHD prophylaxis, conditioning regimen, and donor source, we explored the correlation of 10 previously identified biomarkers with clinical outcomes after allogeneic HCT. We measured biomarkers from plasma samples collected in 211 patients using enzyme-linked immunosorbent assay (Tac/Sir5 104, Tac/ Mtx =107). High suppression of tumorigenicity-2 (ST2) and T-cell immunoglobulin mucin-3 (TIM3) at day 28 correlated with 2-year nonrelapse mortality in multivariate analysis (P =.0050, P =.0075, respectively) and in a proportional hazards model with time-dependent covariates (adjusted hazard ratio: 2.43 [1.49-3.95], P =.0038 and 4.87 [2.53-9.34], P <.0001, respectively). High ST2 and TIM3 correlated with overall survival. Chemokine (C-X-C motif) ligand 9 (CXCL9) levels above the median were associated with chronic GVHD compared with levels below the median in a time-dependent proportional hazard analysis (P=.0069). Low L-Ficolin was associated with hepatic veno-occlusive disease (P =.0053, AUC= 0.80). We confirmed the correlation of plasma-derived proteins, previously assessed in single-center cohorts, with clinical outcomes after allogeneic HCT within this prospective, multicenter study. C1 [Abu Zaid, Mohammad; Yu, Jeffrey; Paczesny, Sophie] Indiana Univ Sch Med, Dept Pediat, 1044 West Walnut St,Room 425, Indianapolis, IN 46202 USA. [Abu Zaid, Mohammad; Yu, Jeffrey; Paczesny, Sophie] Indiana Univ, Melvin & Bren Simon Canc Ctr, Indianapolis, IN 46204 USA. [Wu, Juan; Wu, Cindy] Emmes Corp, Rockville, MD USA. [Logan, Brent R.] Med Coll Wisconsin, Dept Biostat, Milwaukee, WI 53226 USA. [Cutler, Corey; Antin, Joseph H.] Harvard Med Sch, Dana Farber Canc Inst, Boston, MA USA. [Choi, Sung Won] Univ Michigan, Sch Med, Dept Pediat, Ann Arbor, MI USA. RP Paczesny, S (reprint author), Indiana Univ Sch Med, Dept Pediat, 1044 West Walnut St,Room 425, Indianapolis, IN 46202 USA.; Choi, SW (reprint author), Univ Michigan, Sch Med, 1500 East Med Ctr Dr,D4118 Med Profess Bldg, Ann Arbor, MI 48109 USA.; Paczesny, S (reprint author), Indiana Univ Sch Med, Dept Immunol, 1044 West Walnut St,Room 425, Indianapolis, IN 46202 USA. EM sophpacz@iu.edu; sungchoi@med.umich.edu FU National Institutes of Health (NIH), National Cancer Institute [R01CA168814, K23AI091623]; A. Alfred Taubman Medical Research Institute Emerging Scholar/Edith Briskin and Shirley K. Schlafer Foundation Award; Leukemia and Lymphoma Society Scholar Award [1293-15]; Lilly Physician Scientist Initiative Award; NIH, National Heart, Lung, and Blood Institute [U10HL069294]; NIH, National Cancer Institute FX This work was supported by grants from the National Institutes of Health (NIH), National Cancer Institute (R01CA168814) (S.P.) and (K23AI091623) (S.W.C.), the A. Alfred Taubman Medical Research Institute Emerging Scholar/Edith Briskin and Shirley K. Schlafer Foundation Award (S.W.C.), the Leukemia and Lymphoma Society Scholar Award (1293-15) (S.P.), and the Lilly Physician Scientist Initiative Award (S.P.). Support for this study was provided by grant U10HL069294 to the BMT CTN from the NIH, National Heart, Lung, and Blood Institute and the NIH, National Cancer Institute, along with contributions by Wyeth Pharmaceuticals Inc. NR 31 TC 1 Z9 1 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD JAN 12 PY 2017 VL 129 IS 2 BP 162 EP 170 DI 10.1182/blood-2016-08-735324 PG 9 WC Hematology SC Hematology GA EO2LO UT WOS:000396528200012 PM 27827824 ER PT J AU Han, X Zhang, JY Peng, YL Peng, MY Chen, X Chen, HY Song, JH Hu, X Ye, M Li, JL Sankaran, VG Hillyer, CD Mohandas, N An, XL Liu, J AF Han, Xu Zhang, Jieying Peng, Yuanliang Peng, Minyuan Chen, Xiao Chen, Huiyong Song, Jianhui Hu, Xiao Ye, Mao Li, Jianglin Sankaran, Vijay G. Hillyer, Christopher D. Mohandas, Narla An, Xiuli Liu, Jing TI Unexpected role for p19(INK4d) in posttranscriptional regulation of GATA1 and modulation of human terminal erythropoiesis SO BLOOD LA English DT Article ID TRANSCRIPTION FACTOR GATA-1; CELL-CYCLE EXIT; ERYTHROID-DIFFERENTIATION; DISORDERED ERYTHROPOIESIS; GLOBAL TRANSCRIPTOME; HEMATOPOIETIC STEM; GENE-EXPRESSION; MICE LACKING; KINASE; PROLIFERATION AB Terminal erythroid differentiation is tightly coordinated with cell-cycle exit, which is regulated by cyclins, cyclin-dependent kinases, and cyclin-dependent kinase inhibitors (CDKI), yet their roles in erythropoiesis remain to be fully defined. We show here that p19 (INK4d,) a member of CDKI family, is abundantly expressed in erythroblasts and that p19 (INK4d) knockdown delayed erythroid differentiation, inhibited cell growth, and led to increased apoptosis and generation of abnormally nucleated late-stage erythroblasts. Unexpectedly, p19 (INK4d) knockdown did not affect cell cycle. Rather, it led to decreased expression of GATA1 protein. Importantly, the differentiation and nuclear defects were rescued by ectopic expression of GATA1. Because the GATA1 protein is protected by nuclear heat shock protein family (HSP) member HSP70, we examined the effects of p19 (INK4d) knockdown on HSP70 and found that p19 (INK4d) knockdown led to decreased expression of HSP70 and its nuclear localization. The reduced levels of HSP70 are the result of reduced extracellular signal-regulated kinase (ERK) activation. Further biochemical analysis revealed that p19 (INK4d) directly binds to Raf kinase inhibitor PEBP1 and that p19 (INK4d) knockdown increased the expression of PEBP1, which in turn led to reduced ERK activation. Thus we have identified an unexpected role for p19 INK4d via a novel PEBP1p- ERK-HSP70-GATA1 pathway. These findings are likely to have implications for improved understanding of disordered erythropoiesis. C1 [Han, Xu; Zhang, Jieying; Peng, Yuanliang; Chen, Xiao; Chen, Huiyong; Liu, Jing] Cent S Univ, State Key Lab Med Genet, 110 Xiangya Rd, Changsha 410078, Hunan, Peoples R China. [Han, Xu; Zhang, Jieying; Peng, Yuanliang; Chen, Xiao; Chen, Huiyong; Liu, Jing] Cent S Univ, Sch Life Sci, 110 Xiangya Rd, Changsha 410078, Hunan, Peoples R China. [Zhang, Jieying; An, Xiuli] New York Blood Ctr, Lab Membrane Biol, 310 E 67th St, New York, NY 10065 USA. [Peng, Minyuan; Song, Jianhui] Cent S Univ, Xiangya Hosp, Changsha, Hunan, Peoples R China. [Hu, Xiao] Chinese Acad Med Sci, Inst Hematol, Key Lab Expt Hematol, Tianjin, Peoples R China. [Hu, Xiao] Chinese Acad Med Sci, Blood Dis Hosp, Tianjin, Peoples R China. [Hu, Xiao] Peking Union Med Coll, Tianjin, Peoples R China. [Ye, Mao; Li, Jianglin] Hunan Univ, Mol Sci & Biomed Lab, State Key Lab Chemo Biosensing & Chemometr, Coll Biol,Coll Chem & Chem Engn, Changsha, Hunan, Peoples R China. [Sankaran, Vijay G.] Broad Inst Massachusetts Inst Technol & Harvard, Cambridge, MA USA. [Sankaran, Vijay G.] Harvard Med Sch, Div Hematol Oncol, Boston Childrens Hosp, Boston, MA USA. [Sankaran, Vijay G.] Harvard Med Sch, Dept Pediat Oncol, Dana Farber Canc Inst, Boston, MA USA. [Hillyer, Christopher D.; Mohandas, Narla] New York Blood Ctr, Red Cell Physiol Lab, New York, NY 10021 USA. [An, Xiuli] Zhengzhou Univ, Coll Life Sci, Zhengzhou, Peoples R China. RP Liu, J (reprint author), Cent S Univ, State Key Lab Med Genet, 110 Xiangya Rd, Changsha 410078, Hunan, Peoples R China.; Liu, J (reprint author), Cent S Univ, Sch Life Sci, 110 Xiangya Rd, Changsha 410078, Hunan, Peoples R China.; An, XL (reprint author), New York Blood Ctr, Lab Membrane Biol, 310 E 67th St, New York, NY 10065 USA. EM anxl@zzu.edu.cn; liujing2@sklmg.edu.cn FU Natural Science Foundation of China [81270576, 81470362, 81530005, 81170459]; National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [DK100810, DK26263]; Science and Technology key project of Hunan Province [2015JC3010]; postgraduate innovation project of Central South University of China [2015zzts095]; Mittal students' innovation project of Central South University of China [15MX48] FX This work was supported in part by the Natural Science Foundation of China (grants 81270576, 81470362, 81530005, and 81170459), the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases (DK100810 and DK26263), the Science and Technology key project of Hunan Province (2015JC3010), and the postgraduate innovation project of Central South University of China (2015zzts095), and the Mittal students' innovation project of Central South University of China (15MX48). NR 53 TC 1 Z9 1 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD JAN 12 PY 2017 VL 129 IS 2 BP 226 EP 237 DI 10.1182/blood-2016-09-739268 PG 12 WC Hematology SC Hematology GA EO2LO UT WOS:000396528200018 PM 27879259 ER PT J AU Rowe, RG Daley, GQ AF Rowe, R. Grant Daley, George Q. TI STEM CELLS Valine starvation leads to a hungry niche SO NATURE LA English DT Editorial Material ID TRANSPLANTATION C1 [Rowe, R. Grant; Daley, George Q.] Boston Childrens Hosp, Div Pediat Hematol Oncol, Boston, MA 02115 USA. [Rowe, R. Grant; Daley, George Q.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Daley, George Q.] Howard Hughes Med Inst, Boston, MA 02115 USA. RP Daley, GQ (reprint author), Boston Childrens Hosp, Div Pediat Hematol Oncol, Boston, MA 02115 USA.; Daley, GQ (reprint author), Dana Farber Canc Inst, Boston, MA 02115 USA. EM george.daley@childrens.harvard.edu FU NHLBI NIH HHS [T32 HL007574]; NIDDK NIH HHS [R01 DK059279] NR 8 TC 0 Z9 0 U1 4 U2 4 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 JAN 12 PY 2017 VL 541 IS 7636 BP 166 EP 167 PG 3 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EN6PI UT WOS:000396125500028 PM 27974805 ER PT J AU Kim, J Bowlby, R Mungall, AJ Robertson, AG Odze, RD Cherniack, AD Shih, J Pedamallu, CS Cibulskis, C Dunford, A Meier, SR Kim, J Raphael, BJ Wu, HT Wong, AM Willis, JE Bass, AJ Derks, S Garman, K McCall, SJ Wiznerowicz, M Pantazi, A Parfenov, M Thorsson, V Shmulevich, I Dhankani, V Miller, M Sakai, R Wang, K Schultz, N Shen, R Arora, A Weinhold, N Sanchez-Vega, F Kelsen, DP Zhang, J Felau, I Demchok, J Rabkin, CS Camargo, MC Zenklusen, JC Bowen, J Leraas, K Lichtenberg, TM Curtis, C Seoane, JA Ojesina, AI Beer, DG Gulley, ML Pennathur, A Luketich, JD Zhou, ZR Weisenberger, DJ Akbani, R Lee, JS Liu, W Mills, GB Zhang, W Reid, BJ Hinoue, T Laird, PW Shen, H Piazuelo, MB Schneider, BG McLellan, M Taylor-Weiner, A Cibulskis, C Lawrence, M Cibulskis, K Stewart, C Getz, G Lander, E Gabriel, SB Ding, L McLellan, MD Miller, CA Appelbaum, EL Cordes, MG Fronick, CC Fulton, LA Mardis, ER Wilson, RK Schmidt, HK Fulton, RS Ally, A Balasundaram, M Bowlby, R Carlsen, R Chuah, E Dhalla, N Holt, RA Jones, SJM Kasaian, K Brooks, D Li, HI Ma, Y Marra, MA Mayo, M Moore, RA Mungall, AJ Mungall, KL Robertson, AG Schein, JE Sipahimalani, P Tam, A Thiessen, N Wong, T Cherniack, AD Shih, J Pedamallu, CS Beroukhim, R Bullman, S Cibulskis, C Murray, BA Saksena, G Schumacher, SE Gabriel, S Meyerson, M Hadjipanayis, A Kucherlapati, R Pantazi, A Parfenov, M Ren, X Park, PJ Lee, S Kucherlapati, M Yang, LX Baylin, SB Hoadley, KA Weisenberger, DJ Bootwalla, MS Lai, PH Van den Berg, DJ Berrios, M Holbrook, A Akbani, R Hwang, JE Jang, HJ Liu, WB Weinstein, JN Lee, JS Lu, YL Sohn, BH Mills, G Seth, S Protopopov, A Bristow, CA Mahadeshwar, HS Tang, JB Song, XZ Zhang, JH Laird, PW Hinoue, T Shen, H Cho, J Defrietas, T Frazer, S Gehlenborg, N Heiman, DI Lawrence, MS Lin, P Meier, SR Noble, MS Voet, D Zhang, HL Kim, J Polak, P Saksena, G Chin, L Getz, G Wong, AM Raphael, BJ Wu, HT Lee, S Park, PJ Yang, LX Thorsson, V Bernard, B Iype, L Miller, M Reynolds, SM Shmulevich, I Dhankani, V Abeshouse, A Arora, A Armenia, J Kundra, R Ladanyi, M Kjong-Van Lehmann Gao, J Sander, C Schultz, N Sanchez-Vega, F Shen, RL Weinhold, N Chakravarty, D Zhang, HX Radenbaugh, A Hegde, A Akbani, R Liu, WB Weinstein, JN Chin, L Bristow, CA Lu, YL Penny, R Crain, D Gardner, J Curley, E Mallery, D Morris, S Paulauskis, J Shelton, T Shelton, C Bowen, J Frick, J Gastier-Foster, JM Gerken, M Leraas, KM Lichtenberg, TM Ramirez, NC Wise, L Zmuda, E Tarvin, K Saller, C Park, YS Button, M Carvalho, AL Reis, RM Matsushita, MM Lucchesi, F de Oliveira, AT Le, X Paklina, O Setdikova, G Lee, JH Bennett, J Iacocca, M Huelsenbeck-Dill, L Potapova, CO Voronina, O Liu, O Fulidou, V Cates, C Sharp, A Behera, M Force, S Khuri, F Owonikoko, T Pickens, A Ramalingam, S Sica, G Dinjens, W van Nistelrooij, A Wijnhoven, B Sandusky, G Stepa, S Crain, D Paulauskis, J Penny, R Gardner, J Mallery, D Morris, S Shelton, T Shelton, C Curley, E Juhl, IH Zornig, C Kwon, SY Kelsen, D Kim, GHK Bartlett, J Parfitt, J Chetty, R Darling, G Knox, J Wong, R El-Zimaity, H Liu, G Boussioutas, A Park, DY Kemp, R Carlotti, CG Tirapelli, DPD Saggioro, FP Sankarankutty, AK Noushmehr, H dos Santos, JS Trevisan, FA Eschbacher, J Eschbacher, J Dubina, M Mozgovoy, E Carey, F Chalmers, S Forgie, I Godwin, A Reilly, C Madan, R Naima, Z Ferrer-Torres, D Vinco, M Dhir, R Luketich, J Pennathur, A Ajani, JA McCall, SJ Janjigian, Y Kelsen, D Ladanyi, M Tang, L Camargo, MC Ajani, JA Cheong, JH Chudamani, S Liu, J Lolla, L Naresh, R Pihl, T Sun, Q Wan, YH Wu, Y Demchok, JA Felau, I Ferguson, ML Shaw, KRM Sheth, M Tarnuzzer, R Wang, ZN Yang, LM Zenklusen, JC Hutter, CM Sofia, HJ Zhang, JS AF Kim, Jihun Bowlby, Reanne Mungall, Andrew J. Robertson, A. Gordon Odze, Robert D. Cherniack, Andrew D. Shih, Juliann Pedamallu, Chandra Sekhar Cibulskis, Carrie Dunford, Andrew Meier, Samuel R. Kim, Jaegil Raphael, Benjamin J. Wu, Hsin-Ta Wong, Alexandra M. Willis, Joseph E. Bass, Adam J. Derks, Sarah Garman, Katherine McCall, Shannon J. Wiznerowicz, Maciej Pantazi, Angeliki Parfenov, Michael Thorsson, Vesteinn Shmulevich, Ilya Dhankani, Varsha Miller, Michael Sakai, Ryo Wang, Kenneth Schultz, Nikolaus Shen, Ronglai Arora, Arshi Weinhold, Nils Sanchez-Vega, Francisco Kelsen, David P. Zhang, Julia Felau, Ina Demchok, John Rabkin, Charles S. Camargo, M. Constanza Zenklusen, Jean Claude Bowen, Jay Leraas, Kristen Lichtenberg, Tara M. Curtis, Christina Seoane, Jose A. Ojesina, Akinyemi I. Beer, David G. Gulley, Margaret L. Pennathur, Arjun Luketich, James D. Zhou, Zhongren Weisenberger, Daniel J. Akbani, Rehan Lee, Ju-Seog Liu, Wenbin Mills, Gordon B. Zhang, Wei Reid, Brian J. Hinoue, Toshinori Laird, Peter W. Shen, Hui Piazuelo, M. Blanca Schneider, Barbara G. McLellan, Michael Taylor-Weiner, Amaro Cibulskis, Carrie Lawrence, Michael Cibulskis, Kristian Stewart, Chip Getz, Gad Lander, Eric Gabriel, Stacey B. Ding, Li McLellan, Michael D. Miller, Christopher A. Appelbaum, Elizabeth L. Cordes, Matthew G. Fronick, Catrina C. Fulton, Lucinda A. Mardis, Elaine R. Wilson, Richard K. Schmidt, Heather K. Fulton, Robert S. Ally, Adrian Balasundaram, Miruna Bowlby, Reanne Carlsen, Rebecca Chuah, Eric Dhalla, Noreen Holt, Robert A. Jones, Steven J. M. Kasaian, Katayoon Brooks, Denise Li, Haiyan I. Ma, Yussanne Marra, Marco A. Mayo, Michael Moore, Richard A. Mungall, Andrew J. Mungall, Karen L. Robertson, A. Gordon Schein, Jacqueline E. Sipahimalani, Payal Tam, Angela Thiessen, Nina Wong, Tina Cherniack, Andrew D. Shih, Juliann Pedamallu, Chandra Sekhar Beroukhim, Rameen Bullman, Susan Cibulskis, Carrie Murray, Bradley A. Saksena, Gordon Schumacher, Steven E. Gabriel, Stacey Meyerson, Matthew Hadjipanayis, Angela Kucherlapati, Raju Pantazi, Angeliki Parfenov, Michael Ren, Xiaojia Park, Peter J. Lee, Semin Kucherlapati, Melanie Yang, Lixing Baylin, Stephen B. Hoadley, Katherine A. Weisenberger, Daniel J. Bootwalla, Moiz S. Lai, Phillip H. Van den Berg, David J. Berrios, Mario Holbrook, Andrea Akbani, Rehan Hwang, Jun-Eul Jang, Hee-Jin Liu, Wenbin Weinstein, John N. Lee, Ju-Seog Lu, Yiling Sohn, Bo Hwa Mills, Gordon Seth, Sahil Protopopov, Alexei Bristow, Christopher A. Mahadeshwar, Harshad S. Tang, Jiabin Song, Xingzhi Zhang, Jianhua Laird, Peter W. Hinoue, Toshinori Shen, Hui Cho, Juok Defrietas, Timothy Frazer, Scott Gehlenborg, Nils Heiman, David I. Lawrence, Michael S. Lin, Pei Meier, Samuel R. Noble, Michael S. Doug Voet Zhang, Hailei Kim, Jaegil Polak, Paz Saksena, Gordon Chin, Lynda Getz, Gad Wong, Alexandra M. Raphael, Benjamin J. Wu, Hsin-Ta Lee, Semin Park, Peter J. Yang, Lixing Thorsson, Vesteinn Bernard, Brady Iype, Lisa Miller, Michael Reynolds, Sheila M. Shmulevich, Ilya Dhankani, Varsha Abeshouse, Adam Arora, Arshi Armenia, Joshua Kundra, Ritika Ladanyi, Marc Kjong-Van Lehmann Gao, Jianjiong Sander, Chris Schultz, Nikolaus Sanchez-Vega, Francisco Shen, Ronglai Weinhold, Nils Chakravarty, Debyani Zhang, Hongxin Radenbaugh, Amie Hegde, Apruva Akbani, Rehan Liu, Wenbin Weinstein, John N. Chin, Lynda Bristow, Christopher A. Lu, Yiling Penny, Robert Crain, Daniel Gardner, Johanna Curley, Erin Mallery, David Morris, Scott Paulauskis, Joseph Shelton, Troy Shelton, Candace Bowen, Jay Frick, Jessica Gastier-Foster, Julie M. Gerken, Mark Leraas, Kristen M. Lichtenberg, Tara M. Ramirez, Nilsa C. Wise, Lisa Zmuda, Erik Tarvin, Katherine Saller, Charles Park, Young Soo Button, Michael Carvalho, Andre L. Reis, Rui Manuel Matsushita, Marcus Medeiros Lucchesi, Fabiano de Oliveira, Antonio Talvane Le, Xuan Paklina, Oxana Setdikova, Galiya Lee, Jae-Hyuck Bennett, Joseph Iacocca, Mary Huelsenbeck-Dill, Lori Potapova, Cureline Olga Voronina, Olga Liu, Ouida Fulidou, Victoria Cates, Crystal Sharp, Alexis Behera, Madhusmitara Force, Seth Khuri, Fadio Owonikoko, Taofeek Pickens, Allan Ramalingam, Suresh Sica, Gabriel Dinjens, Winand van Nistelrooij, Anna Wijnhoven, Bas Sandusky, George Stepa, Serghei Crain, Daniel Paulauskis, Joseph Penny, Robert Gardner, Johanna Mallery, David Morris, Scott Shelton, Troy Shelton, Candace Curley, Erin Juhl, Invidumed Hartmut Zornig, Carsten Kwon, Sun Young Kelsen, David Kim, Goyang Hark Kyun Bartlett, John Parfitt, Jeremy Chetty, Runjan Darling, Gail Knox, Jennifer Wong, Rebecca El-Zimaity, Haila Liu, Geoffrey Boussioutas, Alex Park, Do Young Kemp, Rafael Carlotti, Carlos Gilberto, Jr. da Cunha Tirapelli, Daniela Pretti Saggioro, Fabiano Pinto Sankarankutty, Ajith Kumar Noushmehr, Houtan dos Santos, Jose Sebastiao Trevisan, Felipe Amstalden Eschbacher, Jennifer Eschbacher, Jennifer Dubina, Michael Mozgovoy, Eugene Carey, Frank Chalmers, Sally Forgie, Ian Godwin, Andrew Reilly, Colleen Madan, Rashna Naima, Zaid Ferrer-Torres, Daysha Rathmell, W. Kimryn Dhir, Rajiv Luketich, James Pennathur, Arjun Ajani, Jaffer A. McCall, Shannon J. Janjigian, Yelena Kelsen, David Ladanyi, Marc Tang, Laura Camargo, M. Constanza Ajani, Jaffer A. Cheong, Jae-Ho Chudamani, Sudha Liu, Jai Lolla, Laxmi Naresh, Rashi Pihl, Todd Sun, Qiang Wan, Yunhu Wu, Ye Demchok, John A. Felau, Ina Ferguson, Martin L. Shaw, Kenna R. Mills sheth, Margi Tarnuzzer, Roy Wang, Zhining Yang, Liming Zenklusen, Jean Claude Hutter, Carolyn M. Sofia, Heidi J. Zhang, Jiashan CA Canc Genome Atlas Res Network TI Integrated genomic characterization of oesophageal carcinoma SO NATURE LA English DT Article ID SQUAMOUS-CELL CARCINOMA; HUMAN CANCER; ESOPHAGOGASTRIC JUNCTION; STRUCTURAL VARIATIONS; LINEAGE-SURVIVAL; SEQUENCING DATA; ADENOCARCINOMA; GENES; LUNG; IDENTIFICATION AB Oesophageal cancers are prominent worldwide; however, there are few targeted therapies and survival rates for these cancers remain dismal. Here we performed a comprehensive molecular analysis of 164 carcinomas of the oesophagus derived from Western and Eastern populations. Beyond known histopathological and epidemiologic distinctions, molecular features differentiated oesophageal squamous cell carcinomas from oesophageal adenocarcinomas. Oesophageal squamous cell carcinomas resembled squamous carcinomas of other organs more than they did oesophageal adenocarcinomas. Our analyses identified three molecular subclasses of oesophageal squamous cell carcinomas, but none showed evidence for an aetiological role of human papillomavirus. Squamous cell carcinomas showed frequent genomic amplifications of CCND1 and SOX2 and/or TP63, whereas ERBB2, VEGFA and GATA4 and GATA6 were more commonly amplified in adenocarcinomas. Oesophageal adenocarcinomas strongly resembled the chromosomally unstable variant of gastric adenocarcinoma, suggesting that these cancers could be considered a single disease entity. However, some molecular features, including DNA hypermethylation, occurred disproportionally in oesophageal adenocarcinomas. These data provide a framework to facilitate more rational categorization of these tumours and a foundation for new therapies. C1 [Kim, Jihun; Park, Young Soo] Univ Ulsan, Coll Med, Asan Med Ctr, Dept Pathol, Seoul 05505, South Korea. [Ally, Adrian; Balasundaram, Miruna; Carlsen, Rebecca; Chuah, Eric; Dhalla, Noreen; Holt, Robert A.; Jones, Steven J. M.; Kasaian, Katayoon; Brooks, Denise; Li, Haiyan I.; Ma, Yussanne; Marra, Marco A.; Mayo, Michael; Moore, Richard A.; Mungall, Karen L.; Schein, Jacqueline E.; Sipahimalani, Payal; Tam, Angela; Thiessen, Nina; Wong, Tina] BC Canc Agcy, Canadas Michael Smith Genome Sci Ctr, Vancouver, BC V5Z 4S6, Canada. [Odze, Robert D.] Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA. [Odze, Robert D.; Meyerson, Matthew] Harvard Med Sch, Dept Pathol, Boston, MA 02215 USA. [Cherniack, Andrew D.; Pedamallu, Chandra Sekhar; Dunford, Andrew; Taylor-Weiner, Amaro; Lawrence, Michael; Cibulskis, Kristian; Stewart, Chip; Lander, Eric; Gabriel, Stacey B.; Cherniack, Andrew D.; Pedamallu, Chandra Sekhar; Beroukhim, Rameen; Bullman, Susan; Murray, Bradley A.; Schumacher, Steven E.; Gabriel, Stacey; Cho, Juok; Defrietas, Timothy; Frazer, Scott; Gehlenborg, Nils; Heiman, David I.; Lawrence, Michael S.; Lin, Pei; Noble, Michael S.; Doug Voet; Zhang, Hailei; Polak, Paz] Eli & Edythe L Broad Inst Massachusetts Inst Tech, Cambridge, MA 02142 USA. [Pedamallu, Chandra Sekhar; Bass, Adam J.; Derks, Sarah; Cherniack, Andrew D.; Beroukhim, Rameen; Bullman, Susan; Meyerson, Matthew] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Raphael, Benjamin J.; Wu, Hsin-Ta; Wong, Alexandra M.] Brown Univ, Dept Comp Sci, Providence, RI 02912 USA. [Raphael, Benjamin J.; Wu, Hsin-Ta; Wong, Alexandra M.] Brown Univ, Ctr Computat Mol Biol, Providence, RI 02912 USA. [Willis, Joseph E.] Case Western Reserve Univ, Dept Pathol, Cleveland, OH 44106 USA. [Willis, Joseph E.] Case Med Ctr, Dept Pathol, Cleveland, OH 44106 USA. [Bass, Adam J.] Dana Farber Canc Inst, Ctr Canc Genome Discovery, Boston, MA 02115 USA. [Derks, Sarah] Vrije Univ Amsterdam, Med Ctr, Dept Med Oncol, Amsterdam, Netherlands. [Garman, Katherine; Cates, Crystal; Sharp, Alexis] Duke Univ, Dept Pathol, Durham, NC 27710 USA. [Wiznerowicz, Maciej] Int Inst Mol Oncol, PL-60203 Poznan, Poland. [Wiznerowicz, Maciej] Greater Poland Canc Ctr, PL-61866 Poznan, Poland. [Wiznerowicz, Maciej] Poznan Univ Med Sci, PL-61866 Poznan, Poland. [Hadjipanayis, Angela; Kucherlapati, Raju; Ren, Xiaojia; Kucherlapati, Melanie] Harvard Med Sch, Dept Genet, Boston, MA 02115 USA. [Ren, Xiaojia; Protopopov, Alexei] KEW Grp Inc, Cambridge, MA 02139 USA. [Thorsson, Vesteinn; Bernard, Brady; Iype, Lisa; Reynolds, Sheila M.] Inst Syst Biol, Seattle, WA 98109 USA. [Sakai, Ryo] Katholieke Univ Leuven, Dept Elect Engn ESAT STADIUS, Leuven, Belgium. [Sakai, Ryo] Katholieke Univ Leuven, iMinds Med IT, B-3001 Leuven, Belgium. [Wang, Kenneth] Mayo Clin, Div Gastroenterol & Hepatol, Rochester, MN 55905 USA. [Schultz, Nikolaus; Armenia, Joshua; Kundra, Ritika; Gao, Jianjiong; Chakravarty, Debyani; Zhang, Hongxin] Mem Sloan Kettering Canc Ctr, Ctr Mol Oncol, New York, NY 10065 USA. [Shen, Ronglai] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10065 USA. [Abeshouse, Adam; Kjong-Van Lehmann; Sander, Chris] Mem Sloan Kettering Canc Ctr, Computat Biol Ctr, New York, NY 10065 USA. [Kelsen, David P.; Janjigian, Yelena] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10065 USA. [Zhang, Julia; Demchok, John; Demchok, John A.; Ferguson, Martin L.; Shaw, Kenna R. Mills; sheth, Margi; Tarnuzzer, Roy; Wang, Zhining; Yang, Liming; Zhang, Jiashan] NCI, Bethesda, MD 20892 USA. [Rabkin, Charles S.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Leraas, Kristen; Frick, Jessica; Gastier-Foster, Julie M.; Gerken, Mark; Leraas, Kristen M.; Ramirez, Nilsa C.; Wise, Lisa; Zmuda, Erik] Nationwide Childrens Hosp, Res Inst, Columbus, OH 43205 USA. [Curtis, Christina; Seoane, Jose A.] Stanford Univ, Sch Med, Div Oncol, Dept Med, Stanford, CA 94305 USA. [Curtis, Christina; Seoane, Jose A.] Stanford Univ, Sch Med, Dept Genet, Stanford, CA 94305 USA. [Ojesina, Akinyemi I.] Univ Alabama Birmingham, Dept Epidemiol, Birmingham, AL 35294 USA. [Ojesina, Akinyemi I.] HudsonAlpha Inst Biotechnol, Huntsville, AL 35806 USA. [Beer, David G.; Ferrer-Torres, Daysha] Univ Michigan, Ctr Comprehens Canc, Dept Thorac Surg, Ann Arbor, MI 48109 USA. [Gulley, Margaret L.] Univ North Carolina Chapel Hill, Dept Pathol & Lab Med, Chapel Hill, NC 27599 USA. [Luketich, James D.; Luketich, James] Univ Pittsburgh, Med Ctr, Sch Med, Dept Cardiothorac Surg, Pittsburgh, PA 15213 USA. [Zhou, Zhongren] Univ Rochester, Dept Pathol & Lab Med, Rochester, NY 14642 USA. [Weisenberger, Daniel J.] Univ Southern Calif, Dept Biochem & Mol Biol, Los Angeles, CA 90033 USA. [Liu, Wenbin; Weinstein, John N.; Hegde, Apruva] Univ Texas MD Anderson Canc Ctr, Dept Bioinformat & Computat Biol, Houston, TX 77030 USA. [Lee, Ju-Seog; Mills, Gordon B.; Mills, Gordon] Univ Texas MD Anderson Canc Ctr, Dept Syst Biol, Houston, TX 77030 USA. [Zhang, Wei] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA. [Reid, Brian J.] Fred Hutchinson Canc Res Ctr, North Seattle, WA 98109 USA. [Hinoue, Toshinori] Van Andel Res Inst, Ctr Epigenet, Grand Rapids, MI 49503 USA. [Piazuelo, M. Blanca; Schneider, Barbara G.] Vanderbilt Univ, Med Ctr, Div Gastroenterol, Dept Med, Nashville, TN 37232 USA. [McLellan, Michael; Ding, Li; McLellan, Michael D.; Miller, Christopher A.; Appelbaum, Elizabeth L.; Cordes, Matthew G.; Fronick, Catrina C.; Fulton, Lucinda A.; Mardis, Elaine R.; Wilson, Richard K.; Schmidt, Heather K.; Fulton, Robert S.] Washington Univ, McDonnell Genome Inst, St Louis, MO 63108 USA. [Taylor-Weiner, Amaro; Lee, Semin; Gehlenborg, Nils] Harvard Med Sch, Dept Biomed Informat, Boston, MA 02115 USA. [Polak, Paz] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Ding, Li] Washington Univ, Sch Med, Dept Med, St Louis, MO 63108 USA. [Beroukhim, Rameen] Harvard Med Sch, Dept Med, Boston, MA 02215 USA. [Schumacher, Steven E.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA. [Hadjipanayis, Angela; Kucherlapati, Raju; Kucherlapati, Melanie] Brigham & Womens Hosp, Div Genet, 75 Francis St, Boston, MA 02115 USA. [Baylin, Stephen B.] Johns Hopkins Univ, Sidney Kimmel Comprehens Canc Ctr, Canc Biol Div, Baltimore, MD 21231 USA. [Hoadley, Katherine A.] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27514 USA. [Bootwalla, Moiz S.; Lai, Phillip H.; Berrios, Mario; Holbrook, Andrea] USC, Norris Comprehens Canc Ctr, Los Angeles, CA 90033 USA. [Van den Berg, David J.] Univ So Calif, Dept Prevent Med, Los Angeles, CA 90033 USA. [Hwang, Jun-Eul; Jang, Hee-Jin; Lee, Ju-Seog; Sohn, Bo Hwa] Univ Texas MD Anderson Canc Ctr, Dept Syst Biol, Inst Personalized Canc Treatment, Houston, TX 77030 USA. [Hwang, Jun-Eul] Chonnam Natl Univ, Sch Med, Dept Hematooncol, Kwangju, South Korea. [Seth, Sahil; Protopopov, Alexei; Mahadeshwar, Harshad S.; Tang, Jiabin; Song, Xingzhi; Zhang, Jianhua] Univ Texas MD Anderson Canc Ctr, Dept Genom Med, Inst Appl Canc Sci, Houston, TX 77054 USA. [Weinstein, John N.; Le, Xuan; Tang, Laura] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10065 USA. [Radenbaugh, Amie] Univ Calif Santa Cruz, Genom Inst, Santa Cruz, CA 95064 USA. [Gardner, Johanna; Morris, Scott; Paulauskis, Joseph; Shelton, Troy] Int Genom Consortium, Phoenix, AZ 85004 USA. [Tarvin, Katherine; Saller, Charles] Analyt Biol Serv Inc, Wilmington, DE 19801 USA. [Button, Michael] Asterand Biosci, Detroit, MI 48202 USA. [Carvalho, Andre L.; Reis, Rui Manuel] Barretos Canc Hosp, Mol Oncol Res Ctr, Sao Paulo, Brazil. [Reis, Rui Manuel] Univ Minho, Sch Hlth Sci, Life & Hlth Sci Res Inst ICVS, Braga, Portugal. [Matsushita, Marcus Medeiros] Barretos Canc Hosp, Dept Pathol, Sao Paulo, Brazil. [Lucchesi, Fabiano] Barretos Canc Hosp, Dept Radiol, Sao Paulo, Brazil. [de Oliveira, Antonio Talvane] Barretos Canc Hosp, Dept Surg, Sao Paulo, Brazil. [Le, Xuan] BioreclamationIVT, Dept Res Pathol, Chestertown, MD 21620 USA. [Paklina, Oxana; Setdikova, Galiya] Botkin Municipal Clin, Moscow 125284, Russia. [Lee, Jae-Hyuck] Chonnam Natl Univ, Sch Med, Dept Pathol, Hwasun, South Korea. [Bennett, Joseph; Iacocca, Mary; Huelsenbeck-Dill, Lori] Christiana Care Hlth Syst, Helen F Graham Canc Ctr & Res Inst, Newark, DE 19713 USA. [Potapova, Cureline Olga; Voronina, Olga; Liu, Ouida; Fulidou, Victoria] Cureline Inc, San Francisco, CA 94080 USA. [Behera, Madhusmitara; Force, Seth; Khuri, Fadio; Owonikoko, Taofeek; Pickens, Allan; Ramalingam, Suresh; Sica, Gabriel] Emory Univ, Atlanta, GA 30322 USA. [Behera, Madhusmitara; Force, Seth; Khuri, Fadio; Owonikoko, Taofeek; Pickens, Allan; Ramalingam, Suresh; Sica, Gabriel] Winship Canc Inst, Atlanta, GA 30322 USA. [Dinjens, Winand] Univ Med Ctr, Erasmus MC Canc Inst, Dept Pathol, NL-3000 CA Rotterdam, Netherlands. [van Nistelrooij, Anna; Wijnhoven, Bas] Univ Med Ctr Rotterdam, Erasmus MC Canc Inst, Dept Surg, NL-3000 CA Rotterdam, Netherlands. [van Nistelrooij, Anna] Univ Med Ctr Rotterdam, Erasmus MC Canc Inst, Dept Pathol, NL-3000 CA Rotterdam, Netherlands. [Sandusky, George] Indiana Univ Sch Med, Dept Pathol & Lab Med, Indianapolis, IN 46202 USA. [Stepa, Serghei] Inst Oncol Moldova, Kishinev, Moldova. [Juhl, Invidumed Hartmut] Indivumed GmbH, D-20251 Hamburg, Germany. [Zornig, Carsten] Israelit Krankenhaus Hamburg, D-22297 Hamburg, Germany. [Kwon, Sun Young] Keimyung Univ, Sch Med, Dept Pathol, Daegu, South Korea. [Kim, Goyang Hark Kyun] Natl Canc Ctr, Ctr Gastr Canc, Goyang, South Korea. [Bartlett, John] Ontario Inst Canc Res, Ontario Tumour Bank, Toronto, ON M5G 0A3, Canada. [Parfitt, Jeremy] London Hlth Sci Ctr, Ontario Tumour Bank, London, ON N6A 5A5, Canada. [Chetty, Runjan; Darling, Gail; Knox, Jennifer; Wong, Rebecca; El-Zimaity, Haila; Liu, Geoffrey] Princess Margaret Canc Ctr, Toronto, ON M5G 2M9, Canada. [Boussioutas, Alex] Univ Melbourne, Sir Peter MacCallum Canc Dept Oncol, Melbourne, Vic 3002, Australia. [Park, Do Young] Pusan Natl Univ, Sch Med, Dept Pathol, Pusan, South Korea. [Kemp, Rafael; Carlotti, Carlos Gilberto, Jr.; da Cunha Tirapelli, Daniela Pretti; Sankarankutty, Ajith Kumar; dos Santos, Jose Sebastiao; Trevisan, Felipe Amstalden] Univ Sao Paulo, Ribeirao Preto Med School FMRP, Dept Surg & Anat, BR-14049900 Sao Paulo, Brazil. [Saggioro, Fabiano Pinto] Univ Sao Paulo, Ribeirao Preto Med School FMRP, Dept Pathol, BR-14049900 Sao Paulo, Brazil. [Noushmehr, Houtan] Univ Sao Paulo, Ribeirao Preto Med School FMRP, Dept Genet, BR-14049900 Sao Paulo, Brazil. [Eschbacher, Jennifer] St Josephs Hosp, Dept Pathol, Phoenix, AZ 85013 USA. [Dubina, Michael; Mozgovoy, Eugene] St Petersburg Acad Univ, RAS, St Petersburg 194021, Russia. [Carey, Frank; Chalmers, Sally; Forgie, Ian] Univ Dundee, Ninewells Hosp & Med Sch, Tayside Tissue Bank, Dundee DD1 9SY, Scotland. [Godwin, Andrew; Reilly, Colleen; Madan, Rashna; Naima, Zaid] Univ Kansas, Med Ctr, Kansas City, KS 66160 USA. [Ferrer-Torres, Daysha] Univ Michigan, Dept Pathol, Ann Arbor, MI 48109 USA. [Rathmell, W. Kimryn] Univ North Carolina Chapel Hill, Lineberger Comprehens Canc Ctr, Dept Med, Chapel Hill, NC 27599 USA. [Dhir, Rajiv] Univ Pittsburgh, Dept Pathol, Pittsburgh, PA 15213 USA. [Ajani, Jaffer A.] Univ Texas MD Anderson Canc Ctr, Dept GI Med Oncol, Houston, TX 77030 USA. [Cheong, Jae-Ho] Yonsei Univ, Coll Med, Dept Surg, Seoul 120752, South Korea. [Chudamani, Sudha; Liu, Jai; Lolla, Laxmi; Wu, Ye] Leidos Biomed, Rockville, MD 20850 USA. [Naresh, Rashi; Pihl, Todd; Sun, Qiang; Wan, Yunhu] CSRA Inc, Falls Church, VA 22042 USA. [Hutter, Carolyn M.] NHGRI, NIH, Bethesda, MD 20892 USA. RP Bass, AJ (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA.; Bass, AJ (reprint author), Dana Farber Canc Inst, Ctr Canc Genome Discovery, Boston, MA 02115 USA.; Thorsson, V (reprint author), Inst Syst Biol, Seattle, WA 98109 USA. EM adam_bass@dfci.harvard.edu; Vesteinn.Thorsson@systemsbiology.org RI Carlotti, Carlos/C-1608-2012; OI Carlotti, Carlos/0000-0002-7055-0564; Reis, Rui/0000-0002-9639-7940 FU Intramural Research Program; United States National Institutes of Health [5U24CA143799, 5U24CA143835, 5U24CA143840, 5U24CA143843, 5U24CA143845, 5U24CA143848, 5U24CA143858, 5U24CA143866, 5U24CA143867, 5U24CA143882, 5U24CA143883, 5U24CA144025, U54HG003067, U54HG003079, U54HG003273, P30CA16672] FX We are grateful to all patients who contributed to this study, to K. Hoadley and R. Kucherlapati for scientific editing, and to J. Zhang and I. Felau for administrative support. This work was supported by the Intramural Research Program and the following grants from the United States National Institutes of Health: 5U24CA143799, 5U24CA143835, 5U24CA143840, 5U24CA143843, 5U24CA143845, 5U24CA143848, 5U24CA143858, 5U24CA143866, 5U24CA143867, 5U24CA143882, 5U24CA143883, 5U24CA144025, U54HG003067, U54HG003079, and U54HG003273, P30CA16672. NR 58 TC 0 Z9 0 U1 5 U2 5 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 JAN 12 PY 2017 VL 541 IS 7636 BP 169 EP + DI 10.1038/nature20805 PG 22 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EN6PI UT WOS:000396125500030 ER PT J AU Weir, GC Bonner-Weir, S AF Weir, Gordon C. Bonner-Weir, Susan TI GABA Signaling Stimulates beta Cell Regeneration in Diabetic Mice SO CELL LA English DT Editorial Material ID IN-VITRO; GENERATION; PANCREAS C1 [Weir, Gordon C.; Bonner-Weir, Susan] Harvard Med Sch, Div Res, Joslin Diabet Ctr, Boston, MA 02215 USA. RP Weir, GC (reprint author), Harvard Med Sch, Div Res, Joslin Diabet Ctr, Boston, MA 02215 USA. EM gordon.weir@joslin.harvard.edu NR 12 TC 0 Z9 0 U1 2 U2 2 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 JAN 12 PY 2017 VL 168 IS 1-2 BP 7 EP 9 DI 10.1016/j.cell.2016.12.006 PG 3 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA EN8JM UT WOS:000396246700003 PM 28086099 ER PT J AU Tenente, IM Hayes, MN Ignatius, MS McCarthy, K Yohe, M Sindiri, S Gryder, B Oliveira, ML Ramakrishnan, A Tang, Q Chen, EY Nielsen, GP Khan, J Langenau, DM AF Tenente, Ines M. Hayes, Madeline N. Ignatius, Myron S. McCarthy, Karin Yohe, Marielle Sindiri, Sivasish Gryder, Berkley Oliveira, Mariana L. Ramakrishnan, Ashwin Tang, Qin Chen, Eleanor Y. Nielsen, G. Petur Khan, Javed Langenau, David M. TI Myogenic regulatory transcription factors regulate growth in rhabdomyosarcoma SO ELIFE LA English DT Article ID ACUTE LYMPHOBLASTIC-LEUKEMIA; CHILDRENS ONCOLOGY GROUP; ACUTE MYELOID-LEUKEMIA; GENOME-WIDE BINDING; SKELETAL-MUSCLE; EMBRYONAL RHABDOMYOSARCOMA; TRANSGENIC ZEBRAFISH; CELL TRANSPLANTATION; SELF-RENEWAL; SATELLITE CELL AB Rhabdomyosarcoma (RMS) is a pediatric malignacy of muscle with myogenic regulatory transcription factors MYOD and MYF5 being expressed in this disease. Consensus in the field has been that expression of these factors likely reflects the target cell of transformation rather than being required for continued tumor growth. Here, we used a transgenic zebrafish model to show that Myf5 is sufficient to confer tumor-propagating potential to RMS cells and caused tumors to initiate earlier and have higher penetrance. Analysis of human RMS revealed that MYF5 and MYOD are mutually-exclusively expressed and each is required for sustained tumor growth. ChIP-seq and mechanistic studies in human RMS uncovered that MYF5 and MYOD bind common DNA regulatory elements to alter transcription of genes that regulate muscle development and cell cycle progression. Our data support unappreciated and dominant oncogenic roles for MYF5 and MYOD convergence on common transcriptional targets to regulate human RMS growth. C1 [Tenente, Ines M.; Hayes, Madeline N.; Ignatius, Myron S.; McCarthy, Karin; Oliveira, Mariana L.; Ramakrishnan, Ashwin; Tang, Qin; Langenau, David M.] Massachusetts Gen Hosp, Mol Pathol Canc Ctr & Regenerat Med, Boston, MA 02114 USA. [Tenente, Ines M.; Hayes, Madeline N.; Ignatius, Myron S.; McCarthy, Karin; Oliveira, Mariana L.; Ramakrishnan, Ashwin; Tang, Qin; Langenau, David M.] Harvard Stem Cell Inst, Cambridge, MA 02138 USA. [Tenente, Ines M.] Univ Porto, Abel Salazar Biomed Sci Inst, GABBA Program, Oporto, Portugal. [Ignatius, Myron S.] Greehey Childrens Canc Res Inst, Mol Med, San Antonio, TX USA. [Yohe, Marielle; Sindiri, Sivasish; Gryder, Berkley; Khan, Javed] NCI, Adv Technol Ctr, Pediat Oncol Branch, Oncogen Sec, Gaithersburg, MD USA. [Oliveira, Mariana L.] Univ Lisbon, Fac Med, Inst Mol Med, Lisbon, Portugal. [Chen, Eleanor Y.] Univ Washington, Dept Pathol, Seattle, WA 98195 USA. [Nielsen, G. Petur] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. RP Langenau, DM (reprint author), Massachusetts Gen Hosp, Mol Pathol Canc Ctr & Regenerat Med, Boston, MA 02114 USA.; Langenau, DM (reprint author), Harvard Stem Cell Inst, Cambridge, MA 02138 USA. EM dlangenau@mgh.harvard.edu RI Khan, Javed/P-9157-2014 OI Khan, Javed/0000-0002-5858-0488 FU National Institutes of Health [R01CA154923, U54CA168512]; Fundacao para a Ciencia e a Tecnologia; China Scholarship Council; Alex's Lemonade Stand Foundation for Childhood Cancer; Saint Baldrick's Foundation; NIH Office of the Director [R24OD016761] FX National Institutes of Health Ines M Tenente; Fundacao para a Ciencia e a Tecnologia Myron S Ignatius David M Langenau; China Scholarship Council Qin Tang; Alex's Lemonade Stand Foundation for Childhood Cancer David M Langena; Saint Baldrick's Foundation David M Langenau; National Institutes of Health R01CA154923 David M Langenau; National Institutes of Health U54CA168512 David M Langenau; NIH Office of the Director R24OD016761 David M Langenau; The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. NR 80 TC 0 Z9 0 U1 2 U2 2 PU ELIFE SCIENCES PUBLICATIONS LTD PI CAMBRIDGE PA SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND SN 2050-084X J9 ELIFE JI eLife PD JAN 12 PY 2017 VL 6 AR e19214 DI 10.7554/eLife.19214 PG 24 WC Biology SC Life Sciences & Biomedicine - Other Topics GA EJ7RN UT WOS:000393420000001 ER PT J AU Stopa, JD Neuberg, D Puligandla, M Furie, B Flaumenhaft, R Zwicker, JI AF Stopa, Jack D. Neuberg, Donna Puligandla, Maneka Furie, Bruce Flaumenhaft, Robert Zwicker, Jeffrey I. TI Protein disulfide isomerase inhibition blocks thrombin generation in humans by interfering with platelet factor V activation SO JCI INSIGHT LA English DT Article ID TISSUE FACTOR; HEALTHY-VOLUNTEERS; QUERCETIN; DISEASE; BINDING; PHARMACOKINETICS; THROMBOGRAPHY; COAGULATION; DEFICIENCY; FLAVONOIDS AB BACKGROUND: Protein disulfide isomerase (PDI) is required for thrombus formation. We previously demonstrated that glycosylated quercetin flavonoids such as isoquercetin inhibit PDI activity and thrombus formation in animal models, but whether extracellular PDI represents a viable anticoagulant target in humans and how its inhibition affects blood coagulation remain unknown. METHODS: We evaluated effects of oral administration of isoquercetin on platelet-dependent thrombin generation in healthy subjects and patients with persistently elevated anti-phospholipid antibodies. RESULTS: Following oral administration of 1,000 mg isoquercetin to healthy adults, the measured peak plasma quercetin concentration (9.2 mu M) exceeded its IC50 for inhibition of PDI by isoquercetin in vitro (2.5 +/- 0.4 mu M). Platelet-dependent thrombin generation decreased by 51% in the healthy volunteers compared with baseline (P = 0.0004) and by 64% in the anti-phospholipid antibody cohort (P = 0.015) following isoquercetin ingestion. To understand how PDI affects thrombin generation, we evaluated substrates of PDI identified using an unbiased mechanistic-based substrate trapping approach. These studies identified platelet factor V as a PDI substrate. Isoquercetin blocked both platelet factor Va and thrombin generation with an IC50 of similar to 5 mu M. Inhibition of PDI by isoquercetin ingestion resulted in a 53% decrease in the generation of platelet factor Va (P = 0.001). Isoquercetin-mediated inhibition was reversed with addition of exogenous factor Va. CONCLUSION: These studies show that oral administration of isoquercetin inhibits PDI activity in plasma and diminishes platelet-dependent thrombin generation predominantly by blocking the generation of platelet factor Va. These pharmacodynamic and mechanistic observations represent an important step in the development of a novel class of antithrombotic agents targeting PDI. C1 [Stopa, Jack D.; Furie, Bruce; Flaumenhaft, Robert; Zwicker, Jeffrey I.] Beth Israel Deaconess Med Ctr, Div Hemostasis & Thrombosis, Boston, MA 02215 USA. [Stopa, Jack D.; Furie, Bruce; Flaumenhaft, Robert; Zwicker, Jeffrey I.] Harvard Med Sch, Boston, MA USA. [Neuberg, Donna; Puligandla, Maneka] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. RP Flaumenhaft, R; Zwicker, JI (reprint author), Harvard Med Sch, Beth Israel Deaconess Med Ctr, Div Hemostasis & Thrombosis, 330 Brookline Ave, Boston, MA 02215 USA. EM rflaumen@bidmc.harvard.edu; jzwicker@bidmc.harvard.edu FU National Heart, Lung, and Blood Institute [U54 HL112302, HL007917, HL125275]; Quercegen Pharma; Lupus Research Institute; Harvard Catalyst; Harvard Clinical and Translational Science Center (National Center for Research Resources); Harvard Clinical and Translational Science Center (National Center for Advancing Translational Sciences, NIH) [8UL1TR000170-05]; Harvard University FX This work was supported by a grant from the National Heart, Lung, and Blood Institute (U54 HL112302, HL007917, and HL125275) as well as research support from Quercegen Pharma. Research in patients with anti-phospholipid antibodies was supported, in part, by the Lupus Research Institute. Clinical research support was provided in part by the Harvard Catalyst, the Harvard Clinical and Translational Science Center (National Center for Research Resources and the National Center for Advancing Translational Sciences, NIH award 8UL1TR000170-05 and financial contributions from Harvard University and its affiliated academic health care centers). Anti-multimerin-1 antibody was a gift from the Hayward group (McMaster University, Ontario, Canada). The content is solely the responsibility of the authors and does not necessarily represent the official views of Harvard Catalyst, Harvard University and its affiliated academic health care centers, or the NIH. NR 41 TC 0 Z9 0 U1 2 U2 2 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 2015 MANCHESTER RD, ANN ARBOR, MI 48104 USA SN 2379-3708 J9 JCI INSIGHT JI JCI Insight PD JAN 12 PY 2017 VL 2 IS 1 AR e89373 DI 10.1172/jci.insight.89373 PG 13 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EK0BO UT WOS:000393591600005 PM 28097231 ER PT J AU Woods, SE Lieberman, MT Lebreton, F Trowel, E de la Fuente-Nunez, C Dzink-Fox, J Gilmore, MS Fox, JG AF Woods, Stephanie E. Lieberman, Mia T. Lebreton, Francois Trowel, Elise de la Fuente-Nunez, Cesar Dzink-Fox, Joanne Gilmore, Michael S. Fox, James G. TI Characterization of Multi-Drug Resistant Enterococcus faecalis Isolated from Cephalic Recording Chambers in Research Macaques (Macaca spp.) SO PLOS ONE LA English DT Article ID HIGH-LEVEL GENTAMICIN; BIOFILM FORMATION; SURFACE PROTEIN; SEX-PHEROMONE; VIRULENCE; ESP; SUSCEPTIBILITY; IDENTIFICATION; INFECTIONS; MULATTA AB Nonhuman primates are commonly used for cognitive neuroscience research and often surgically implanted with cephalic recording chambers for electrophysiological recording. Aerobic bacterial cultures from 25 macaques identified 72 bacterial isolates, including 15 Enterococcus faecalis isolates. The E. faecalis isolates displayed multi-drug resistant phenotypes, with resistance to ciprofloxacin, enrofloxacin, trimethoprim-sulfamethoxazole, tetracycline, chloramphenicol, bacitracin, and erythromycin, as well as high-level aminoglycoside resistance. Multi-locus sequence typing showed that most belonged to two E. faecalis sequence types (ST): ST 4 and ST 55. The genomes of three representative isolates were sequenced to identify genes encoding antimicrobial resistances and other traits. Antimicrobial resistance genes identified included aac(6')-aph(2 ''), aph(3')-III, str, ant(6)-Ia, tetM, tetS, tetL, ermB, bcrABR, cat, and dfrG, and polymorphisms in parC (S80I) and gyrA (S83I) were observed. These isolates also harbored virulence factors including the cytolysin toxin genes in ST 4 isolates, as well as multiple biofilm-associated genes (esp, agg, ace, SrtA, gelE, ebpABC), hyaluronidases (hylA, hylB), and other survival genes (ElrA, tpx). Crystal violet biofilm assays confirmed that ST 4 isolates produced more biofilm than ST 55 isolates. The abundance of antimicrobial resistance and virulence factor genes in the ST 4 isolates likely relates to the loss of CRISPR-cas. This macaque colony represents a unique model for studying E. faecalis infection associated with indwelling devices, and provides an opportunity to understand the basis of persistence of this pathogen in a healthcare setting. C1 [Woods, Stephanie E.; Lieberman, Mia T.; Trowel, Elise; Dzink-Fox, Joanne; Fox, James G.] MIT, Div Comparat Med, Cambridge, MA 02139 USA. [Lieberman, Mia T.; de la Fuente-Nunez, Cesar; Gilmore, Michael S.; Fox, James G.] MIT, Dept Biol Engn, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Lebreton, Francois] Harvard Med Sch, Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Boston, MA USA. [Lebreton, Francois] Harvard Med Sch, Massachusetts Eye & Ear Infirm, Dept Microbiol, Boston, MA USA. [Lebreton, Francois] Harvard Med Sch, Massachusetts Eye & Ear Infirm, Dept Immunobiol, Boston, MA USA. [de la Fuente-Nunez, Cesar] MIT, Synthet Biol Grp, MIT Synthet Biol Ctr, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [de la Fuente-Nunez, Cesar] MIT, Elect Res Lab, Cambridge, MA 02139 USA. [de la Fuente-Nunez, Cesar] MIT, Dept Elect Engn & Comp Sci, Cambridge, MA 02139 USA. [de la Fuente-Nunez, Cesar] Broad Inst MIT & Harvard, Cambridge, MA USA. [de la Fuente-Nunez, Cesar] Harvard Univ, Harvard Biophys Program, Boston, MA 02115 USA. [de la Fuente-Nunez, Cesar] Ctr Microbiome Informat & Therapeut, Cambridge, MA USA. [Woods, Stephanie E.] James J Peters VA Med Ctr, Res & Dev, Bronx, NY USA. RP Lieberman, MT (reprint author), MIT, Div Comparat Med, Cambridge, MA 02139 USA.; Lieberman, MT (reprint author), MIT, Dept Biol Engn, 77 Massachusetts Ave, Cambridge, MA 02139 USA. EM MTRL01@mit.edu OI /0000-0002-2993-5198 FU National Institutes of Health [T32 OD010978, P30 ES02109, 5P01AI083214-07]; United States Public Health Service [AI072360, AI108710]; Harvard-wide Program on Antibiotic Resistance [AI083214]; Fundacion Ramon Areces (Spain); PHS grant [AI072360, AI108710] FX This research was supported by National Institutes of Health (www.nih.gov) grants T32 OD010978 and P30 ES02109 (to JGF) and 5P01AI083214-07 (to MSG). The contributions ofauthors FL and MSG were supported by United States Public Health Service (www.usphs.gov) grants AI072360, AI108710, and the Harvard-wide Program on Antibiotic Resistance AI083214. CDLF-N holds a postdoctoral scholarship from Fundacion Ramon Areces (Spain). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.; We acknowledge Ellen Buckley and Carolyn Madden for their diagnostic microbiology expertise, and Dr. Robert Marini, Dr. Mary Patterson and Monica Siddalls for their veterinary support. We acknowledge Eric J Ma for his assistance with beeswarm plot generation. The contributions of SEW, MTL, ET, and JDF were supported by NIH grants T32 OD010978 and P30 ES02109 (to JGF). The contributions of FL and MSG were supported by PHS grant AI072360, AI108710, and the Harvard-wide Program on Antibiotic Resistance AI083214. CDLF-N holds a postdoctoral scholarship from Fundacion Ramon Areces (Spain). NR 61 TC 0 Z9 0 U1 6 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 JAN 12 PY 2017 VL 12 IS 1 AR e0169293 DI 10.1371/journal.pone.0169293 PG 20 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EH7JQ UT WOS:000391949500040 PM 28081148 ER PT J AU Meyer, AF Williamson, RS Linden, JF Sahani, M AF Meyer, Arne F. Williamson, Ross S. Linden, Jennifer F. Sahani, Maneesh TI Models of Neuronal Stimulus-Response Functions: Elaboration, Estimation, and Evaluation SO FRONTIERS IN SYSTEMS NEUROSCIENCE LA English DT Article DE receptive field; sensory system; neural coding ID PRIMARY AUDITORY-CORTEX; SPECTROTEMPORAL RECEPTIVE-FIELDS; MAXIMUM-LIKELIHOOD-ESTIMATION; GENERALIZED LINEAR-MODELS; NEURAL ENCODING MODELS; NATURAL STIMULI; VISUAL-CORTEX; GAIN-CONTROL; INFORMATION-TRANSMISSION; POPULATION ACTIVITY AB Rich, dynamic, and dense sensory stimuli are encoded within the nervous system by the time-varying activity of many individual neurons. A fundamental approach to understanding the nature of the encoded representation is to characterize the function that relates the moment-by-moment firing of a neuron to the recent history of a complex sensory input. This review provides a unifying and critical survey of the techniques that have been brought to bear on this effort thus far-ranging from the classical linear receptive field model to modern approaches incorporating normalization and other nonlinearities. We address separately the structure of the models; the criteria and algorithms used to identify the model parameters; and the role of regularizing terms or priors. In each case we consider benefits or drawbacks of various proposals, providing examples for when these methods work and when they may fail. Emphasis is placed on key concepts rather than mathematical details, so as to make the discussion accessible to readers from outside the field. Finally, we review ways in which the agreement between an assumed model and the neuron's response may be quantified. Re-implemented and unified code for many of the methods are made freely available. C1 [Meyer, Arne F.; Sahani, Maneesh] UCL, Gatsby Computat Neurosci Unit, London, England. [Williamson, Ross S.] Massachusetts Eye & Ear Infirm, Eaton Peabody Labs, Boston, MA 02114 USA. [Williamson, Ross S.] Harvard Med Sch, Dept Otol & Laryngol, Boston, MA USA. [Linden, Jennifer F.] UCL, Ear Inst, London, England. [Linden, Jennifer F.] UCL, Dept Neurosci Physiol & Pharmacol, London, England. RP Sahani, M (reprint author), UCL, Gatsby Computat Neurosci Unit, London, England. EM maneesh@gatsby.ucl.ac.uk FU Gatsby Charitable Foundation; Simons Foundation [SCGB323228]; Action on Hearing Loss [G77, F44, F61]; National Institutes of Health [F32-DC015376] FX This work was supported by Gatsby Charitable Foundation (MS), Simons Foundation (SCGB323228; MS), Action on Hearing Loss (G77, F44, F61; JFL), and National Institutes of Health (F32-DC015376; RSW). NR 104 TC 0 Z9 0 U1 1 U2 1 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1662-5137 J9 FRONT SYST NEUROSCI JI Front. Syst. Neurosci. PD JAN 12 PY 2017 VL 10 AR 109 DI 10.3389/fnsys.2016.00109 PG 25 WC Neurosciences SC Neurosciences & Neurology GA EH4FY UT WOS:000391728300001 ER PT J AU Strosberg, J El-Haddad, G Wolin, E Hendifar, A Yao, J Chasen, B Mittra, E Kunz, PL Kulke, MH Jacene, H Bushnell, D O'Dorisio, TM Baum, RP Kulkarni, HR Caplin, M Lebtahi, R Hobday, T Delpassand, E Van Cutsem, E Benson, A Srirajaskanthan, R Pavel, M Mora, J Berlin, J Grande, E Reed, N Seregni, E Oberg, K Sierra, ML Santoro, P Thevenet, T Erion, JL Ruszniewski, P Kwekkeboom, D Krenning, E AF Strosberg, J. El-Haddad, G. Wolin, E. Hendifar, A. Yao, J. Chasen, B. Mittra, E. Kunz, P. L. Kulke, M. H. Jacene, H. Bushnell, D. O'Dorisio, T. M. Baum, R. P. Kulkarni, H. R. Caplin, M. Lebtahi, R. Hobday, T. Delpassand, E. Van Cutsem, E. Benson, A. Srirajaskanthan, R. Pavel, M. Mora, J. Berlin, J. Grande, E. Reed, N. Seregni, E. Oberg, K. Sierra, M. Lopera Santoro, P. Thevenet, T. Erion, J. L. Ruszniewski, P. Kwekkeboom, D. Krenning, E. CA NETTER-1 Trial Investigators TI Phase 3 Trial of Lu-177-Dotatate for Midgut Neuroendocrine Tumors SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID RECEPTOR RADIONUCLIDE THERAPY; RADIOLABELED SOMATOSTATIN ANALOG; CARCINOID-SYNDROME; PROGNOSTIC-FACTORS; SURVIVAL; PRRT; LU-177-DOTA-OCTREOTATE; LU-177-OCTREOTATE; SCINTIGRAPHY; OCTREOTIDE AB BACKGROUND Patients with advanced midgut neuroendocrine tumors who have had disease progression during first-line somatostatin analogue therapy have limited therapeutic options. This randomized, controlled trial evaluated the efficacy and safety of lutetium-177 (Lu-177)-Dotatate in patients with advanced, progressive, somatostatin-receptor-positive midgut neuroendocrine tumors. METHODS We randomly assigned 229 patients who had well-differentiated, metastatic midgut neuroendocrine tumors to receive either Lu-177-Dotatate (116 patients) at a dose of 7.4 GBq every 8 weeks (four intravenous infusions, plus best supportive care including octreotide long-acting repeatable [LAR] administered intramuscularly at a dose of 30 mg) (Lu-177-Dotatate group) or octreotide LAR alone (113 patients) administered intramuscularly at a dose of 60 mg every 4 weeks (control group). The primary end point was progression-free survival. Secondary end points included the objective response rate, overall survival, safety, and the side-effect profile. The final analysis of overall survival will be conducted in the future as specified in the protocol; a prespecified interim analysis of overall survival was conducted and is reported here. RESULTS At the data-cutoff date for the primary analysis, the estimated rate of progression-free survival at month 20 was 65.2% (95% confidence interval [CI], 50.0 to 76.8) in the Lu-177-Dotatate group and 10.8% (95% CI, 3.5 to 23.0) in the control group. The response rate was 18% in the Lu-177-Dotatate group versus 3% in the control group (P<0.001). In the planned interim analysis of overall survival, 14 deaths occurred in the Lu-177-Dotatate group and 26 in the control group (P = 0.004). Grade 3 or 4 neutropenia, thrombocytopenia, and lymphopenia occurred in 1%, 2%, and 9%, respectively, of patients in the Lu-177-Dotatate group as compared with no patients in the control group, with no evidence of renal toxic effects during the observed time frame. CONCLUSIONS Treatment with Lu-177-Dotatate resulted in markedly longer progression-free survival and a significantly higher response rate than high-dose octreotide LAR among patients with advanced midgut neuroendocrine tumors. Preliminary evidence of an overall survival benefit was seen in an interim analysis; confirmation will be required in the planned final analysis. Clinically significant myelosuppression occurred in less than 10% of patients in the Lu-177-Dotatate group. (Funded by Advanced Accelerator Applications; NETTER-1 ClinicalTrials. gov number, NCT01578239; EudraCT number 2011-005049-11.) C1 [Strosberg, J.; El-Haddad, G.] H Lee Moffitt Canc Ctr & Res Inst, 12902 Magnolia Dr, Tampa, FL 33612 USA. [Wolin, E.] Univ Kentucky, Markey Canc Ctr, Lexington, KY USA. [Hendifar, A.] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. [Mittra, E.; Kunz, P. L.] Stanford Univ, Sch Med, Stanford, CA 94305 USA. [Yao, J.; Chasen, B.] Univ Texas Hlth Sci Ctr Houston, Houston, TX 77030 USA. [Delpassand, E.] Excel Diagnost Imaging Clin, Houston, TX USA. [Kulke, M. H.; Jacene, H.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Bushnell, D.; O'Dorisio, T. M.] Univ Iowa, Iowa City, IA USA. [Baum, R. P.; Kulkarni, H. R.] Zentralklin, Bad Berka, Germany. [Pavel, M.] Charite, Berlin, Germany. [Caplin, M.] Royal Free Hosp, London, England. [Srirajaskanthan, R.] Kings Coll Hosp NHS FDN Trust, London, England. [Reed, N.] Beatson Oncol Ctr, Glasgow, Lanark, Scotland. [Lebtahi, R.; Ruszniewski, P.] Hop Beaujon, Clichy, France. [Thevenet, T.] Adv Accelerator Applicat, St Genis Pouilly, France. [Hobday, T.] Mayo Clin Coll Med, Rochester, MN USA. [Van Cutsem, E.] Univ Hosp, Leuven, Belgium. [Van Cutsem, E.] Katholieke Univ Leuven, Leuven, Belgium. [Benson, A.] Robert H Lurie Comprehens Canc Ctr, Chicago, IL USA. [Mora, J.] Hosp Univ Bellvitge, Barcelona, Spain. [Grande, E.] Hosp Univ Ramon & Cajal, Madrid, Spain. [Berlin, J.] Vanderbilt Univ, Med Ctr, Nashville, TN USA. [Seregni, E.] Ist Nazl Tumori, Fdn Ist Ricovero & Cura Carattere Sci, Milan, Italy. [Oberg, K.] Uppsala Univ, Univ Hosp, Uppsala, Sweden. [Sierra, M. Lopera; Santoro, P.; Erion, J. L.] Adv Accelerator Applicat USA, New York, NY USA. [Kwekkeboom, D.; Krenning, E.] Erasmus MC, Rotterdam, Netherlands. RP Strosberg, J (reprint author), H Lee Moffitt Canc Ctr & Res Inst, 12902 Magnolia Dr, Tampa, FL 33612 USA. EM jonathan.strosberg@moffitt.org OI Seregni, Ettore/0000-0002-5097-049X FU Advanced Accelerator Applications; EudraCT [2011-005049-11] FX Funded by Advanced Accelerator Applications; NETTER-1 ClinicalTrials.gov number, NCT01578239; EudraCT number 2011-005049-11.) NR 30 TC 6 Z9 6 U1 5 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 JAN 12 PY 2017 VL 376 IS 2 BP 125 EP 135 DI 10.1056/NEJMoa1607427 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA EI0XI UT WOS:000392198400007 PM 28076709 ER PT J AU Mesulam, MM Dickerson, BC Sherman, JC Hochberg, D Gonzalez, RG Johnson, KA Frosch, MP AF Mesulam, M-Marsel Dickerson, Bradford C. Sherman, Janet C. Hochberg, Daisy Gilberto Gonzalez, R. Johnson, Keith A. Frosch, Matthew P. TI Case 1-2017: A 70-Year-Old Woman with Gradually Progressive Loss of Language SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID FRONTOTEMPORAL LOBAR DEGENERATION; TEMPORAL-LOBE; NEUROPATHOLOGIC ASSESSMENT; ALZHEIMERS-DISEASE; APHASIA; DEMENTIA; DEPOSITION; CONSENSUS; SEVERITY; SUBTYPES C1 [Mesulam, M-Marsel] Northwestern Med, Dept Neurol, Chicago, IL 60611 USA. [Dickerson, Bradford C.; Sherman, Janet C.; Johnson, Keith A.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Sherman, Janet C.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Hochberg, Daisy] Massachusetts Gen Hosp, Dept Speech Language & Swallowing Disorders & Rea, Boston, MA 02114 USA. [Gilberto Gonzalez, R.; Johnson, Keith A.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Frosch, Matthew P.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Dickerson, Bradford C.] Harvard Med Sch, Dept Neurol, Boston, MA USA. [Sherman, Janet C.] Harvard Med Sch, Dept Psychiat, Boston, MA USA. [Gilberto Gonzalez, R.; Johnson, Keith A.] Harvard Med Sch, Dept Radiol, Boston, MA USA. [Frosch, Matthew P.] Harvard Med Sch, Dept Pathol, Boston, MA USA. RP Mesulam, MM (reprint author), Northwestern Med, Dept Neurol, Chicago, IL 60611 USA. FU Massachusetts Alzheimer's Disease Research Center [P50 AG005134] FX The neuropathological evaluation in this case was supported by the Massachusetts Alzheimer's Disease Research Center (P50 AG005134). NR 29 TC 0 Z9 0 U1 6 U2 6 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JAN 12 PY 2017 VL 376 IS 2 BP 158 EP 167 DI 10.1056/NEJMcpc1613459 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA EI0XI UT WOS:000392198400012 PM 28076711 ER PT J AU Sacks, CA Goldstein, RH Walensky, RP AF Sacks, Chana A. Goldstein, Robert H. Walensky, Rochelle P. TI Rethinking the Ban - The US Blood Supply and Men Who Have Sex with Men SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID TRANSFUSION C1 [Sacks, Chana A.] Brigham & Womens Hosp, Div Pharmacoepidemiol & Pharmacoecon, 75 Francis St, Boston, MA 02115 USA. [Sacks, Chana A.; Goldstein, Robert H.] Massachusetts Gen Hosp, Div Gen Internal Med, Boston, MA 02114 USA. [Goldstein, Robert H.; Walensky, Rochelle P.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Walensky, Rochelle P.] Harvard Univ, Ctr AIDS Res, Harvard Med Sch, Boston, MA 02115 USA. RP Sacks, CA (reprint author), Brigham & Womens Hosp, Div Pharmacoepidemiol & Pharmacoecon, 75 Francis St, Boston, MA 02115 USA.; Sacks, CA (reprint author), Massachusetts Gen Hosp, Div Gen Internal Med, Boston, MA 02114 USA. NR 14 TC 1 Z9 1 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 JAN 12 PY 2017 VL 376 IS 2 BP 174 EP 177 DI 10.1056/NEJMms1613425 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA EI0XI UT WOS:000392198400015 PM 27959708 ER PT J AU Franco, LH Nair, VR Scharn, CR Xavier, RJ Torrealba, JR Shiloh, MU Levine, B AF Franco, Luis H. Nair, Vidhya R. Scharn, Caitlyn R. Xavier, Ramnik J. Torrealba, Jose R. Shiloh, Michael U. Levine, Beth TI The Ubiquitin Ligase Smurf1 Functions in Selective Autophagy of Mycobacterium tuberculosis and Anti-tuberculous Host Defense SO CELL HOST & MICROBE LA English DT Article ID GMP-AMP SYNTHASE; C2 DOMAIN; DENDRITIC CELLS; DNA SENSOR; RECOGNITION; DEGRADATION; INFECTION; SYSTEM; INFLAMMATION; RESISTANCE AB During antibacterial autophagy, ubiquitination of intracellular bacteria recruits proteins that mediate bacterial delivery to the lysosome for degradation. Smurf1 is an E3 ubiquitin ligase whose role in selective bacterial autophagy is unknown. We show that Smurf1 facilitates selective autophagy of the human pathogen Mycobacterium tuberculosis (Mtb). Smurf1(-/-) macrophages are defective in recruiting polyubiquitin, the proteasome, the ubiquitin-binding autophagy adaptor NBR1, the autophagy protein LC3, and the lysosomal marker LAMP1 to Mtb-associated structures and are more permissive for Mtb growth. This function of Smurf1 requires both its ubiquitin-ligase and C2 phospholipid-binding domains, and involves K48- rather than K63-linked ubiquitination. Chronically infected Smurf1(-/-) mice have increased bacterial load, increased lung inflammation, and accelerated mortality. SMURF1 controls Mtb replication in human macrophages and associates with bacteria in lungs of patients with pulmonary tuberculosis. Thus, Smurf1 is required for selective autophagy of Mtb and host defense against tuberculosis infection. C1 [Franco, Luis H.; Levine, Beth] Univ Texas Southwestern Med Ctr Dallas, Ctr Autophagy Res, Dallas, TX 75390 USA. [Franco, Luis H.; Nair, Vidhya R.; Scharn, Caitlyn R.; Shiloh, Michael U.; Levine, Beth] Univ Texas Southwestern Med Ctr Dallas, Dept Internal Med, Dallas, TX 75390 USA. [Xavier, Ramnik J.] Massachusetts Gen Hosp, Gastrointestinal Unit, Cambridge, MA 02142 USA. [Xavier, Ramnik J.] Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Cambridge, MA 02142 USA. [Xavier, Ramnik J.] Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA. [Torrealba, Jose R.] Univ Texas Southwestern Med Ctr Dallas, Dept Pathol, Dallas, TX 75390 USA. [Shiloh, Michael U.; Levine, Beth] Univ Texas Southwestern Med Ctr Dallas, Dept Microbiol, Dallas, TX 75390 USA. [Levine, Beth] Univ Texas Southwestern Med Ctr Dallas, Howard Hughes Med Inst, Dallas, TX 75390 USA. RP Levine, B (reprint author), Univ Texas Southwestern Med Ctr Dallas, Ctr Autophagy Res, Dallas, TX 75390 USA.; Shiloh, MU; Levine, B (reprint author), Univ Texas Southwestern Med Ctr Dallas, Dept Internal Med, Dallas, TX 75390 USA.; Shiloh, MU; Levine, B (reprint author), Univ Texas Southwestern Med Ctr Dallas, Dept Microbiol, Dallas, TX 75390 USA.; Levine, B (reprint author), Univ Texas Southwestern Med Ctr Dallas, Howard Hughes Med Inst, Dallas, TX 75390 USA. EM michael.shiloh@utsouthwestern.edu; beth.levine@utsouthwestern.edu FU NIH [R01-AI099439, R21-AI111023, R01-DK097485, T32-AI528436, U19-AI109725] FX We thank BEI Resources, Genentech, N. Mizushima, and D. Portnoy for providing critical reagents; Zhongju Zou and Lori Nguyen for technical assistance; K. Luby-Phelps and A. Darehshouri for helpful discussions and assistance with immunogold electron microscopy (EM); and H. Smith for assistance with manuscript preparation. EM studies were carried out in the UT Southwestern Live Cell and Electron Microscopy Facility. This work was supported by NIH grants R01-AI099439 and R21-AI111023 (M.U.S.), R01-DK097485 (R.J.X.), T32-AI528436 (C.R.S.), and U19-AI109725 (R.J.X., M.U.S., B.L.). NR 42 TC 0 Z9 0 U1 1 U2 1 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1931-3128 EI 1934-6069 J9 CELL HOST MICROBE JI Cell Host Microbe PD JAN 11 PY 2017 VL 21 IS 1 BP 59 EP 72 DI 10.1016/j.chom.2016.11.002 PG 14 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA EI9QN UT WOS:000392843900009 PM 28017659 ER PT J AU Scarisoreanu, ND Craciun, F Ion, V Birjega, R Bercea, A Dinca, V Dinescu, M Sima, LE Icriverz, M Roseanu, A Gruionu, L Graionu, G AF Scarisoreanu, N. D. Craciun, F. Ion, V. Birjega, R. Bercea, A. Dinca, V. Dinescu, M. Sima, L. E. Icriverz, M. Roseanu, A. Gruionu, L. Graionu, G. TI Lead-Free Piezoelectric (Ba,Ca)(Zr,Ti)O-3 Thin Films for Biocompatible and Flexible Devices SO ACS APPLIED MATERIALS & INTERFACES LA English DT Article DE biocompatible materials; lead-free thin films; laser processing; osteogenic differentiation; mesenchymal stem cells ID MESENCHYMAL STEM-CELLS; BONE AB In this work, we report the synthesis of functional biocompatible piezoelectric (1 - x)Ba(Ti0.8Zr0.2)TiO3-x(Ba0.7Ca0.3)TiO3, x = 0.45 (BCZT45), thin films with high piezoelectric properties. Pulsed-laser-based techniques, classical pulsed-laser deposition and matrix-assisted pulsed-laser evaporation, were used to synthesize the BCZT45 thin films. The second technique was employed in order to ensure growth on polymer flexible Kapton substrates. The BCZT45 thin films grown by both techniques show similar structural properties and high piezoelectric coefficient coupling between the mechanical loading and electrical potential. While it has long been shown that the electrical potential favors biological processes like osteogenesis, the assessment of cell adhesion and osteogenic differentiation onto BCZT materials has not yet been demonstrated. We prove here for the first time that BCZT 45 coatings on Kapton polymer substrates provide optimal support for osteogenic differentiation of mesenchymal stem cells in the bone marrow. C1 [Scarisoreanu, N. D.; Ion, V.; Birjega, R.; Bercea, A.; Dinca, V.; Dinescu, M.] Natl Inst Laser Plasma & Radiat Phys, Magurele 077125, Romania. [Craciun, F.] CNR, ISC, Area Ric Roma Tor Vergata, Via Fosso del Cavaliere 100, I-00133 Rome, Italy. [Sima, L. E.; Icriverz, M.; Roseanu, A.] Romanian Acad, Inst Biochem, 296 Splaiul Independentei, Bucharest 060031, Romania. [Gruionu, L.; Graionu, G.] Medinsys Craiova, Calea Unirii 32, Craiova 200409, Romania. [Gruionu, L.] Univ Craiova, Fac Mech, Alexandru loan Cuza 13, Craiova 200585, Romania. [Graionu, G.] Harvard Med Sch, Dept Surg, 55 Fruit St White 506, Boston, MA 02114 USA. [Graionu, G.] Massachusetts Gen Hosp, 55 Fruit St White 506, Boston, MA 02114 USA. RP Dinescu, M (reprint author), Natl Inst Laser Plasma & Radiat Phys, Magurele 077125, Romania. EM dinescum@nipne.ro FU PCCA TumorSense [12/2014 UEFISCDI]; Romanian Academy of the Institute of Biochemistry FX We thank and acknowledge the support of Dr. Simona Ghenea for confocal microscopy work and of Gabriela Chiritoiu for SEM sample preparation. N.D.S., M.D., V.I., L.G., and G.G. gratefully acknowledge partial financial support from the PCCA TumorSense 12/2014 UEFISCDI project. L.E.S., M.I., and A.R. acknowledge partial financial support from the Romanian Academy Project 2015-2016 of the Institute of Biochemistry. NR 28 TC 0 Z9 0 U1 14 U2 14 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1944-8244 J9 ACS APPL MATER INTER JI ACS Appl. Mater. Interfaces PD JAN 11 PY 2017 VL 9 IS 1 BP 266 EP 278 DI 10.1021/acsami.6b14774 PG 13 WC Nanoscience & Nanotechnology; Materials Science, Multidisciplinary SC Science & Technology - Other Topics; Materials Science GA EH8QM UT WOS:000392037400033 PM 28009160 ER PT J AU Telenczuk, B Dehghani, N Le Van Quyen, M Cash, SS Halgren, E Hatsopoulos, NG Destexhe, A AF Telenczuk, Bartosz Dehghani, Nima Le Van Quyen, Michel Cash, Sydney S. Halgren, Eric Hatsopoulos, Nicholas G. Destexhe, Alain TI Local field potentials primarily reflect inhibitory neuron activity in human and monkey cortex SO SCIENTIFIC REPORTS LA English DT Article ID VISUAL-CORTEX; PYRAMIDAL CELLS; FUNCTIONAL CONNECTIVITY; SPIKES; POPULATION; EXCITATION; NEOCORTEX; CURRENTS; SLEEP; MOTOR AB The local field potential (LFP) is generated by large populations of neurons, but unitary contribution of spiking neurons to LFP is not well characterised. We investigated this contribution in multi-electrode array recordings from human and monkey neocortex by examining the spike-triggered LFP average (st-LFP). The resulting st-LFPs were dominated by broad spatio-temporal components due to ongoing activity, synaptic inputs and recurrent connectivity. To reduce the spatial reach of the st-LFP and observe the local field related to a single spike we applied a spatial filter, whose weights were adapted to the covariance of ongoing LFP. The filtered st-LFPs were limited to the perimeter of 800 mu m around the neuron, and propagated at axonal speed, which is consistent with their unitary nature. In addition, we discriminated between putative inhibitory and excitatory neurons and found that the inhibitory st-LFP peaked at shorter latencies, consistently with previous findings in hippocampal slices. Thus, in human and monkey neocortex, the LFP reflects primarily inhibitory neuron activity. C1 [Telenczuk, Bartosz; Destexhe, Alain] CNRS, Unite Neurosci Informat & Complex, F-91198 Gif Sur Yvette, France. [Dehghani, Nima] Harvard Univ, Wyss Inst Biol Inspired Engn, Boston, MA 02115 USA. [Dehghani, Nima] New England Complex Syst Inst, Cambridge, MA USA. [Le Van Quyen, Michel] Hop La Pitie Salpetriere, Inst Cerveau & Moelle Epiniere, CNRS, UMRS 1127,UMR 7225, Paris, France. [Cash, Sydney S.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Cash, Sydney S.] Harvard Med Sch, Boston, MA USA. [Halgren, Eric] Univ Calif San Diego, Multimodal Imaging Lab, Dept Neurosci, La Jolla, CA 92093 USA. [Halgren, Eric] Univ Calif San Diego, Multimodal Imaging Lab, Dept Radiol, La Jolla, CA 92093 USA. [Hatsopoulos, Nicholas G.] Univ Chicago, Comm Computat Neurosci, Dept Organismal Biol & Anat, Chicago, IL 60637 USA. RP Telenczuk, B (reprint author), CNRS, Unite Neurosci Informat & Complex, F-91198 Gif Sur Yvette, France. EM telenczuk@unic.cnrs-gif.fr FU Centre National de la Recherche Scientifique (CNRS, France); European Community Future and Emerging Technologies program [FP7-269921, FP7-604102, H2020-720270]; National Institutes of Health (NIH) [5R01NS062092, R01EB009282, R01NS045853, R01MH099645]; Office of Naval Research (MURI) [N00014-13-1-0672] FX Research funded by Centre National de la Recherche Scientifique (CNRS, France), European Community Future and Emerging Technologies program (BrainScales FP7-269921; The Human Brain Project FP7-604102, H2020-720270), National Institutes of Health (NIH grants 5R01NS062092, R01EB009282 and R01NS045853, R01MH099645) and Office of Naval Research (MURI grant number N00014-13-1-0672). NR 39 TC 0 Z9 0 U1 3 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD JAN 11 PY 2017 VL 7 AR 40211 DI 10.1038/srep40211 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EH1NN UT WOS:000391533700001 PM 28074856 ER PT J AU McGarry, A McDermott, M Kieburtz, K de Blieck, EA Beal, F Marder, K Ross, C Shoulson, I Gilbert, P Mallonee, WM Guttman, M Wojcieszek, J Kumar, R LeDoux, MS Jenkins, M Rosas, HD Nance, M Biglan, K Como, P Dubinsky, RM Shannon, KM O'Suilleabhain, P Chou, K Walker, F Martin, W Wheelock, VL McCusker, E Jankovic, J Singer, C Sanchez-Ramos, J Scott, B Suchowersky, O Factor, SA Higgins, DS Molho, E Revilla, F Caviness, JN Friedman, JH Perlmutter, JS Feigin, A Anderson, K Rodriguez, R McFarland, NR Margolis, RL Farbman, ES Raymond, LA Suski, V Kostyk, S Colcher, A Seeberger, L Epping, E Esmail, S Diaz, N Fung, WLA Diamond, A Frank, S Hanna, P Hermanowicz, N Dure, LS Cudkowicz, M AF McGarry, Andrew McDermott, Michael Kieburtz, Karl de Blieck, Elisabeth A. Beal, Flint Marder, Karen Ross, Christopher Shoulson, Ira Gilbert, Peter Mallonee, William M. Guttman, Mark Wojcieszek, Joanne Kumar, Rajeev LeDoux, Mark S. Jenkins, Mary Rosas, H. Diana Nance, Martha Biglan, Kevin Como, Peter Dubinsky, Richard M. Shannon, Kathleen M. O'Suilleabhain, Padraig Chou, Kelvin Walker, Francis Martin, Wayne Wheelock, Vicki L. McCusker, Elizabeth Jankovic, Joseph Singer, Carlos Sanchez-Ramos, Juan Scott, Burton Suchowersky, Oksana Factor, Stewart A. Higgins, Donald S., Jr. Molho, Eric Revilla, Fredy Caviness, John N. Friedman, Joseph H. Perlmutter, Joel S. Feigin, Andrew Anderson, Karen Rodriguez, Ramon McFarland, Nikolaus R. Margolis, Russell L. Farbman, Eric S. Raymond, Lynn A. Suski, Valerie Kostyk, Sandra Colcher, Amy Seeberger, Lauren Epping, Eric Esmail, Sherali Diaz, Nancy Fung, Wai Lun Alan Diamond, Alan Frank, Samuel Hanna, Philip Hermanowicz, Neal Dure, Leon S. Cudkowicz, Merit CA Huntington Study Grp 2CARE TI A randomized, double-blind, placebo-controlled trial of coenzyme Q10 in Huntington disease SO NEUROLOGY LA English DT Article ID TRANSGENIC MOUSE MODEL; ENERGY-METABOLISM; CLINICAL-TRIALS; IN-VIVO; Q(10); CREATINE; IMPAIRMENT; REMACEMIDE; DEFECTS; MICE AB Objective: To test the hypothesis that chronic treatment of early-stage Huntington disease (HD) with high-dose coenzyme Q10 (CoQ) will slow the progressive functional decline of HD. Methods: We performed a multicenter randomized, double-blind, placebo-controlled trial. Patients with early-stage HD (n = 609) were enrolled at 48 sites in the United States, Canada, and Australia from 2008 to 2012. Patients were randomized to receive either CoQ 2,400 mg/d or matching placebo, then followed for 60 months. The primary outcome variable was the change from baseline to month 60 in Total Functional Capacity score (for patients who survived) combined with time to death (for patients who died) analyzed using a joint-rank analysis approach. Results: An interim analysis for futility revealed a conditional power of <5% for the primary analysis, prompting premature conclusion in July 2014. No statistically significant differences were seen between treatment groups for the primary or secondary outcome measures. CoQ was generally safe and well-tolerated throughout the study. Conclusions: These data do not justify use of CoQ as a treatment to slow functional decline in HD. ClinicalTrials.gov identifier: NCT00608881. Classification of evidence: This article provides Class I evidence that CoQ does not slow the progressive functional decline of patients with HD. Neurology (R) 2017;88:152-159 C1 [McGarry, Andrew] Rowan Univ, Cooper Univ Healthcare, Camden, NJ 08102 USA. [McDermott, Michael; Kieburtz, Karl; de Blieck, Elisabeth A.; Biglan, Kevin; Como, Peter] Univ Rochester, Rochester, NY 14627 USA. [Beal, Flint] Weill Cornell Med Ctr, New York, NY USA. [Marder, Karen] Columbia Presbyterian Med Ctr, New York, NY 10032 USA. [Ross, Christopher] Johns Hopkins Med Ctr, Baltimore, MD USA. [Shoulson, Ira; Anderson, Karen] Georgetown Univ, Washington, DC USA. [Gilbert, Peter] NINDS, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Mallonee, William M.] Hereditary Neurol Dis Ctr, Wichita, KS USA. [Guttman, Mark] Ctr Movement Disorders, Toronto, ON, Canada. [Wojcieszek, Joanne] Indiana Univ Sch Med, Indianapolis, IN 46202 USA. [Kumar, Rajeev] Colorado Neurol Inst, Englewood, CO USA. [LeDoux, Mark S.] Univ Tennessee, Ctr Hlth Sci, Memphis, TN 38163 USA. [Jenkins, Mary] London Hlth Sci Ctr, London, ON, Canada. [Rosas, H. Diana] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Nance, Martha] Struthers Parkinsons Ctr, Minneapolis, MN USA. [Dubinsky, Richard M.] Univ Kansas Med Ctr, Kansas City, KS USA. [Shannon, Kathleen M.] Rush Univ Med Ctr, Chicago, IL USA. [O'Suilleabhain, Padraig] Univ Texas Southwestern Med Ctr, Dallas, TX USA. [Chou, Kelvin] Univ Michigan, Ann Arbor, MI 48109 USA. [Walker, Francis] Wake Forest Univ, Winston Salem, NC 27109 USA. [Martin, Wayne] Univ Alberta, Edmonton, AB, Canada. [Wheelock, Vicki L.] Univ Calif Davis, Sacramento, CA 95817 USA. [McCusker, Elizabeth] Westmead Hosp, Westmead, NSW, Australia. [Jankovic, Joseph] Baylor Coll Med, Houston, TX 77030 USA. [Singer, Carlos] Univ Miami, Miller Sch Med, Coral Gables, FL 33124 USA. [Sanchez-Ramos, Juan] Univ S Florida, Tampa, FL USA. [Scott, Burton] Duke Univ, Durham, NC USA. [Suchowersky, Oksana] Univ Calgary, Calgary, AB T2N 1N4, Canada. [Factor, Stewart A.] Emory Univ, Sch Med, Atlanta, GA USA. [Higgins, Donald S., Jr.; Molho, Eric] Albany Med Coll, Albany, NY 12208 USA. [Revilla, Fredy] Univ Cincinnati, Cincinnati, OH 45221 USA. [Caviness, John N.] Mayo Clin Arizona, Scottsdale, AZ USA. [Friedman, Joseph H.] Butler Hosp, Providence, RI 02906 USA. [Perlmutter, Joel S.] Washington Univ, St Louis, MO USA. [Feigin, Andrew] Feinstein Inst Med Res, Manhasset, NY USA. [Rodriguez, Ramon; McFarland, Nikolaus R.] Univ Florida, Gainesville, FL USA. [Margolis, Russell L.] Johns Hopkins Univ, Baltimore, MD USA. [Farbman, Eric S.] Univ Nevada, Sch Med, Reno, NV 89557 USA. [Raymond, Lynn A.] Univ British Columbia, Vancouver, BC, Canada. [Suski, Valerie] Univ Pittsburgh, Pittsburgh, PA 15260 USA. [Kostyk, Sandra] Ohio State Univ, Columbus, OH 43210 USA. [Colcher, Amy] Cooper Univ Hlth Syst, Camden, NJ USA. [Seeberger, Lauren] Idaho Elks Rehabil Hosp, Boise, ID USA. [Epping, Eric] Univ Iowa, Iowa City, IA USA. [Esmail, Sherali] North York Gen Hosp 1, Toronto, ON, Canada. [Diaz, Nancy] St Lukes Hosp, Allentown, PA USA. [Fung, Wai Lun Alan] Univ Toronto, North York Gen Hosp 2, Toronto, ON M5S 1A1, Canada. [Diamond, Alan] Washington Reg Med Ctr, Fayetteville, AR USA. [Frank, Samuel] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Hanna, Philip] NJ Neurosci Inst, Edison, NJ USA. [Hermanowicz, Neal] Univ Calif Irvine, Irvine, CA 92717 USA. [Dure, Leon S.] Univ Alabama Birmingham, Birmingham, AL USA. [Cudkowicz, Merit] Harvard Med Sch, Massachusetts Gen Hosp, Boston, MA USA. RP McGarry, A (reprint author), Rowan Univ, Cooper Univ Healthcare, Camden, NJ 08102 USA. EM mcgarry-andrew@cooperhealth.edu RI Raymond, Lynn/A-6664-2010 OI Raymond, Lynn/0000-0002-8610-1042 FU National Institute of Neurological Disorders and Stroke [NS052592, NS052619] FX Study funded by National Institute of Neurological Disorders and Stroke (grants NS052592 and NS052619). NR 34 TC 2 Z9 2 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD JAN 10 PY 2017 VL 88 IS 2 BP 152 EP 159 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA EO2YH UT WOS:000396561500011 PM 27913695 ER PT J AU Castro, VM Dligach, D Finan, S Yu, S Can, A Abd-El-Barr, M Gainer, V Shadick, NA Murphy, S Cai, TX Savova, G Weiss, ST Du, R AF Castro, Victor M. Dligach, Dmitriy Finan, Sean Yu, Sheng Can, Anil Abd-El-Barr, Muhammad Gainer, Vivian Shadick, Nancy A. Murphy, Shawn Cai, Tianxi Savova, Guergana Weiss, Scott T. Du, Rose TI Large-scale identification of patients with cerebral aneurysms using natural language processing SO NEUROLOGY LA English DT Article ID VALIDATION; RECORDS AB Objective: To use natural language processing (NLP) in conjunction with the electronic medical record (EMR) to accurately identify patients with cerebral aneurysms and their matched controls. Methods: ICD-9 and Current Procedural Terminology codes were used to obtain an initial data mart of potential aneurysm patients from the EMR. NLP was then used to train a classification algorithm with .632 bootstrap cross-validation used for correction of overfitting bias. The classification rule was then applied to the full data mart. Additional validation was performed on 300 patients classified as having aneurysms. Controls were obtained by matching age, sex, race, and healthcare use. Results: We identified 55,675 patients of 4.2 million patients with ICD-9 and Current Procedural Terminology codes consistent with cerebral aneurysms. Of those, 16,823 patients had the term aneurysm occur near relevant anatomic terms. After training, a final algorithm consisting of 8 coded and 14 NLP variables was selected, yielding an overall area under the receiver-operating characteristic curve of 0.95. After the final algorithm was applied, 5,589 patients were classified as having aneurysms, and 54,952 controls were matched to those patients. The positive predictive value based on a validation cohort of 300 patients was 0.86. Conclusions: We harnessed the power of the EMR by applying NLP to obtain a large cohort of patients with intracranial aneurysms and their matched controls. Such algorithms can be generalized to other diseases for epidemiologic and genetic studies. Neurology (R) 2017; 88:164-168 C1 [Castro, Victor M.; Gainer, Vivian; Murphy, Shawn] Partners Healthcare, Res Informat Syst & Comp, Boston, MA USA. [Dligach, Dmitriy; Finan, Sean; Savova, Guergana] Boston Childrens Hosp Informat Program, Boston, MA USA. [Dligach, Dmitriy; Yu, Sheng; Can, Anil; Abd-El-Barr, Muhammad; Shadick, Nancy A.; Murphy, Shawn; Weiss, Scott T.; Du, Rose] Harvard Med Sch, Boston, MA USA. [Yu, Sheng; Weiss, Scott T.] Brigham & Womens Hosp, Dept Med, 75 Francis St, Boston, MA 02115 USA. [Can, Anil; Abd-El-Barr, Muhammad; Du, Rose] Brigham & Womens Hosp, Dept Neurosurg, 75 Francis St, Boston, MA 02115 USA. [Shadick, Nancy A.] Brigham & Womens Hosp, Div Rheumatol Immunol & Allergy, 75 Francis St, Boston, MA 02115 USA. [Weiss, Scott T.; Du, Rose] Brigham & Womens Hosp, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA. [Yu, Sheng] Tsinghua Univ, Ctr Stat Sci, Beijing, Peoples R China. [Murphy, Shawn] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Cai, Tianxi] Harvard Sch Publ Hlth, Biostat, Boston, MA USA. RP Du, R (reprint author), Harvard Med Sch, Boston, MA USA.; Du, R (reprint author), Brigham & Womens Hosp, Dept Neurosurg, 75 Francis St, Boston, MA 02115 USA.; Du, R (reprint author), Brigham & Womens Hosp, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA. EM rdu@partners.org FU Partners Personalized Medicine FX This study was supported by Partners Personalized Medicine. NR 15 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD JAN 10 PY 2017 VL 88 IS 2 BP 164 EP 168 PG 5 WC Clinical Neurology SC Neurosciences & Neurology GA EO2YH UT WOS:000396561500013 PM 27927935 ER PT J AU van Etten, ES Verbeek, MM van der Grond, J Zielman, R van Rooden, S van Zwet, EW van Opstal, AM Haan, J Greenberg, SM van Buchem, MA Wermer, MJH Terwindt, GM AF van Etten, Ellis S. Verbeek, Marcel M. van der Grond, Jeroen Zielman, Ronald van Rooden, Sanneke van Zwet, Erik W. van Opstal, Anna M. Haan, Joost Greenberg, Steven M. van Buchem, Mark A. Wermer, Marieke J. H. Terwindt, Gisela M. TI beta-Amyloid in CSF Biomarker for preclinical cerebral amyloid angiopathy SO NEUROLOGY LA English DT Article ID SMALL VESSEL DISEASE; ALZHEIMERS-DISEASE; DUTCH TYPE; CLINICAL-DIAGNOSIS; BOSTON CRITERIA; BLOOD-PRESSURE; HCHWA-D; HEREDITARY; HEMORRHAGE; BRAIN AB Objective: To investigate CSF biomarkers in presymptomatic and symptomatic mutation carriers with hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D), a model for sporadic cerebral amyloid angiopathy, and to determine the earliest deposited form of beta-amyloid (A beta). Methods: HCHWA-D mutation carriers and controls were enrolled in the cross-sectional EDAN (Early Diagnosis of Amyloid Angiopathy Network) study. The HCHWA-D group was divided into symptomatic carriers with a previous intracerebral hemorrhage and presymptomatic carriers. CSF concentrations of A beta(40), A beta(42), total tau, and phosphorylated tau(181) proteins were compared to those of controls of a similar age. Correlations between CSF biomarkers, MRI markers, and age were investigated with multivariate linear regression analyses. Results: We included 10 symptomatic patients with HCHWA-D (mean age 55 +/- 6 years), 5 presymptomatic HCHWA-D carriers (mean age 36 +/- 13 years), 31 controls < 50 years old (mean age 31 +/- 7 years), and 50 controls >= 50 years old (mean age 61 +/- 8 years). After correction for age, CSF A beta(40) and A beta(42) were significantly decreased in symptomatic carriers vs controls (median A beta(40) 1,386 vs 3,867 ng/L, p < 0.001; median A beta(42) 289 vs 839 ng/L, p < 0.001) and in presymptomatic carriers vs controls (median A beta(40) 3,501 vs 4,684 ng/L, p = 0.011; median A beta(42) 581 vs 1,058 ng/L, p < 0.001). Among mutation carriers, decreasing CSF A beta(40) was associated with higher lobar microbleed count (p = 0.010), increasing white matter hyperintensity volume (p = 0.008), and presence of cortical superficial siderosis (p = 0.02). Conclusions: Decreased levels of CSF A beta(40) and A beta(42) occur before HCHWA-D mutation carriers develop clinical symptoms, implicating vascular deposition of both A beta species as early steps in cerebral amyloid angiopathy pathogenesis. CSF A beta(40) and A beta(42) may serve as preclinical biomarkers of cerebral amyloid angiopathy pathology. Neurology (R) 2017; 88: 169-176 C1 [van Etten, Ellis S.; Zielman, Ronald; Haan, Joost; Wermer, Marieke J. H.; Terwindt, Gisela M.] Leiden Univ Med Ctr, Dept Neurol, Leiden, Netherlands. [van der Grond, Jeroen; van Rooden, Sanneke; van Opstal, Anna M.; van Buchem, Mark A.] Leiden Univ Med Ctr, Dept Radiol, Leiden, Netherlands. [van Zwet, Erik W.] Leiden Univ Med Ctr, Dept Biostat, Leiden, Netherlands. [Verbeek, Marcel M.] Radboud Univ Nijmegen Med Ctr, Radboud Alzheimer Ctr, Donders Inst Brain Cognit & Behav, Dept Neurol, Nijmegen, Netherlands. [Verbeek, Marcel M.] Radboud Univ Nijmegen Med Ctr, Radboud Alzheimer Ctr, Donders Inst Brain Cognit & Behav, Dept Lab Med, Nijmegen, Netherlands. [Haan, Joost] Alrijne Hosp, Dept Neurol, Leiderdorp, Netherlands. [Greenberg, Steven M.] Massachusetts Gen Hosp, J Philip Kistler Stroke Res Ctr, Boston, MA 02114 USA. RP van Etten, ES (reprint author), Leiden Univ Med Ctr, Dept Neurol, Leiden, Netherlands. EM e.s.van_etten@lumc.nl RI Verbeek, Marcel/D-1971-2010 FU NIH [R01 NS070834]; CAVIA project [733050202] FX Funding was provided by NIH R01 NS070834 (S.M.G.) This study was part of the CAVIA project (No. 733050202; M.M.V.), which has been made possible by ZonMW. The CAVIA project is part of Memorabel, the research and innovation program for dementia, as part of the Dutch national Deltaplan for Dementia (zonmw.nl/dementiaresearch). The CAVIA project is a consortium of RUNMC, LUMC, Erasmus University Medical Center, VU University Medical Center, ADX Neurosciences, Philips Healthcare, Stony Brook University, and Massachusetts General Hospital. NR 34 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD JAN 10 PY 2017 VL 88 IS 2 BP 169 EP 176 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA EO2YH UT WOS:000396561500014 PM 27903811 ER PT J AU Bradshaw, MJ Vu, N Hunley, TE Chitnis, T AF Bradshaw, Michael J. NgocHanh Vu Hunley, Tracy E. Chitnis, Tanuja TI Child Neurology: Neuromyelitis optica spectrum disorders SO NEUROLOGY LA English DT Editorial Material C1 [Bradshaw, Michael J.; NgocHanh Vu] Vanderbilt Univ, Med Ctr, Dept Neurol, Nashville, TN 37232 USA. [Hunley, Tracy E.] Vanderbilt Childrens Hosp, Div Nephrol & Hypertens, Nashville, TN USA. [Chitnis, Tanuja] Massachusetts Gen Hosp, Brigham & Womens Hosp, Partners MS Ctr, Ctr Neurol Dis, Boston, MA USA. RP Bradshaw, MJ (reprint author), Vanderbilt Univ, Med Ctr, Dept Neurol, Nashville, TN 37232 USA. EM Michael.j.bradshaw@vanderbilt.edu NR 10 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD JAN 10 PY 2017 VL 88 IS 2 BP E10 EP E13 DI 10.1212/WNL.0000000000003495 PG 4 WC Clinical Neurology SC Neurosciences & Neurology GA EO2YH UT WOS:000396561500001 PM 28069981 ER PT J AU Charney, AW Ruderfer, DM Stahl, EA Moran, JL Chambert, K Belliveau, RA Forty, L Gordon-Smith, K Di Florio, A Lee, PH Bromet, EJ Buckley, PF Escamilla, MA Fanous, AH Fochtmann, LJ Lehrer, DS Malaspina, D Marder, SR Morley, CP Nicolini, H Perkins, DO Rakofsky, JJ Rapaport, MH Medeiros, H Sobell, JL Green, EK Backlund, L Bergen, SE Jureus, A Schalling, M Lichtenstein, P Roussos, P Knowles, JA Jones, I Jones, LA Hultman, CM Perlis, RH Purcell, SM McCarroll, SA Pato, CN Pato, MT Craddock, N Landen, M Smoller, JW Sklar, P AF Charney, A. W. Ruderfer, D. M. Stahl, E. A. Moran, J. L. Chambert, K. Belliveau, R. A. Forty, L. Gordon-Smith, K. Di Florio, A. Lee, P. H. Bromet, E. J. Buckley, P. F. Escamilla, M. A. Fanous, A. H. Fochtmann, L. J. Lehrer, D. S. Malaspina, D. Marder, S. R. Morley, C. P. Nicolini, H. Perkins, D. O. Rakofsky, J. J. Rapaport, M. H. Medeiros, H. Sobell, J. L. Green, E. K. Backlund, L. Bergen, S. E. Jureus, A. Schalling, M. Lichtenstein, P. Roussos, P. Knowles, J. A. Jones, I. Jones, L. A. Hultman, C. M. Perlis, R. H. Purcell, S. M. McCarroll, S. A. Pato, C. N. Pato, M. T. Craddock, N. Landen, M. Smoller, J. W. Sklar, P. TI Evidence for genetic heterogeneity between clinical subtypes of bipolar disorder SO TRANSLATIONAL PSYCHIATRY LA English DT Article ID GENOME-WIDE ASSOCIATION; SPECTRUM DISORDER; II DISORDER; RISK LOCI; SCHIZOPHRENIA; FAMILY; DEPRESSION; UNIPOLAR; ILLNESS; SUSCEPTIBILITY AB We performed a genome-wide association study of 6447 bipolar disorder (BD) cases and 12 639 controls from the International Cohort Collection for Bipolar Disorder (ICCBD). Meta-analysis was performed with prior results from the Psychiatric Genomics Consortium Bipolar Disorder Working Group for a combined sample of 13 902 cases and 19 279 controls. We identified eight genome-wide significant, associated regions, including a novel associated region on chromosome 10 (rs10884920; P = 3.28 x 10(-8)) that includes the brain-enriched cytoskeleton protein adducin 3 (ADD3), a non-coding RNA, and a neuropeptide-specific aminopeptidase P (XPNPEP1). Our large sample size allowed us to test the heritability and genetic correlation of BD subtypes and investigate their genetic overlap with schizophrenia and major depressive disorder. We found a significant difference in heritability of the two most common forms of BD (BD I SNP-h(2) = 0.35; BD II SNP-h(2) = 0.25; P = 0.02). The genetic correlation between BD I and BD II was 0.78, whereas the genetic correlation was 0.97 when BD cohorts containing both types were compared. In addition, we demonstrated a significantly greater load of polygenic risk alleles for schizophrenia and BD in patients with BD I compared with patients with BD II, and a greater load of schizophrenia risk alleles in patients with the bipolar type of schizoaffective disorder compared with patients with either BD I or BD II. These results point to a partial difference in the genetic architecture of BD subtypes as currently defined. C1 [Charney, A. W.; Ruderfer, D. M.; Stahl, E. A.; Roussos, P.; Hultman, C. M.; Purcell, S. M.] Icahn Sch Med Mt Sinai, Dept Psychiat, 1 Gustave L Levy Pl, New York, NY 10029 USA. [Ruderfer, D. M.; Stahl, E. A.; Bergen, S. E.; Roussos, P.; Purcell, S. M.; McCarroll, S. A.; Smoller, J. W.] Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, Inst Genom & Multiscale Biol, 1 Gustave L Levy Pl, New York, NY 10029 USA. [Moran, J. L.; Chambert, K.; Belliveau, R. A.; Lee, P. H.] Broad Inst Harvard, Stanley Ctr Psychiat Res, Cambridge, MA USA. [Moran, J. L.; Chambert, K.; Belliveau, R. A.; Lee, P. H.] MIT, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Forty, L.; Di Florio, A.] Cardiff Unviers, MRC Ctr Psychiat Genet & Genom, Cardiff, S Glam, Wales. [Gordon-Smith, K.; Di Florio, A.] Univ Worcester, Dept Psychol Med, Worcester, England. [Perkins, D. O.] Univ N Carolina, Dept Psychiat, Chapel Hill, NC USA. [Lee, P. H.] Harvard Med Sch, Dept Psychiat, Boston, MA USA. [Lee, P. H.; Smoller, J. W.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Bromet, E. J.; Fochtmann, L. J.] SUNY Stony Brook, Dept Psychiat, Stony Brook, NY 11794 USA. [Buckley, P. F.] Georgia Regents Univ, Med Ctr, Dept Psychiat, Augusta, GA USA. [Escamilla, M. A.] Texas Tech Univ, Hlth Sci Ctr, Dept Psychiat, Ctr Excellence Neurosci, El Paso, TX USA. [Fanous, A. H.] Vet Adm Med Ctr, Dept Psychiat, Washington, DC 20422 USA. [Fanous, A. H.] Georgetown Univ, Dept Psychiat, Washington, DC USA. [Lehrer, D. S.] Wright State Univ, Dept Psychiat, Dayton, OH 45435 USA. [Malaspina, D.] NYU, Dept Psychiat, 550 1St Ave, New York, NY 10016 USA. [Marder, S. R.] Univ Calif Los Angeles, Dept Psychiat, Los Angeles, CA USA. [Morley, C. P.] SUNY Upstate Med Univ, Dept Psychiat & Behav Neurosci, Syracuse, NY 13210 USA. [Morley, C. P.] SUNY Upstate Med Univ, Dept Family Med, Syracuse, NY 13210 USA. [Morley, C. P.] SUNY Upstate Med Univ, Dept Publ Hlth & Prevent Med, Syracuse, NY 13210 USA. [Nicolini, H.] Univ Autonoma Ciudad Mexico, Ctr Genom Sci, Mexico City, DF, Mexico. [Nicolini, H.] Carracci Med Grp, Dept Psychiat, Mexico City, DF, Mexico. [Rakofsky, J. J.] Emory Univ, Dept Psychiat & Behav Sci, Atlanta, GA 30322 USA. [Sobell, J. L.] Univ Southern Calif, Keck Sch Med, Dept Psychiat & Behav Sci, Los Angeles, CA 90033 USA. [Green, E. K.] Univ Plymouth, Peninsula Schools Med & Dent, Sch Biomed & Hlth Sci, Plymouth, Devon, England. [Backlund, L.] Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden. [Backlund, L.] Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden. [Bergen, S. E.; Jureus, A.; Lichtenstein, P.; Landen, M.] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. Icahn Sch Med Mt Sinai, Dept Neurosci, Friedman Brain Inst, 1 Gustave L Levy Pl, New York, NY 10029 USA. [Knowles, J. A.; Pato, C. N.] Univ Southern Calif, Keck Sch Med, Zilkha Neurogenet Inst, Los Angeles, CA 90033 USA. [Perlis, R. H.] Massachusetts Gen Hosp, Ctr Expt Therapeut, Boston, MA 02114 USA. [McCarroll, S. A.] Harvard Med Sch, Dept Genet, Boston, MA USA. [Landen, M.] Gothenburg Univ, Sahlgenska Acad, Inst Neurosci Physiol, Gothenburg, Sweden. [Smoller, J. W.] Massachusetts Gen Hosp, Ctr Human Genet Res, Psychiat & Neurodevelopmental Genet Unit, Boston, MA 02114 USA. RP Sklar, P (reprint author), Icahn Sch Med Mt Sinai, Dept Psychiat, 1 Gustave L Levy Pl, New York, NY 10029 USA. EM pamela.sklar@mssm.edu FU National Institutes of Health (NIH)/National Institute of Mental Health (NIMH) [R01MH085542, R01MH085545, R01MH085548, K99MH101367]; Swedish Research Council [2013- 3196]; Swedish Medical Research Council grants [K2014-62X-14647-12-51, K2010-61 P-21568-01-4]; Swedish foundation for Strategic Research grant [KF10-0039]; Swedish Federal Government under the LUA/ALF agreement grants [ALF 20130032, ALFGBG-142041]; Stanley Medical Research Institute; European Commission-Marie Curie Fellowship; Wellcome Trust; Institute for Genomics and Multiscale Biology (including computational resources and staff expertise provided by the Department of Scientific Computing) FX We are grateful for the participation of all subjects contributing to this research, and to the collection team that worked to recruit them. We acknowledge funding support from National Institutes of Health (NIH)/National Institute of Mental Health (NIMH) grant R01MH085542 (AWC, JWS and PS), NIH/NIMH grant R01MH085545 (JWS), NIH/ NIMH grant R01MH085548 (AHF, CNP, CPM, DM, DOP, DSL, ELB, HM, HN, JAK, JJR, JLS, LJF, MAE, MHR, MTP, PFB and SRM), NIH/NIMH grant K99MH101367 (PHL), the Stanley Medical Research Institute (JLM, KC, RAB and SAM), philanthropic gifts from Kent and Elizabeth Dauten and Ted and Vada Stanley (JLM, KC, RAB and SAM), the Swedish Research Council 2013- 3196 (CMH), the Swedish Medical Research Council grants K2014-62X-14647-12-51 and K2010-61 P-21568-01-4 (ML), the Swedish foundation for Strategic Research grant KF10-0039 (ML), the Swedish Federal Government under the LUA/ALF agreement grants ALF 20130032 and ALFGBG-142041 (ML), European Commission-Marie Curie Fellowship (AD), Wellcome Trust (IJ, KG, LAJ, LF and NC). 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). NR 56 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 2158-3188 J9 TRANSL PSYCHIAT JI Transl. Psychiatr. PD JAN 10 PY 2017 VL 7 AR e993 DI 10.1038/tp.2016.242 PG 9 WC Psychiatry SC Psychiatry GA EO1IA UT WOS:000396450700001 PM 28072414 ER PT J AU Erk, S Mohnke, S Ripke, S Lett, TA Veer, IM Wackerhagen, C Grimm, O Romanczuk-Seiferth, N Degenhardt, F Tost, H Mattheisen, M Muhleisen, TW Charlet, K Skarabis, N Kiefer, F Cichon, S Witt, SH Nothen, MM Rietschel, M Heinz, A Meyer-Lindenberg, A Walter, H AF Erk, S. Mohnke, S. Ripke, S. Lett, T. A. Veer, I. M. Wackerhagen, C. Grimm, O. Romanczuk-Seiferth, N. Degenhardt, F. Tost, H. Mattheisen, M. Muehleisen, T. W. Charlet, K. Skarabis, N. Kiefer, F. Cichon, S. Witt, S. H. Noethen, M. M. Rietschel, M. Heinz, A. Meyer-Lindenberg, A. Walter, H. TI Functional neuroimaging effects of recently discovered genetic risk loci for schizophrenia and polygenic risk profile in five RDoC subdomains SO TRANSLATIONAL PSYCHIATRY LA English DT Article ID BIPOLAR DISORDER; INTERMEDIATE PHENOTYPE; IMAGING GENETICS; SOCIAL COGNITION; COMMON VARIATION; BRAIN-FUNCTION; VARIANT; HIPPOCAMPAL; PSYCHOSIS; CACNA1C AB Recently, 125 loci with genome-wide support for association with schizophrenia were identified. We investigated the impact of these variants and their accumulated genetic risk on brain activation in five neurocognitive domains of the Research Domain Criteria (working memory, reward processing, episodic memory, social cognition and emotion processing). In 578 healthy subjects we tested for association (i) of a polygenic risk profile score (RPS) including all single-nucleotide polymorphisms (SNPs) reaching genome-wide significance in the recent genome-wide association studies (GWAS) meta-analysis and (ii) of all independent genome-wide significant loci separately that showed sufficient distribution of all allelic groups in our sample (105 SNPs). The RPS was nominally associated with perigenual anterior cingulate and posterior cingulate/precuneus activation during episodic memory (P-FWE(ROI) = 0.047) and social cognition (P-FWE(ROI) = 0.025), respectively. Single SNP analyses revealed that rs9607782, located near EP300, was significantly associated with amygdala recruitment during emotion processing (P-FWE(ROI) = 1.63 x 10(-4), surpassing Bonferroni correction for the number of SNPs). Importantly, this association was replicable in an independent sample (N = 150; (P-FWE(ROI) < 0.025). Other SNP effects previously associated with imaging phenotypes were nominally significant, but did not withstand correction for the number of SNPs tested. To assess whether there was true signal within our data, we repeated single SNP analyses with 105 randomly chosen non-schizophrenia-associated variants, observing fewer significant results and lower association probabilities. Applying stringent methodological procedures, we found preliminary evidence for the notion that genetic risk for schizophrenia conferred by rs9607782 may be mediated by amygdala function. We critically evaluate the potential caveats of the methodological approaches employed and offer suggestions for future studies. C1 [Erk, S.; Mohnke, S.; Ripke, S.; Lett, T. A.; Veer, I. M.; Wackerhagen, C.; Romanczuk-Seiferth, N.; Charlet, K.; Skarabis, N.; Heinz, A.; Walter, H.] Charite Univ Med Berlin, Dept Psychiat & Psychotherapy, Campus Mitte, Berlin, Germany. [Erk, S.; Mohnke, S.; Lett, T. A.; Veer, I. M.; Wackerhagen, C.; Skarabis, N.; Walter, H.] Charite Univ Med Berlin, Div Mind & Brain Res, Campus Mitte, Berlin, Germany. [Ripke, S.] Massachusetts Gen Hosp, Dept Med, Analyt & Translat Genet Unit, Boston, MA 02114 USA. [Ripke, S.] Harvard Med Sch, Boston, MA USA. [Grimm, O.] Goethe Univ Frankfurt, Dept Psychiat, Psychosomat Med, Psychotherapy, Frankfurt, Germany. [Degenhardt, F.; Noethen, M. M.] Univ Bonn, Life & Brain Ctr, Dept Genom, Bonn, Germany. [Degenhardt, F.; Noethen, M. M.] Univ Bonn, Inst Human Genet, Bonn, Germany. [Tost, H.; Kiefer, F.; Meyer-Lindenberg, A.] Heidelberg Univ, Fac Med Mannheim, Cent Inst Mental Hlth, Dept Psychiat & Psychotherapy, Mannheim, Germany. [Mattheisen, M.] Univ Aarhus, Dept Biomed, Aarhus, Denmark. [Muehleisen, T. W.; Cichon, S.] Res Ctr Julich, Inst Neurosci & Med, Julich, Germany. [Muehleisen, T. W.; Cichon, S.] Univ Basel, Dept Biomed, Div Med Genet, Basel, Switzerland. [Witt, S. H.; Rietschel, M.] Heidelberg Univ, Fac Med Mannheim, Cent Inst Mental Hlth, Dept Genet Epidemiol Psychiat, Mannheim, Germany. RP Erk, S; Mohnke, S (reprint author), Charite Univ Med Berlin, Div Mind & Brain Res, Dept Psychiat & Psychotherapy, Campus Mitte,Charitepl 1, D-10117 Berlin, Germany. EM susanne.erk@charite.de; sebastian.mohnke@charite.de OI Wackerhagen, Carolin/0000-0002-5689-3472 FU German Ministry for Education and Research (BMBF) grants NGFNplus MooDS (Systematic Investigation of the Molecular Causes of Major Mood Disorders and Schizophrenia); NGFN-Plus Genetics of Alcohol Addiction/ e:Med Alcoholism [FKZ 01GS08159, 01ZX1311E]; Integrated Network IntegraMent (Integrated Understanding of Causes and Mechanisms in Mental Disorders), under e:Med program [O1ZX1314B]; German Research Foundation (DFG) grant [SFB 636-B7]; local Bonfor programme FX This work was supported by the German Ministry for Education and Research (BMBF) grants NGFNplus MooDS (Systematic Investigation of the Molecular Causes of Major Mood Disorders and Schizophrenia), NGFN-Plus Genetics of Alcohol Addiction/ e:Med Alcoholism (FKZ 01GS08159, 01ZX1311E), the Integrated Network IntegraMent (Integrated Understanding of Causes and Mechanisms in Mental Disorders), under the auspices of the e:Med program (grant number O1ZX1314B) and the German Research Foundation (DFG) grant SFB 636-B7. MMN is a member of the DFG funded Excellence-Cluster Immuno-Sensation. FD received financial support from the local Bonfor programme. We thank Swapnil Awasthi for help with genetic analyses. NR 52 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 2158-3188 J9 TRANSL PSYCHIAT JI Transl. Psychiatr. PD JAN 10 PY 2017 VL 7 AR e997 DI 10.1038/tp.2016.272 PG 9 WC Psychiatry SC Psychiatry GA EO1IA UT WOS:000396450700005 PM 28072415 ER PT J AU Shim, WH Suh, JY Kim, JK Jeong, J Kim, YR AF Shim, Woo H. Suh, Ji-Yeon Kim, Jeong K. Jeong, Jaeseung Kim, Young R. TI Enhanced Thalamic Functional Connectivity with No fMRI Responses to Affected Forelimb Stimulation in Stroke-Recovered Rats SO FRONTIERS IN NEURAL CIRCUITS LA English DT Article DE stroke recovery; rat; resting state fMRI; stimulus-induced fMRI; plastic reorganization ID FOCAL CEREBRAL-ISCHEMIA; MOTOR RECOVERY; BOLD FMRI; BRAIN; REORGANIZATION; VISUALIZATION; HEMODYNAMICS; MEDETOMIDINE; PREDICTION; SOFTWARE AB Neurological recovery after stroke has been extensively investigated to provide better understanding of neurobiological mechanism, therapy, and patient management. Recent advances in neuroimaging techniques, particularly functional MRI (fMRI), have widely contributed to unravel the relationship between the altered neural function and stroke-affected brain areas. As results of previous investigations, the plastic reorganization and/or gradual restoration of the hemodynamic fMRI responses to neural stimuli have been suggested as relevant mechanisms underlying the stroke recovery process. However, divergent study results and modality-dependent outcomes have clouded the proper interpretation of variable fMRI signals. Here, we performed both evoked and resting state fMRI (rs-fMRI) to clarify the link between the fMRI phenotypes and post-stroke functional recovery. The experiments were designed to examine the altered neural activity within the contra-lesional hemisphere and other undamaged brain regions using rat models with large unilateral stroke, which despite the severe injury, exhibited nearly full recovery at similar to 6 months after stroke. Surprisingly, both blood oxygenation level-dependent and blood volume-weighted (CBVw) fMRI activities elicited by electrical stimulation of the stroke-affected forelimb were completely absent, failing to reveal the neural origin of the behavioral recovery. In contrast, the functional connectivity maps showed highly robust rs-fMRI activity concentrated in the contra-lesional ventromedial nucleus of thalamus (VM). The negative finding in the stimuli-induced fMRI study using the popular rat middle cerebral artery model denotes weak association between the fMRI hemodynamic responses and neurological improvement. The results strongly caution the indiscreet interpretation of stroke-affected fMRI signals and demonstrate rs-fMRI as a complementary tool for efficiently characterizing stroke recovery. C1 [Shim, Woo H.; Suh, Ji-Yeon; Kim, Jeong K.] Univ Ulsan, Dept Radiol, ASAN Med Ctr, Coll Med, Ulsan, South Korea. [Shim, Woo H.] Univ Ulsan, ASAN Inst Life Sci, ASAN Med Ctr, Coll Med, Ulsan, South Korea. [Shim, Woo H.; Jeong, Jaeseung] Korea Adv Inst Sci & Technol, Dept Bio & Brain Engn, Daejeon, South Korea. [Shim, Woo H.; Suh, Ji-Yeon; Kim, Young R.] Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Boston, MA 02114 USA. RP Jeong, J (reprint author), Korea Adv Inst Sci & Technol, Dept Bio & Brain Engn, Daejeon, South Korea.; Kim, YR (reprint author), Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Boston, MA 02114 USA. EM jsjeong@kaist.ac.kr; spmn@nmr.mgh.harvard.edu FU NIH [1 R21 EY026379-01]; Basic Science Research Program through the National Research Foundation of Korea (NU) - Ministry of Science, ICT & Future Planning [2015M3A9D7067260] FX This research was supported by NIH 1 R21 EY026379-01, and Basic Science Research Program through the National Research Foundation of Korea (NU) funded by the Ministry of Science, ICT & Future Planning (2015M3A9D7067260). NR 35 TC 0 Z9 0 U1 0 U2 0 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1662-5110 J9 FRONT NEURAL CIRCUIT JI Front. Neural Circuits PD JAN 10 PY 2017 VL 10 AR 113 DI 10.3389/fncir.2016.00113 PG 11 WC Neurosciences SC Neurosciences & Neurology GA EP0HK UT WOS:000397067700001 ER PT J AU Thibaut, A Russo, C Morales-Quezada, L Hurtado-Puerto, A Deitos, A Freedman, S Carvalho, S Fregni, F AF Thibaut, Aurore Russo, Cristina Morales-Quezada, Leon Hurtado-Puerto, Aura Deitos, Alicia Freedman, Steven Carvalho, Sandra Fregni, Felipe TI Neural signature of tDCS, tPCS and their combination: Comparing the effects on neural plasticity SO NEUROSCIENCE LETTERS LA English DT Article DE Non-invasive brain stimulation; tPCS; tDCS; EEG; Top-down/bottom-up connectivity ID DIRECT-CURRENT STIMULATION; PULSED CURRENT STIMULATION; PAIN; CONNECTIVITY; TRIAL; ELECTROENCEPHALOGRAPHY; EXCITABILITY; PERCEPTION; MODULATION; HUMANS AB Transcranial pulsed current stimulation (tPCS) and transcranial direct current stimulation (tDCS) are two noninvasive neuromodulatory brain stimulation techniques whose effects on human brain and behavior have been studied individually. In the present study we aimed to quantify the effects of tDCS and tPCS, individually and in combination, on cortical activity, sensitivity and pain-related assessments in healthy individuals in order to understand their neurophysiological mechanisms and potential applications in clinical populations. A total of 48 healthy individuals participated in this randomized double blind sham controlled study. Participants were randomized to receive a single stimulation session of either: active or sham tPCS and active or sham tDCS. Quantitative electroencephalography (qEEG), sensitivity and pain assessments were used before and after each stimulation session. We observed that tPCS had a higher effect on power, as compared to tDCS, in several bandwidths on various cortical regions: the theta band in the parietal region (p = 0.021), the alpha band in the temporal (p=0.009), parietal (p = 0.0063), and occipital (p < 0.0001) regions. We found that the combination of tPCS and tDCS significantly decreased power in the low beta bandwidth of the frontal (p = 0.0006), central (p = 0.0001), and occipital (p = 0.0003) regions, when compared to sham stimulation. Additionally, tDCS significantly increased power in high beta over the temporal (p = 0.0015) and parietal (p = 0.0007) regions, as compared to sham. We found no effect on sensitivity or pain-related assessments. We concluded that tPCS and tDCS have different neurophysiological mechanisms, elicit distinct signatures, and that the combination of the two leads to no effect or a decrease on qEEG power. Further studies are required to examine the effects of these techniques on clinical populations in which EEG signatures have been found altered. (C) 2016 Published by Elsevier Ireland Ltd. C1 [Thibaut, Aurore; Russo, Cristina; Morales-Quezada, Leon; Deitos, Alicia; Carvalho, Sandra; Fregni, Felipe] Harvard Med Sch, Spaulding Rehabil Hosp, Spaulding Labuschagne Neuromodulat Ctr, Dept Phys Med & Rehabil, Boston, MA USA. [Thibaut, Aurore] Univ & Univ Hosp, GIGA Res, Coma Sci Grp, Liege, Belgium. [Russo, Cristina] Univ Milano Bicocca, Dept Psychol, Milan, Italy. [Russo, Cristina] Univ Milano Bicocca, Milan Ctr Neurosci NeuroMi, Milan, Italy. [Hurtado-Puerto, Aura] Massachusetts Gen Hosp, Dept Psychiat, Transcranial Magnet Stimulat Clin Serv, Lab Neuropsychiat & Neuromodulat, Boston, MA 02114 USA. [Deitos, Alicia] Univ Fed Rio Grande do Sul, Sch Med, Postgrad Program Med Sci, Porto Alegre, RS, Brazil. [Deitos, Alicia] Univ Fed Rio Grande do Sul, Lab Pain & Neuromodulat, Porto Alegre, RS, Brazil. [Freedman, Steven] Beth Israel Deaconess Med Ctr, Div Translat Res, Boston, MA 02215 USA. [Carvalho, Sandra] Univ Minho, Sch Psychol EPsi, CIPsi, Neuropsychophysiol Lab, Campus Gualtar, P-4710057 Braga, Portugal. RP Fregni, F (reprint author), Spaulding Labuschagne Neuromodulat Ctr, 79-96 13th St, Charlestown, MA 02129 USA. EM felipe.fregni@mgh.harvard.edu FU Labuschagne Foundation; Institutional National Research Service Award from the National Center for Complementary and Integrative Health [T32AT000051]; Ryoichi Sasakawa Fellowship Fund; Program in Placebo Studies at Beth Israel Deaconess Medical Center; NIH RO1 grant [1R01HD082302-01A1]; International Cooperation General Program - PGCI [023/11] FX This research was supported by Labuschagne Foundation. Dr. Thibaut was founded by the Belgian American Educational Foundation (BAEF) and the Duesberg Foundation. Dr. Morales-Quezada received funding support from an Institutional National Research Service Award from the National Center for Complementary and Integrative Health grant T32AT000051, the Ryoichi Sasakawa Fellowship Fund, and by the Program in Placebo Studies at Beth Israel Deaconess Medical Center. Deitos, A. was founded by the Coordination for the Improvement of Higher Education Personnel - CAPES, International Cooperation General Program - PGCI (no 023/11). Prof. Fregni has been supported by NIH RO1 grant (1R01HD082302-01A1). NR 42 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3940 EI 1872-7972 J9 NEUROSCI LETT JI Neurosci. Lett. PD JAN 10 PY 2017 VL 637 BP 207 EP 214 DI 10.1016/j.neulet.2016.10.026 PG 8 WC Neurosciences SC Neurosciences & Neurology GA EI8XA UT WOS:000392790300034 PM 27765610 ER PT J AU Ren, J AF Ren, Jian TI Dispersion analysis and measurement of potassium tantalate niobate crystals by broadband optical interferometers SO APPLIED OPTICS LA English DT Article ID PARTIAL COHERENCE INTERFEROMETRY; ULTRAHIGH-RESOLUTION; SINGLE-CRYSTALS; KTN-CRYSTAL; HIGH-SPEED; TOMOGRAPHY; COMPENSATION; PHASE; PERFORMANCE; DEFLECTOR AB Electro-optic crystals, such as potassium tantalate niobate [KTa1-xNbxO3(KTN)], are enabling materials for many optical devices. Their utility in broadband applications heavily depends on their dispersion property. To this end, an analysis of dispersion mismatch in broadband optical interferometers is first presented. Then a method utilizing polynomial phase fitting to measure the dispersion property of materials composing the arms of an interferometer is introduced. As a demonstration, an interferometry system based on optical coherence tomography (OCT) was built, where, for the first time, the group velocity dispersion of a KTN crystal around 1310 nm was measured and numerically compensated for OCT imaging. Several advantages over a widely used method in OCT, which is based on metric functions, are discussed. The results show the fitting method can provide a more reliable measurement with reduced computation complexity. (C) 2017 Optical Society of America C1 [Ren, Jian] oProbe LLC, 556 South Fair Oaks Ave, Pasadena, CA 91105 USA. [Ren, Jian] Massachusetts Gen Hosp, Wellman Ctr Photomed, 40 Blossom St, Boston, MA 02114 USA. [Ren, Jian] Harvard Med Sch, 25 Shattuck St, Boston, MA 02115 USA. RP Ren, J (reprint author), oProbe LLC, 556 South Fair Oaks Ave, Pasadena, CA 91105 USA.; Ren, J (reprint author), Massachusetts Gen Hosp, Wellman Ctr Photomed, 40 Blossom St, Boston, MA 02114 USA.; Ren, J (reprint author), Harvard Med Sch, 25 Shattuck St, Boston, MA 02115 USA. EM JREN@mgh.harvard.edu FU oProbe LLC. FX oProbe LLC. NR 29 TC 0 Z9 0 U1 4 U2 4 PU OPTICAL SOC AMER PI WASHINGTON PA 2010 MASSACHUSETTS AVE NW, WASHINGTON, DC 20036 USA SN 1559-128X EI 2155-3165 J9 APPL OPTICS JI Appl. Optics PD JAN 10 PY 2017 VL 56 IS 2 BP 234 EP 238 DI 10.1364/AO.56.000234 PG 5 WC Optics SC Optics GA EH9NH UT WOS:000392097500014 PM 28085857 ER PT J AU Gaggin, HK Liu, YY Lyass, A van Kimmenade, RRJ Motiwala, SR Kelly, NP Mallick, A Gandhi, PU Ibrahim, NE Simon, ML Bhardwaj, A Belcher, AM Harisiades, JE Massaro, JM D'Agostino, RB Januzzi, JL AF Gaggin, Hanna K. Liu, Yuyin Lyass, Asya van Kimmenade, Roland R. J. Motiwala, Shweta R. Kelly, Noreen P. Mallick, Aditi Gandhi, Parul U. Ibrahim, Nasrien E. Simon, Mandy L. Bhardwaj, Anju Belcher, Arianna M. Harisiades, Jamie E. Massaro, Joseph M. D'Agostino, Ralph B. Januzzi, James L., Jr. TI Incident Type 2 Myocardial Infarction in a Cohort of Patients Undergoing Coronary or Peripheral Arterial Angiography SO CIRCULATION LA English DT Article DE angiography; supply/demand mismatch; myocardial infarction; prognosis ID 3RD UNIVERSAL DEFINITION; OPTIMIZING PLATELET INHIBITION; CRITICALLY-ILL PATIENTS; CLASSIFICATION-SYSTEM; PRASUGREL-THROMBOLYSIS; THERAPEUTIC OUTCOMES; ASSESS IMPROVEMENT; TRIAL; ASSAY AB BACKGROUND: Despite growing recognition of type 2 myocardial infarction (T2MI; related to supply/demand mismatch), little is known about its risk factors or its association with outcome. METHODS: A single-center cohort of patients undergoing coronary or peripheral angiography with or without intervention was prospectively enrolled and followed for incident type 1 and T2MI, and major adverse cardiovascular events (MACE, a composite of all-cause death, nonfatal myocardial infarction [MI], heart failure, stroke, transient ischemic attack, peripheral arterial complication, and cardiac arrhythmia), as well. T2MI was adjudicated using criteria from the Third Universal Definition of MI. Baseline characteristics, blood samples, and angiography information were obtained. Major end points subsequent to first MI were assessed using landmark analyses to compare the rates of first events only where everyone with a prior history of any MACE before MI were censored and adjusted for follow-up times. Cox proportional hazard models were used for time-to-event analyses with age and sex forced into all models and additional covariates evaluated by using the stepwise option for the selection. RESULTS: One thousand two hundred fifty-one patients were enrolled and followed for a median of 3.4 years. Of these patients, 152 (12.2%) had T2MI during follow-up; T2MI was frequently recurrent. Multivariable predictors of T2MI were older age, lower systolic blood pressure, history of coronary artery disease, heart failure, chronic obstructive pulmonary disease, diabetes mellitus, nitrate use, and elevated concentrations of glucose, N-terminal pro-B type natriuretic peptide, and cystatin C. Patients with T2MI had higher rates of subsequent adverse events than those without T2MI (per 100 person-years: MACE, 53.7 versus 21.1, P<0.001; all-cause death, 23.3 versus 3.3, P<0.001; cardiovascular death, 17.5 versus 2.6, P<0.001; heart failure events, 22.4 versus 7.4, P<0.001); these rates are similar to those seen in patients with type 1 MI. Incident diagnosis of T2MI strongly predicted risk for subsequent MACE (adjusted hazard ratio, 1.90; 95% confidence interval, 1.46-2.48; P<0.001), all-cause death (adjusted hazard ratio, 2.96; 95% confidence interval, 2.01-4.36; P<0.001), and cardiovascular death (adjusted hazard ratio, 2.16; 95% confidence interval, 1.36-3.43; P=0.001). CONCLUSIONS: T2MI is common and associated with poor prognosis. Studies evaluating treatment strategies for management of T2MI are needed. C1 [Gaggin, Hanna K.; Mallick, Aditi; Ibrahim, Nasrien E.; Simon, Mandy L.; Belcher, Arianna M.; Harisiades, Jamie E.; Januzzi, James L., Jr.] Massachusetts Gen Hosp, Div Cardiol, Yawkey 5B,55 Fruit St, Boston, MA 02114 USA. [Gaggin, Hanna K.; Liu, Yuyin; Lyass, Asya; Massaro, Joseph M.; D'Agostino, Ralph B.; Januzzi, James L., Jr.] Baim Inst Clin Res, Boston, MA USA. [Liu, Yuyin; Massaro, Joseph M.] Boston Univ, Dept Biostat, Boston, MA 02215 USA. [Lyass, Asya; D'Agostino, Ralph B.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [van Kimmenade, Roland R. J.] Radboud UMC, Div Cardiol, Nijmegen, Netherlands. [van Kimmenade, Roland R. J.] Maastricht UMC, Div Cardiol, Maastricht, Netherlands. [Motiwala, Shweta R.] Beth Israel Deaconess Med Ctr, Div Cardiol, Boston, MA 02215 USA. [Kelly, Noreen P.] Brigham & Women Hosp, Div Cardiol, Boston, MA USA. [Gandhi, Parul U.] Yale Univ, Sch Med, Div Cardiol, New Haven, CT USA. [Gandhi, Parul U.] VA Connecticut Healthcare Syst, Div Cardiol, West Haven, CT USA. [Bhardwaj, Anju] Case Western Reserve Univ, Div Cardiol, Metrohlth Campus, Cleveland, OH 44106 USA. RP Januzzi, JL (reprint author), Massachusetts Gen Hosp, Div Cardiol, Yawkey 5B,55 Fruit St, Boston, MA 02114 USA. EM jjanuzzi@mgh.harvard.edu FU Siemens Diagnostics, Inc.; Dennis and Marilyn Barry Fellowship in Cardiology; Clark Fund for Cardiac Research Innovation; ICIN (Interuniversity Cardiology Institute of the Netherlands) fellowship grant; Hutter Family Professorship FX The CASABLANCA study was funded in part by Siemens Diagnostics, Inc.; the sponsor had no involvement in study design, collection, analysis, and interpretation of data, in the writing of the report and in the decision to submit the article for publication. Support for statistical analysis was provided by Baim Institute for Clinical Research. Drs Gaggin, Motiwala, Gandhi, Ibrahim, and Bhardwaj were supported by the Dennis and Marilyn Barry Fellowship in Cardiology, Dr Gaggin is supported in part by the Clark Fund for Cardiac Research Innovation, Dr van Kimmenade was supported by a ICIN (Interuniversity Cardiology Institute of the Netherlands) fellowship grant, and Dr Januzzi is supported in part by the Hutter Family Professorship. NR 19 TC 0 Z9 0 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD JAN 10 PY 2017 VL 135 IS 2 BP 116 EP + DI 10.1161/CIRCULATIONAHA.116.023052 PG 39 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA EI2AW UT WOS:000392289500008 PM 27881568 ER PT J AU Kim, JT Fonarow, GC Smith, EE Reeves, MJ Navalkele, DD Grotta, JC Grau-Sepulveda, MV Hernandez, AF Peterson, ED Schwamm, LH Saver, JL AF Kim, Joon-Tae Fonarow, Gregg C. Smith, Eric E. Reeves, Mathew J. Navalkele, Digvijaya D. Grotta, James C. Grau-Sepulveda, Maria V. Hernandez, Adrian F. Peterson, Eric D. Schwamm, Lee H. Saver, Jeffrey L. TI Treatment With Tissue Plasminogen Activator in the Golden Hour and the Shape of the 4.5-Hour Time-Benefit Curve in the National United States Get With The Guidelines-Stroke Population SO CIRCULATION LA English DT Article DE stroke; thrombolytic therapy; time-benefit curve; tissue plasminogen activator ID ACUTE ISCHEMIC-STROKE; RT-PA STROKE; POOLED ANALYSIS; INFARCT VOLUME; THROMBOLYSIS; CARE; ASSOCIATION; MANAGEMENT; OUTCOMES; NINDS AB BACKGROUND: Earlier tissue plasminogen activator treatment improves ischemic stroke outcome, but aspects of the time-benefit relationship still not well delineated are: (1) the degree of additional benefit accrued with treatment in the first 60 minutes after onset, and (2) the shape of the time-benefit curve through 4.5 hours. METHODS: We analyzed patients who had acute ischemic stroke treated with intravenous tissue plasminogen activator within 4.5 hours of onset from the Get With The Guidelines-Stroke US national program. Onset-to-treatment time was analyzed as a continuous, potentially nonlinear variable and as a categorical variable comparing patients treated within 60 minutes of onset with later epochs. RESULTS: Among 65 384 tissue plasminogen activator-treated patients, the median onset-to-treatment time was 141 minutes (interquartile range, 110-173) and 878 patients (1.3%) were treated within the first 60 minutes. Treatment within 60 minutes, compared with treatment within 61 to 270 minutes, was associated with increased odds of discharge to home (adjusted odds ratio, 1.25; 95% confidence interval, 1.07-1.45), independent ambulation at discharge (adjusted odds ratio, 1.22; 95% confidence interval, 1.03-1.45), and freedom from disability (modified Rankin Scale 0-1) at discharge (adjusted odds ratio, 1.72; 95% confidence interval, 1.21-2.46), without increased hemorrhagic complications or in-hospital mortality. The pace of decline in benefit of tissue plasminogen activator from onset-to-treatment times of 20 through 270 minutes was mildly nonlinear for discharge to home, with more rapid benefit loss in the first 170 minutes than later, and linear for independent ambulation and in-hospital mortality. CONCLUSIONS: Thrombolysis started within the first 60 minutes after onset is associated with best outcomes for patients with acute ischemic stroke, and benefit declined more rapidly early after onset for the ability to be discharged home. These findings support intensive efforts to organize stroke systems of care to improve the timeliness of thrombolytic therapy in acute ischemic stroke. C1 [Kim, Joon-Tae] Chonnam Natl Univ Hosp, Dept Neurol, Gwangju, South Korea. [Fonarow, Gregg C.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA. [Smith, Eric E.] Univ Calgary, Hotchkiss Brain Inst, Calgary, AB, Canada. [Reeves, Mathew J.] Michigan State Univ, Dept Epidemiol & Biostat, E Lansing, MI 48824 USA. [Navalkele, Digvijaya D.] Univ Texas Hlth Sci Ctr Houston, Dept Neurol, Houston, TX 77030 USA. [Grotta, James C.] Mem Hermann Hosp, Clin Innovat & Res Inst, Houston, TX USA. [Grau-Sepulveda, Maria V.; Hernandez, Adrian F.; Peterson, Eric D.] Duke Clin Res Inst, Outcome Res & Assessment Grp, Durham, NC USA. [Schwamm, Lee H.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Neurol, Boston, MA USA. [Saver, Jeffrey L.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurol, Los Angeles, CA 90095 USA. RP Saver, JL (reprint author), UCLA, Stroke Ctr, 710 Westwood Plaza, Los Angeles, CA 90095 USA. EM jsaver@mednet.ucla.edu FU Johnson Johnson; Boehringer-Ingelheim; Merck; Bristol-Myers Squibb/Sanofi Pharmaceutical Partnership; AHA Pharmaceutical Roundtable FX The GWTG-Stroke Program is provided by the AHA/American Stroke Association. The GWTG-Stroke Program is currently supported in part by a charitable contribution from Janssen Pharmaceutical Companies of Johnson & Johnson. The GWTG-Stroke Program has been funded in the past through support from Boehringer-Ingelheim, Merck, Bristol-Myers Squibb/Sanofi Pharmaceutical Partnership, and the AHA Pharmaceutical Roundtable. NR 31 TC 3 Z9 3 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD JAN 10 PY 2017 VL 135 IS 2 BP 128 EP + DI 10.1161/CIRCULATIONAHA.116.023336 PG 17 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA EI2AW UT WOS:000392289500009 PM 27815374 ER PT J AU Funatogawa, C Li, Y Chen, Y McDonald, W Szundi, I Fee, JA Stout, CD Einarsdottir, O AF Funatogawa, Chie Li, Yang Chen, Ying McDonald, William Szundi, Istvan Fee, James A. Stout, C. David Einarsdottir, Olof TI Role of the Conserved Valine 236 in Access of Ligands to the Active Site of Thermus thermophilus ba(3) Cytochrome Oxidase SO BIOCHEMISTRY LA English DT Article ID INTRAMOLECULAR ELECTRON-TRANSFER; HEME-COPPER OXIDASES; C-OXIDASE; PARACOCCUS-DENITRIFICANS; RHODOBACTER-SPHAEROIDES; MOLECULAR SIMULATIONS; TERMINAL OXIDASE; BINDING; OXYGEN; O-2 AB Knowledge of the role of conserved residues in the ligand channel of heme-copper oxidases is critical for understanding how the protein scaffold modulates the function of these enzymes. In this study, we investigated the role of the conserved valine 236 in the ligand channel of ba(3) cytochrome c oxidase from Thermus thermophilus by mutating the residue to a more polar (V236T), smaller (V236A), or larger (V236I, V236N, V236L, V236M, and V236F) residue. The crystal structures of the mutants were determined, and the effects of the mutations on the rates of CO, O-2, and NO binding were investigated. O-2 reduction and NO binding were unaffected in V236T, while the oxidation of heme b during 0-0 bond cleavage was not detected in V236A. The V236A results are attributed to a decrease in the rate of electron transfer between heme b and heme a(3) during 0-0 bond cleavage in V236A, followed by faster re-reduction of heme b by Cu-A. This interpretation is supported by classical molecular dynamics simulations of diffusion of O-2 to the active site in V236A that indicated a larger distance between the two hemes compared to that in the wild type and increased contact of heme a(3) with water and weakened interactions with residues R444 and R445. As the size of the mutant side chain increased and protruded more into the ligand cavity, the rates of ligand binding decreased correspondingly. These results demonstrate the importance of V236 in facilitating access of ligands to the active site in T. thermophilus ba(3). C1 [Funatogawa, Chie; McDonald, William; Szundi, Istvan; Einarsdottir, Olof] Univ Calif Santa Cruz, Dept Chem & Biochem, Santa Cruz, CA 95064 USA. [Li, Yang; Chen, Ying; Fee, James A.; Stout, C. David] Scripps Inst, Dept Mol Biol, MB-8,10550 North Torrey Pines Rd, La Jolla, CA 92037 USA. [Li, Yang] Boston Childrens Hosp, Program Cellular & Mol Med, 3 Blackfan Circle, Boston, MA 02115 USA. RP Einarsdottir, O (reprint author), Univ Calif Santa Cruz, Dept Chem & Biochem, Santa Cruz, CA 95064 USA. EM olof@ucsc.edu FU National Science Foundation [CHE-1158548]; National Institutes of Health [GM035342] FX This work was supported by National Science Foundation Grant CHE-1158548 to O.E. and National Institutes of Health Grant GM035342 to C.D.S. NR 59 TC 0 Z9 0 U1 4 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD JAN 10 PY 2017 VL 56 IS 1 BP 107 EP 119 DI 10.1021/acs.biochem.6b00590 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EH6QG UT WOS:000391898400011 PM 28026953 ER PT J AU Sutherasan, Y Ball, L Raimondo, P Caratto, V Sanguineti, E Costantino, F Ferretti, M Kacmarek, RM Pelosi, P AF Sutherasan, Yuda Ball, Lorenzo Raimondo, Pasquale Caratto, Valentina Sanguineti, Elisa Costantino, Federico Ferretti, Maurizio Kacmarek, Robert M. Pelosi, Paolo TI Effects of ventilator settings, nebulizer and exhalation port position on albuterol delivery during non-invasive ventilation: an in-vitro study SO BMC PULMONARY MEDICINE LA English DT Article DE Aerosol; Bronchodilators; Albuterol; Continuous positive airway pressure; CPAP; NIV; BIPAP; Nebulizers ID AEROSOL BRONCHODILATOR DELIVERY; OBSTRUCTIVE PULMONARY-DISEASE; PRESSURE VENTILATION; DIFFERENT INTERFACES; RESPIRATORY-FAILURE; TRACHEOSTOMY; COPD; EXPERIENCE; CHILDREN; FLOW AB Background: Few studies have investigated the factors affecting aerosol delivery during non-invasive ventilation (NIV). Our aim was to investigate, using a bench-top model, the effect of different ventilator settings and positions of the exhalation port and nebulizer on the amount of albuterol delivered to a lung simulator. Methods: A lung model simulating spontaneous breathing was connected to a single-limb NIV ventilator, set in bi-level positive airway pressure (BIPAP) with inspiratory/expiratory pressures of 10/5, 15/10, 15/5, and 20/10 cmH(2)O, or continuous positive airway pressure (CPAP) of 5 and 10 cmH(2)O. Three delivery circuits were tested: a vented mask with the nebulizer directly connected to the mask, and an unvented mask with a leak port placed before and after the nebulizer. Albuterol was collected on a filter placed after the mask and then the delivered amount was measured with infrared spectrophotometry. Results: Albuterol delivery during NIV varied between 6.7 +/- 0.4% to 37.0 +/- 4.3% of the nominal dose. The amount delivered in CPAP and BIPAP modes was similar (22.1 +/- 10.1 vs. 24.0 +/- 10.0%, p = 0.070). CPAP level did not affect delivery (p = 0.056); in BIPAP with 15/5 cmH(2)O pressure the delivery was higher compared to 10/5 cmH(2)O (p = 0.033) and 20/10 cmH(2)O (p = 0.014). Leak port position had a major effect on delivery in both CPAP and BIPAP, the best performances were obtained with the unvented mask, and the nebulizer placed between the leak port and the mask (p < 0.001). Conclusions: In this model, albuterol delivery was marginally affected by ventilatory settings in NIV, while position of the leak port had a major effect. Nebulizers should be placed between an unvented mask and the leak port in order to maximize aerosol delivery. C1 [Sutherasan, Yuda; Ball, Lorenzo; Raimondo, Pasquale; Costantino, Federico; Pelosi, Paolo] Univ Genoa, IRCCS AOU San Martino IST, Dept Surg Sci & Integrated Diagnost, Genoa, Italy. [Sutherasan, Yuda] Mahidol Univ, Ramathibodi Hosp, Div Pulm & Crit Care Med, Fac Med, Bangkok, Thailand. [Raimondo, Pasquale] Univ Foggia, Dipartimento Anestesia Rianimaz & Terapia Intens, Foggia, Italy. [Caratto, Valentina; Sanguineti, Elisa; Ferretti, Maurizio] Univ Genoa, Dept Chem & Ind Chem, Genoa, Italy. [Caratto, Valentina; Sanguineti, Elisa; Ferretti, Maurizio] SPIN CNR, Genoa, Italy. [Kacmarek, Robert M.] Harvard Med Sch, Dept Anesthesiol, Dept Anesthesiol Crit Care & Pain Med, Boston, MA USA. [Kacmarek, Robert M.] Massachusetts Gen Hosp, Dept Resp Care, Boston, MA 02114 USA. RP Ball, L (reprint author), Univ Genoa, IRCCS AOU San Martino IST, Dept Surg Sci & Integrated Diagnost, Genoa, Italy. EM lorenzo.ball@edu.unige.it OI Raimondo, Pasquale/0000-0002-4076-588X; Ball, Lorenzo/0000-0002-3876-4730 NR 24 TC 0 Z9 0 U1 1 U2 1 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 JAN 10 PY 2017 VL 17 AR 9 DI 10.1186/s12890-016-0347-5 PG 6 WC Respiratory System SC Respiratory System GA EH6OV UT WOS:000391893800001 PM 28068958 ER PT J AU Timm, FP Houle, TT Grabitz, SD Lihn, AL Stokholm, JB Eikermann-Haerter, K Nozari, A Kurth, T Eikermann, M AF Timm, Fanny P. Houle, Timothy T. Grabitz, Stephanie D. Lihn, Anne-Louise Stokholm, Janne B. Eikermann-Haerter, Katharina Nozari, Ala Kurth, Tobias Eikermann, Matthias TI Migraine and risk of perioperative ischemic stroke and hospital readmission: hospital based registry study SO BMJ-BRITISH MEDICAL JOURNAL LA English DT Article ID PATENT FORAMEN OVALE; WHITE-MATTER HYPERINTENSITIES; SILENT BRAIN INFARCTS; CARDIOVASCULAR-DISEASE; NONVASCULAR SURGERY; CARDIAC-SURGERY; POPULATION; COMPLICATIONS; HEADACHE; WOMEN AB Objective To evaluate whether patients with migraine are at increased risk of perioperative ischemic stroke and whether this may lead to an increased hospital readmission rate. Design Prospective hospital registry study. Setting Massachusetts General Hospital and two satellite campuses between January 2007 and August 2014. Participants 124 558 surgical patients (mean age 52.6 years; 54.5% women). Main outcome measures The primary outcome was perioperative ischemic stroke occurring within 30 days after surgery in patients with and without migraine and migraine aura. The secondary outcome was hospital readmission within 30 days of surgery. Exploratory outcomes included post-discharge stroke and strata of neuroanatomical stroke location. Results 10 179 (8.2%) patients had any migraine diagnosis, of whom 1278 (12.6%) had migraine with aura and 8901 (87.4%) had migraine without aura. 771 (0.6%) perioperative ischemic strokes occurred within 30 days of surgery. Patients with migraine were at increased risk of perioperative ischemic stroke (adjusted odds ratio 1.75, 95% confidence interval 1.39 to 2.21) compared with patients without migraine. The risk was higher in patients with migraine with aura (adjusted odds ratio 2.61, 1.59 to 4.29) than in those with migraine without aura (1.62, 1.26 to 2.09). The predicted absolute risk is 2.4 (2.1 to 2.8) perioperative ischemic strokes for every 1000 surgical patients. This increases to 4.3 (3.2 to 5.3) for every 1000 patients with any migraine diagnosis, 3.9 (2.9 to 5.0) for migraine without aura, and 6.3 (3.2 to 9.5) for migraine with aura. Patients with migraine had a higher rate of readmission to hospital within 30 days of discharge (adjusted odds ratio 1.31, 1.22 to 1.41). Conclusions Surgical patients with a history of migraine are at increased risk of perioperative ischemic stroke and have an increased 30 day hospital readmission rate. Migraine should be considered in the risk assessment for perioperative ischemic stroke. C1 [Timm, Fanny P.; Houle, Timothy T.; Grabitz, Stephanie D.; Lihn, Anne-Louise; Stokholm, Janne B.; Nozari, Ala; Eikermann, Matthias] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, 55 Fruit St, Boston, MA 02114 USA. [Timm, Fanny P.; Houle, Timothy T.; Grabitz, Stephanie D.; Lihn, Anne-Louise; Stokholm, Janne B.; Nozari, Ala; Eikermann, Matthias] Harvard Med Sch, 55 Fruit St, Boston, MA 02114 USA. [Lihn, Anne-Louise; Stokholm, Janne B.] Univ Copenhagen, Herlev Hosp, Dept Anesthesiol, Copenhagen, Denmark. [Eikermann-Haerter, Katharina] Massachusetts Gen Hosp, Dept Radiol, Boston, MA USA. [Eikermann-Haerter, Katharina] Harvard Med Sch, Boston, MA USA. [Kurth, Tobias] Charite Univ Med Berlin, Inst Publ Hlth, Berlin, Germany. RP Eikermann, M (reprint author), Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, 55 Fruit St, Boston, MA 02114 USA.; Eikermann, M (reprint author), Harvard Med Sch, 55 Fruit St, Boston, MA 02114 USA. EM meikermann@partners.org OI Kurth, Tobias/0000-0001-7169-2620 FU Jeff and Judy Buzen FX This study was funded by Jeff and Judy Buzen in an unrestricted grant to ME. NR 67 TC 1 Z9 1 U1 0 U2 0 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1756-1833 J9 BMJ-BRIT MED J JI BMJ-British Medical Journal PD JAN 10 PY 2017 VL 356 AR i6635 DI 10.1136/bmj.i6635 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA EH9BS UT WOS:000392067300001 PM 28073753 ER PT J AU Nogova, L Sequist, LV Garcia, JMP Andre, F Delord, JP Hidalgo, M Schellens, JHM Cassier, PA Camidge, DR Schuler, M Vaishampayan, U Burris, H Tian, GG Campone, M Wainberg, ZA Lim, WT LoRusso, P Shapiro, GI Parker, K Chen, X Choudhury, S Ringeisen, F Graus-Porta, D Porter, D Isaacs, R Buettner, R Wolf, J AF Nogova, Lucia Sequist, Lecia V. Garcia, Jose Manuel Perez Andre, Fabrice Delord, Jean-Pierre Hidalgo, Manuel Schellens, Jan H. M. Cassier, Philippe A. Camidge, D. Ross Schuler, Martin Vaishampayan, Ulka Burris, Howard Tian, G. Gary Campone, Mario Wainberg, Zev A. Lim, Wan-Teck LoRusso, Patricia Shapiro, Geoffrey I. Parker, Katie Chen, Xueying Choudhury, Somesh Ringeisen, Francois Graus-Porta, Diana Porter, Dale Isaacs, Randi Buettner, Reinhard Wolf, Juergen TI Evaluation of BGJ398, a Fibroblast Growth Factor Receptor 1-3 Kinase Inhibitor, in Patients With Advanced Solid Tumors Harboring Genetic Alterations in Fibroblast Growth Factor Receptors: Results of a Global Phase I, Dose-Escalation and Dose-Expansion Study SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID CELL LUNG-CANCER; PROTEIN EXPRESSION; TYROSINE KINASE; CARCINOMA; FGFR1; BLADDER; CHOLANGIOCARCINOMA; SENSITIVITY; NVP-BGJ398; MUTATIONS AB Purpose This two-part, first-in-human study was initiated in patientswith advanced solid tumors harboring genetic alterations in fibroblast growth factor receptors (FGFRs) to determine the maximum tolerated dose (MTD), the recommended phase II dose (RP2D), and the schedule, safety, pharmacokinetics, pharmacodynamics, and antitumor activity of oral BGJ398, a selective FGFR1-3 tyrosine kinase inhibitor. Patients and Methods Adult patients were treated with escalating dosages of BGJ398 5 to 150 mg once daily or 50 mg twice daily continuously in 28-day cycles. During expansion at the MTD, patients with FGFR1amplified squamous cell non-small-cell lung cancer (sqNSCLC; arm 1) or other solid tumors with FGFR genetic alterations (mutations/amplifications/fusions) received BGJ398 daily on a continuous schedule (arm 2), or on a 3-weeks-on/1-week-off schedule (arm 3). Results Data in 132 patients from the escalation and expansion arms are reported (May 15, 2015, cutoff). The MTD, 125 mg daily, was determined on the basis of dose-limiting toxicities in four patients (100 mg, grade 3 aminotransferase elevations [n = 1]; 125 mg, hyperphosphatemia [n = 1]; 150 mg, grade 1 corneal toxicity [n = 1] and grade 3 aminotransferase elevations [n = 1]). Common adverse events in patients treated at the MTD (n = 57) included hyperphosphatemia (82.5%), constipation (50.9%), decreased appetite (45.6%), and stomatitis (45.6%). A similar safety profile was observed using the 3-weeks-on/1-week-off schedule (RP2D). However, adverse event-related dose adjustments/ interruptions were less frequent with the 3-weeks-on/1-week-off (50.0%) versus the continuous (73.7%) schedule. Antitumor activity (seven partial responses [six confirmed]) was demonstrated with BGJ398 doses $ 100 mg in patients with FGFR1-amplified sqNSCLC and FGFR3-mutant bladder/urothelial cancer. Conclusion BGJ398 at the MTD/RP2D had a tolerable and manageable safety profile and showed antitumor activity in several tumor types, including FGFR1-amplified sqNSCLC and FGFR3-mutant bladder/ urothelial cancers. (C) 2016 by American Society of Clinical Oncology C1 [Nogova, Lucia; Buettner, Reinhard; Wolf, Juergen] Univ Hosp Cologne, Cologne, Germany. [Schuler, Martin] Univ Hosp Essen, Essen, Germany. [Schuler, Martin] German Canc Consortium DKTK, Essen, Germany. [Sequist, Lecia V.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Shapiro, Geoffrey I.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Garcia, Jose Manuel Perez] Vall dHebron Inst Oncol, Barcelona, Spain. [Hidalgo, Manuel] Spanish Natl Canc Res Ctr, Madrid, Spain. [Andre, Fabrice] Gustave Roussy, Villejuif, France. [Delord, Jean-Pierre] Inst Univ Canc Toulouse, Toulouse, France. [Cassier, Philippe A.] Ctr Reg Leon Berard, Lyon, France. [Campone, Mario] Inst Cancerol Ouest Rene Gauducheau, Nantes, France. [Schellens, Jan H. M.] Netherlands Canc Inst, Amsterdam, Netherlands. [Schellens, Jan H. M.] Univ Utrecht, Utrecht, Netherlands. [Camidge, D. Ross] Univ Colorado, Aurora, CO USA. [Vaishampayan, Ulka] Barbara Ann Karmanos Canc Inst, Detroit, MI USA. [Burris, Howard] Sarah Cannon Res Inst, Nashville, TN USA. [Tian, G. Gary] West Clin, Memphis, TN USA. [Wainberg, Zev A.] Univ Calif Los Angeles, Sch Med, Los Angeles, CA USA. [Lim, Wan-Teck] Natl Canc Ctr, Singapore, Singapore. [LoRusso, Patricia] Yale Canc Ctr, New Haven, CT USA. [Parker, Katie; Chen, Xueying; Choudhury, Somesh; Isaacs, Randi] Novartis Pharmaceut, E Hanover, NJ USA. [Porter, Dale] Novartis Inst Biomed Res, Cambridge, MA USA. [Ringeisen, Francois] Novartis Pharma AG, Basel, Switzerland. [Graus-Porta, Diana] Novartis Inst Biomed Res, Basel, Switzerland. RP Wolf, J (reprint author), Univ Hosp Cologne, Ctr Integrated Oncol, Dept Internal Med, Lung Canc Grp Cologne, D-50937 Cologne, Germany. EM juergen.wolf@uk-koeln.de FU Novartis Pharmaceuticals FX Supported by Novartis Pharmaceuticals. NR 37 TC 3 Z9 3 U1 3 U2 3 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD JAN 10 PY 2017 VL 35 IS 2 BP 157 EP + DI 10.1200/JCO.2016.67.2048 PG 19 WC Oncology SC Oncology GA EG9MC UT WOS:000391382000007 PM 27870574 ER PT J AU Chen, Q Jain, N Ayer, T Wierda, WG Flowers, CR O'Brien, SM Keating, MJ Kantarjian, HM Chhatwal, J AF Chen, Qiushi Jain, Nitin Ayer, Turgay Wierda, William G. Flowers, Christopher R. O'Brien, Susan M. Keating, Michael J. Kantarjian, Hagop M. Chhatwal, Jagpreet TI Economic Burden of Chronic Lymphocytic Leukemia in the Era of Oral Targeted Therapies in the United States SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID COST-EFFECTIVENESS ANALYSIS; HEMATOPOIETIC-CELL TRANSPLANTATION; METASTATIC COLORECTAL-CANCER; QUALITY-OF-LIFE; INITIAL THERAPY; FOLLOW-UP; PROGNOSTIC-FACTORS; 1ST-LINE THERAPY; RITUXIMAB; FLUDARABINE AB Purpose Oral targeted therapies represent a significant advance for the treatment of patients with chronic lymphocytic leukemia (CLL); however, their high cost has raised concerns about affordability and the economic impact on society. Our objective was to project the future prevalence and cost burden of CLL in the era of oral targeted therapies in the United States. Methods We developed a simulation model that evaluated the evolving management of CLL from 2011 to 2025: chemoimmunotherapy (CIT) as the standard of care before 2014, oral targeted therapies for patients with del(17p) and relapsed CLL from 2014, and for first-line treatment from 2016 onward. A comparator scenario also was simulated where CIT remained the standard of care throughout. Disease progression and survival parameters for each therapy were based on published clinical trials. Results The number of people living with CLL in the United States is projected to increase from 128,000 in 2011 to 199,000 by 2025 (55% increase) due to improved survival; meanwhile, the annual cost of CLL management will increase from $0.74 billion to $5.13 billion (590% increase). The per-patient lifetime cost of CLL treatment will increase from $147,000 to $604,000 (310% increase) as oral targeted therapies become the first-line treatment. For patients enrolled in Medicare, the corresponding total out-of-pocket cost will increase from $9,200 to $57,000 (520% increase). Compared with the CIT scenario, oral targeted therapies resulted in an incremental cost-effectiveness ratio of $189,000 per quality-adjusted life-year. Conclusion The increased benefit and cost of oral targeted therapies is projected to enhance CLL survivorship but can impose a substantial financial burden on both patients and payers. More sustainable pricing strategies for targeted therapies are needed to avoid financial toxicity to patients. (C) 2016 by American Society of Clinical Oncology C1 [Chen, Qiushi; Ayer, Turgay] Georgia Inst Technol, Atlanta, GA 30332 USA. [Flowers, Christopher R.] Emory Univ, Atlanta, GA 30322 USA. [Chen, Qiushi; Chhatwal, Jagpreet] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Chhatwal, Jagpreet] Harvard Med Sch, Boston, MA USA. [Jain, Nitin; Wierda, William G.; Keating, Michael J.; Kantarjian, Hagop M.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [O'Brien, Susan M.] Univ Calif Irvine, Irvine Med Ctr, Orange, CA 92668 USA. RP Chhatwal, J (reprint author), Massachusetts Gen Hosp, Inst Technol, 101 Merrimac St,10th Floor, Boston, MA 02114 USA. EM jagchhatwal@mgh.harvard.edu RI Flowers, Christopher/F-1953-2010 OI Flowers, Christopher/0000-0002-9524-3990 FU GlaxoSmithKline; Novartis; AbbVie; Genetech; Karyopharm; Therapeutics; Pharmacyclics; Acerta Pharma; Gilead Sciences; Janssen Pharmaceuticals; Emergent BioSolutions; Juno Therapeutics; Kite Pharma; Acerta Pharma (Inst); Infinity Pharmaceuticals (Inst); Onyx Pharmaceuticals (Inst); Janssen Pharmaceuticals (Inst); Gilead Sciences (Inst); Celgene (Inst); TG Therapeutics (Inst); Genetech (Inst); Roche (Inst); Pharmacyclics (Inst); AbbVie (Inst); Regeneron Pharmaceuticals FX GlaxoSmithKline, Novartis, AbbVie, Genetech, Karyopharm Therapeutics, Pharmacyclics, Acerta Pharma, Gilead Sciences, Janssen Pharmaceuticals, Emergent BioSolutions, Juno Therapeutics, Kite Pharma; Acerta Pharma (Inst), Infinity Pharmaceuticals (Inst), Onyx Pharmaceuticals (Inst), Janssen Pharmaceuticals (Inst), Gilead Sciences (Inst), Celgene (Inst), TG Therapeutics (Inst), Genetech (Inst), Roche (Inst), Pharmacyclics (Inst), AbbVie (Inst); Acerta Pharma, Regeneron Pharmaceuticals, Gilead Sciences; Gilead Sciences (Inst) NR 63 TC 1 Z9 1 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 JAN 10 PY 2017 VL 35 IS 2 BP 166 EP + DI 10.1200/JCO.2016.68.2856 PG 10 WC Oncology SC Oncology GA EG9MC UT WOS:000391382000008 PM 27870563 ER PT J AU von Allmen, D Davidoff, AM London, WB Van Ryn, C Haas-Kogan, DA Kreissman, SG Khanna, G Rosen, N Park, JR La Quaglia, MP AF von Allmen, Daniel Davidoff, Andrew M. London, Wendy B. Van Ryn, Collin Haas-Kogan, Daphne A. Kreissman, Susan G. Khanna, Geetika Rosen, Nancy Park, Julie R. La Quaglia, Michael P. TI Impact of Extent of Resection on Local Control and Survival in Patients From the COG A3973 Study With High-Risk Neuroblastoma SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID SURGICAL RESECTION; PROLONGS SURVIVAL; COMPETING RISK; CHILDREN; SURGERY; CHEMOTHERAPY; AGE; TRANSPLANTATION; RADIOTHERAPY; AGREEMENT AB Purpose This analysis of patients in the Children's Oncology Group A3973 study evaluated the impact of extent of primary tumor resection on local progression and survival and assessed concordance between clinical and central imaging review-based assessments of resection extent. Patients and Methods The analytic cohort (n = 220) included patients who had both central surgery review and resection of the primary tumor site. For this analysis, resection categories of < 90% and >= 90% were used, with data on resection extent derived from operating surgeons' assessments (all patients), as well as blinded central imaging review of computed tomography scans for a subset of 84 patients; assessment results were compared for concordance. Treatment outcomes included event-free survival (EFS), overall survival (OS), and cumulative incidence of local progression (CILP). Results Surgeon-assessed extent of resection was >= 90% in 154 (70%) patients and, 90% in 66 (30%). Five-year EFS, OS, and CILP (+/- SE) were 43.5% +/- 3.7%, 54.9% +/- 3.7%, and 11.9% +/- 2.2%, espectively. EFS was higher with +/- 90% resection (45.9% +/- 4.3%) than with < 90% resection (37.9% +/- 7.2%; P = .04). Lower CILP (P = .01) was associated with >= 90% resection (8.5% +/- 2.3%) compared with < 90% resection (19.8% +/- 5.0%). On multivariable analysis, >= 90% resection was associated with longer EFS after adjustment for MYCN amplification or diploidy but had no significant effect on OS. Concordance between surgeons' assessments of resection extent and central image-guided review was low, with agreement of 63% (< 90% v >= 90%; simple k = -0.0301). Conclusion Despite discordance between clinical assessment of resection extent and assessment via central imaging review, a surgeon-assessed resection extent >= 90% was associated with significantly better EFS and lower CILP. Improving OS, however, remains a challenge in this disease. These findings support continued attempts at >= 90% resection of the primary tumor in high-risk neuroblastoma. (C) 2016 by American Society of Clinical Oncology C1 [von Allmen, Daniel] Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USA. [Davidoff, Andrew M.] St Jude Childrens Res Hosp, 332 N Lauderdale St, Memphis, TN 38105 USA. [London, Wendy B.] Boston Childrens Hosp, Boston, MA USA. [London, Wendy B.; Haas-Kogan, Daphne A.] Dana Farber Canc Inst, Boston, MA 02115 USA. [London, Wendy B.; Haas-Kogan, Daphne A.] Harvard Med Sch, Boston, MA USA. [Kreissman, Susan G.] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. [Khanna, Geetika] Washington Univ, Sch Med, St Louis, MO USA. [Rosen, Nancy] Qual Assurance Review Comm, Providence, RI USA. [Park, Julie R.] Univ Washington, Sch Med, Seattle, WA USA. [Park, Julie R.] Seattle Childrens Hosp, Seattle, WA USA. [La Quaglia, Michael P.] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. [La Quaglia, Michael P.] Weill Cornell Med Sch, New York, NY USA. RP La Quaglia, MP (reprint author), Mem Sloan Kettering Canc Ctr, Dept Surg, 1275 York Ave, New York, NY 10065 USA. EM laquaglm@mskcc.org FU National Cancer Institute [U10 CA29139, U10 CA98413, U10-CA098543]; National Institutes of Health [P30 CA008748] FX Supported by National Cancer Institute Grants No. U10 CA29139, U10 CA98413, and U10-CA098543 to the Children's Oncology Group; and National Institutes of Health Grant No. P30 CA008748 to Memorial Sloan Kettering Cancer Center (M.P.L.). NR 26 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 JAN 10 PY 2017 VL 35 IS 2 BP 208 EP + DI 10.1200/JCO.2016.67.2642 PG 11 WC Oncology SC Oncology GA EG9MC UT WOS:000391382000013 PM 27870572 ER PT J AU D'Angelo, SP Larkin, J Sosman, JA Lebbe, C Brady, B Neyns, B Schmidt, H Hassel, JC Hodi, FS Lorigan, P Savage, KJ Miller, WH Mohr, P Marquez-Rodas, I Charles, J Kaatz, M Sznol, M Weber, JS Shoushtari, AN Ruisi, M Jiang, J Wolchok, JD AF D'Angelo, Sandra P. Larkin, James Sosman, Jeffrey A. Lebbe, Celeste Brady, Benjamin Neyns, Bart Schmidt, Henrik Hassel, Jessica C. Hodi, F. Stephen Lorigan, Paul Savage, Kerry J. Miller, Wilson H., Jr. Mohr, Peter Marquez-Rodas, Ivan Charles, Julie Kaatz, Martin Sznol, Mario Weber, Jeffrey S. Shoushtari, Alexander N. Ruisi, Mary Jiang, Joel Wolchok, Jedd D. TI Efficacy and Safety of Nivolumab Alone or in Combination With Ipilimumab in Patients With Mucosal Melanoma: A Pooled Analysis SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID METASTATIC MELANOMA; UNTREATED MELANOMA; PRETREATED PATIENTS; CUTANEOUS MELANOMA; OPEN-LABEL; PHASE-II; CHEMOTHERAPY; MULTICENTER; SURVIVAL; TRIALS AB Purpose Mucosal melanoma is an aggressive malignancy with a poor response to conventional therapies. The efficacy and safety of nivolumab (a programmed death-1 checkpoint inhibitor), alone or combined with ipilimumab (a cytotoxic T-lymphocyte antigen-4 checkpoint inhibitor), have not been reported in this rare melanoma subtype. Patients and Methods Data were pooled from 889 patients who received nivolumab monotherapy in clinical studies, including phase III trials; 86 (10%) had mucosal melanoma and 665 (75%) had cutaneous melanoma. Data were also pooled for patients who received nivolumab combined with ipilimumab (n = 35, mucosal melanoma; n = 326, cutaneous melanoma). Results Among patients who received nivolumab monotherapy, median progression-free survival was 3.0 months (95% CI, 2.2 to 5.4 months) and 6.2 months (95% CI, 5.1 to 7.5 months) for mucosal and cutaneous melanoma, with objective response rates of 23.3% (95% CI, 14.8% to 33.6%) and 40.9% (95% CI, 37.1% to 44.7%), respectively. Median progression-free survival in patients treated with nivolumab combined with ipilimumab was 5.9 months (95% CI, 2.8 months to not reached) and 11.7 months (95% CI, 8.9 to 16.7 months) for mucosal and cutaneous melanoma, with objective response rates of 37.1% (95% CI, 21.5% to 55.1%) and 60.4% (95% CI, 54.9% to 65.8%), respectively. For mucosal and cutaneous melanoma, respectively, the incidence of grade 3 or 4 treatment-related adverse events was 8.1% and 12.5% for nivolumab monotherapy and 40.0% and 54.9% for combination therapy. Conclusion To our knowledge, this is the largest analysis of data for anti-programmed death-1 therapy in mucosal melanoma to date. Nivolumab combined with ipilimumab seemed to have greater efficacy than either agent alone, and although the activity was lower in mucosal melanoma, the safety profile was similar between subtypes. (C) 2016 by American Society of Clinical Oncology C1 [D'Angelo, Sandra P.; Shoushtari, Alexander N.; Wolchok, Jedd D.] Mem Sloan Kettering Canc Ctr, 300 East 66th St, New York, NY 10065 USA. [D'Angelo, Sandra P.; Shoushtari, Alexander N.; Wolchok, Jedd D.] Weill Cornell Med Coll, New York, NY USA. [Larkin, James] Royal Marsden Hosp, London, England. [Lorigan, Paul] Univ Manchester, Manchester, Lancs, England. [Sosman, Jeffrey A.] Vanderbilt Univ, Med Ctr, Nashville, TN USA. [Lebbe, Celeste] Univ Paris Diderot, INSERM, U976, St Louis Hosp, Paris, France. [Charles, Julie] Grenoble Alps Univ, Grenoble Univ Hosp, Grenoble, France. [Brady, Benjamin] Cabrini Hlth, Melbourne, Vic, Australia. [Neyns, Bart] Univ Ziekenhuis Brussel, Brussels, Belgium. [Hassel, Jessica C.] Univ Heidelberg Hosp, Heidelberg, Germany. [Kaatz, Martin] Univ Hosp Jena, SRH Waldklinikum Gera, Jena, Germany. [Hodi, F. Stephen] Dana Farber Canc Inst, Boston, MA 02115 USA. [Savage, Kerry J.] Univ British Columbia, BC Canc Agcy, Vancouver, BC, Canada. [Miller, Wilson H., Jr.] McGill Univ, Lady Davis Inst, Montreal, PQ, Canada. [Miller, Wilson H., Jr.] McGill Univ, Jewish Gen Hosp, Montreal, PQ, Canada. [Marquez-Rodas, Ivan] Hosp Gen Univ Gregorio Maranon, Madrid, Spain. [Sznol, Mario] Yale Univ, Sch Med, New Haven, CT USA. [Sznol, Mario] Yale New Haven Med Ctr, Smilow Canc Ctr, 20 York St, New Haven, CT 06504 USA. [Weber, Jeffrey S.] H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL USA. [Ruisi, Mary; Jiang, Joel] Bristol Myers Squibb, Princeton, NJ USA. RP D'Angelo, SP (reprint author), Mem Sloan Kettering Canc Ctr, 300 East 66th St, New York, NY 10065 USA. EM dangelos@mskcc.org FU Bristol-Myers Squibb, Princeton, NJ; Royal Marsden/Institute of Cancer Research Biomedical Research Centre for Cancer FX Supported by Bristol-Myers Squibb, Princeton, NJ. J.L. is supported by the Royal Marsden/Institute of Cancer Research Biomedical Research Centre for Cancer. NR 28 TC 1 Z9 1 U1 5 U2 5 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD JAN 10 PY 2017 VL 35 IS 2 BP 226 EP + DI 10.1200/JCO.2016.67.9258 PG 15 WC Oncology SC Oncology GA EG9MC UT WOS:000391382000015 PM 28056206 ER PT J AU Kassam, A Sutradhar, R Widger, K Rapoport, A Pole, JD Nelson, K Wolfe, J Earle, CC Gupta, S AF Kassam, Alisha Sutradhar, Rinku Widger, Kimberley Rapoport, Adam Pole, Jason D. Nelson, Katherine Wolfe, Joanne Earle, Craig C. Gupta, Sumit TI Predictors of and Trends in High-Intensity End-of-Life Care Among Children With Cancer: A Population-Based Study Using Health Services Data SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID PEDIATRIC PALLIATIVE CARE; SOCIOECONOMIC-STATUS; CHILDHOOD-CANCER; PARENTS; QUALITY; DEATH; PERSPECTIVES; PROGNOSIS; ONTARIO; CANADA AB Purpose Children with cancer often receive high-intensity (HI) medical care at the end-of-life (EOL). Previous studies have been limited to single centers or lacked detailed clinical data. We determined predictors of and trends in HI-EOL care by linking population-based clinical and health-services databases. Methods A retrospective decedent cohort of patients with childhood cancer who died between 2000 and 2012 in Ontario, Canada, was assembled using a provincial cancer registry and linked to population-based health-care data. Based on previous studies, the primary composite measure of HI-EOL care comprised any of the following: intravenous chemotherapy, 14 days from death; more than one emergency department visit; and more than one hospitalization or intensive care unit admission, 30 days from death. Secondary measures included those same individual measures and measures of themost invasive (MI) EOL care (eg, mechanical ventilation, 14 days from death). We determined predictors of outcomes with appropriate regression models. Sensitivity analysis was restricted to cases of cancer-related mortality, excluding treatment-related mortality (TRM) cases. Results The study included 815 patients; of these, 331 (40.6%) experienced HI-EOL care. Those with hematologic malignancies were at highest risk (odds ratio, 2.5; 95% CI, 1.8 to 3.6; P <. 001). Patients with hematologic cancers and those who died after 2004 were more likely to experience the MI-EOL care (eg, intensive care unit, mechanical ventilation, odds ratios from 2.0 to 5.1). Excluding cases of TRM did not substantively change the results. Conclusion Ontario children with cancer continue to experience HI-EOL care. Patients with hematologic malignancies are at highest risk even when excluding TRM. Of concern, rates of the MI-EOL care have increased over time despite increased palliative care access. Linking health services and clinical data allows monitoring of population trends in EOL care and identifies high-risk populations for future interventions. (C) 2016 by American Society of Clinical Oncology C1 [Kassam, Alisha; Widger, Kimberley; Rapoport, Adam; Nelson, Katherine; Gupta, Sumit] Hosp Sick Children, Toronto, ON, Canada. [Kassam, Alisha; Widger, Kimberley; Rapoport, Adam; Gupta, Sumit] Univ Toronto, Toronto, ON, Canada. [Sutradhar, Rinku; Pole, Jason D.; Earle, Craig C.; Gupta, Sumit] Inst Clin Evaluat Sci, Toronto, ON, Canada. [Rapoport, Adam] Emilys House Childrens Hosp, Toronto, ON, Canada. [Pole, Jason D.] Pediat Oncol Grp Ontario, Toronto, ON, Canada. [Kassam, Alisha] Southlake Reg Hlth Ctr, Newmarket, ON, Canada. [Wolfe, Joanne] Dana Farber Canc Inst, Boston, MA 02115 USA. [Wolfe, Joanne] Boston Childrens Hosp, Boston, MA USA. RP Gupta, S (reprint author), Hosp Sick Children, Div Hematol Oncol, 555 Univ Ave, Toronto, ON M5G 1X8, Canada. EM sumit.gupta@sickkids.ca FU Garron Family Cancer Centre at the Hospital for Sick Children, Toronto, Canada; Institute for Clinical Evaluative Sciences; Ontario Ministry of Health and Long-Term Care FX Funded through a Pitblado Discovery Grant from the Garron Family Cancer Centre at the Hospital for Sick Children, Toronto, Canada; and by the Institute for Clinical Evaluative Sciences, which is funded by an annual grant from the Ontario Ministry of Health and Long-Term Care. NR 41 TC 0 Z9 0 U1 3 U2 3 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD JAN 10 PY 2017 VL 35 IS 2 BP 236 EP + DI 10.1200/JCO.2016.68.8283 PG 13 WC Oncology SC Oncology GA EG9MC UT WOS:000391382000016 PM 28056201 ER PT J AU Deen, B Richardson, H Dilks, DD Takahashi, A Keil, B Wald, LL Kanwisher, N Saxe, R AF Deen, Ben Richardson, Hilary Dilks, Daniel D. Takahashi, Atsushi Keil, Boris Wald, Lawrence L. Kanwisher, Nancy Saxe, Rebecca TI Organization of high-level visual cortex in human infants SO NATURE COMMUNICATIONS LA English DT Article ID SELECTIVE CORTICAL REGIONS; HUMAN EXTRASTRIATE CORTEX; INFERIOR TEMPORAL CORTEX; WORD FORM AREA; FUNCTIONAL ARCHITECTURE; FACE RECOGNITION; HUMAN BRAIN; OBJECT; FMRI; PERCEPTION AB How much of the structure of the human mind and brain is already specified at birth, and how much arises from experience? In this article, we consider the test case of extrastriate visual cortex, where a highly systematic functional organization is present in virtually every normal adult, including regions preferring behaviourally significant stimulus categories, such as faces, bodies, and scenes. Novel methods were developed to scan awake infants with fMRI, while they viewed multiple categories of visual stimuli. Here we report that the visual cortex of 4-6-month-old infants contains regions that respond preferentially to abstract categories (faces and scenes), with a spatial organization similar to adults. However, precise response profiles and patterns of activity across multiple visual categories differ between infants and adults. These results demonstrate that the large-scale organization of category preferences in visual cortex is adult-like within a few months after birth, but is subsequently refined through development. C1 [Deen, Ben; Richardson, Hilary; Dilks, Daniel D.; Takahashi, Atsushi; Kanwisher, Nancy; Saxe, Rebecca] MIT, Dept Brain & Cognit Sci, E25-618, Cambridge, MA 02139 USA. [Deen, Ben; Richardson, Hilary; Dilks, Daniel D.; Takahashi, Atsushi; Kanwisher, Nancy; Saxe, Rebecca] MIT, McGovern Inst, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Dilks, Daniel D.] Emory Univ, Dept Psychol, Atlanta, GA 30322 USA. [Keil, Boris; Wald, Lawrence L.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Keil, Boris] Mittelhessen Univ Appl Sci, Dept Life Sci Engn, Inst Med Phys & Radiat Protect, D-35390 Giessen, Germany. [Wald, Lawrence L.] MIT, Harvard MIT Div Hlth Sci & Technol, Cambridge, MA 02139 USA. RP Deen, B (reprint author), MIT, Dept Brain & Cognit Sci, E25-618, Cambridge, MA 02139 USA.; Deen, B (reprint author), MIT, McGovern Inst, 77 Massachusetts Ave, Cambridge, MA 02139 USA. EM benjamin.deen@gmail.com FU Packard Foundation; Ellison Medical Foundation; NSF; Center for Brains, Minds and Machines [CCF-1231216] FX We thank the Packard Foundation, Ellison Medical Foundation and NSF (graduate research fellowship to B.D., and the Center for Brains, Minds and Machines, CCF-1231216 to N.K. and R.S.) for funding this research; Anna Wexler for assistance in stimulus creation; Grace Lisandrelli for assistance with recruitment and data collection; Jorie Koster-Hale, Bob Desimone, Charles Jennings and Winrich Freiwald for useful feedback on the manuscript; and all of our infants and parents for participating. NR 43 TC 1 Z9 1 U1 7 U2 7 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD JAN 10 PY 2017 VL 8 AR 13995 DI 10.1038/ncomms13995 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EH9VB UT WOS:000392118500001 PM 28072399 ER PT J AU Wu, D Qian, TT Nakao, T Xu, JJ Liu, ZG Sun, XH Chu, YW Hong, JX AF Wu, Dan Qian, Tingting Nakao, Takeshi Xu, Jianjiang Liu, Zuguo Sun, Xinghuai Chu, Yiwei Hong, Jiaxu TI Medically uncontrolled conjunctival pyogenic granulomas: correlation between clinical characteristics and histological findings SO ONCOTARGET LA English DT Article DE pyogenic granulomas; clinical characteristic; histology; Pathology Section AB Background: Conjunctival pyogenic granulomas are commonly seen after ocular surgeries or at an ocular wound site. The aim of this study is to describe a novel histological classification for medically uncontrolled conjunctival pyogenic granulomas (MUCPG), and to explore whether the diversity in clinical features correlates to different histological subtypes of MUCPG. Methods: This is an observational cross-section case series. We reviewed 46 consecutive patients with conjunctival pyogenic granulomas who did not respond to topical corticosteroids and underwent surgical excision from January 1, 2006 through December 31, 2015. Clinical features and histological findings were presented and analyzed. Results: Ocular surgery, accidental injury, and chalazion were the main predisposing causes of MUCPG. The lesions tended to occur unilaterally on the bulbar conjunctiva. Forty patients (87%) presented an enrichment of inflammatory cells and proliferated capillaries in their pathological sections (inflammatory pattern). Six patients (13%) showed relatively few inflammatory cells and capillaries within fibrous stroma (fibrous pattern). Patients with the inflammatory pattern were older (p = 0.025) and tended to be located in bulbar conjunctiva (p = 0.002). The predisposing causes were also different between two histological subtypes (p = 0.007). Conclusions: We found the correlation between clinical presentation and histological subtypes in patients with MUCPG, indicating this disease may need a new classification scheme. C1 [Wu, Dan; Xu, Jianjiang; Sun, Xinghuai; Hong, Jiaxu] Fudan Univ, Eye & ENT Hosp, Shanghai Med Coll, Dept Ophthalmol & Visual Sci, Shanghai, Peoples R China. [Wu, Dan; Xu, Jianjiang; Sun, Xinghuai; Hong, Jiaxu] Fudan Univ, Eye & ENT Hosp, Shanghai Med Coll, Eye Res Inst, Shanghai, Peoples R China. [Qian, Tingting; Chu, Yiwei] Fudan Univ, Shanghai Med Coll, Dept Immunol, Shanghai, Peoples R China. [Nakao, Takeshi; Hong, Jiaxu] Harvard Med Sch, Massachusetts Eye & Ear Infirm, Boston, MA USA. [Liu, Zuguo; Hong, Jiaxu] Xiamen Univ, Fujian Prov Key Lab Ophthalmol & Visual Sci, Inst Eye, Xiamen, Fujian, Peoples R China. [Liu, Zuguo] Second Xiangya Hosp, Ctr Eye, Changsha, Hunan, Peoples R China. [Liu, Zuguo] Second Xiangya Hosp, Dept Ophthalmol, Changsha, Hunan, Peoples R China. [Liu, Zuguo] Cent S Univ, Hosp Eye, Changsha, Hunan, Peoples R China. [Liu, Zuguo] Key Lab Myopia, Natl Hlth & Family Planning Commiss, Shanghai, Peoples R China. RP Hong, JX (reprint author), Fudan Univ, Eye & ENT Hosp, Shanghai Med Coll, Dept Ophthalmol & Visual Sci, Shanghai, Peoples R China.; Hong, JX (reprint author), Fudan Univ, Eye & ENT Hosp, Shanghai Med Coll, Eye Res Inst, Shanghai, Peoples R China.; Chu, YW (reprint author), Fudan Univ, Shanghai Med Coll, Dept Immunol, Shanghai, Peoples R China.; Hong, JX (reprint author), Harvard Med Sch, Massachusetts Eye & Ear Infirm, Boston, MA USA.; Hong, JX (reprint author), Xiamen Univ, Fujian Prov Key Lab Ophthalmol & Visual Sci, Inst Eye, Xiamen, Fujian, Peoples R China. EM ywchu@shmu.edu.cn; jiaxu_hong@163.com FU Key Clinic Medicine Research Program, the Ministry of Health, China [201302015]; National Natural Science Foundation of China [81670820, 81670818, 81300735]; Young Scientist Excellence Program, Fudan University; Chinese Postdoctoral Fund [XMU135890]; New Technology Joint Research Project in Shanghai Hospitals [SHDC12014114] FX The authors were supported by grants from the Key Clinic Medicine Research Program, the Ministry of Health, China (201302015); the National Natural Science Foundation of China (81670820, 81670818, 81300735); the Young Scientist Excellence Program, Fudan University (2015); the Chinese Postdoctoral Fund (XMU135890); and the New Technology Joint Research Project in Shanghai Hospitals (SHDC12014114). The sponsor or funding organization had no role in the design or conduct of this research. NR 13 TC 0 Z9 0 U1 0 U2 0 PU IMPACT JOURNALS LLC PI ORCHARD PARK PA 6666 E QUAKER ST, STE 1, ORCHARD PARK, NY 14127 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD JAN 10 PY 2017 VL 8 IS 2 BP 2020 EP 2024 DI 10.18632/oncotarget.13961 PG 5 WC Oncology; Cell Biology SC Oncology; Cell Biology GA EH1EL UT WOS:000391506300007 PM 28008138 ER PT J AU Huang, PY Almeciga-Pinto, I Jarpe, M van Duzer, JH Mazitschek, R Yang, M Jones, SS Quayle, SN AF Huang, Pengyu Almeciga-Pinto, Ingrid Jarpe, Matthew van Duzer, John H. Mazitschek, Ralph Yang, Min Jones, Simon S. Quayle, Steven N. TI Selective HDAC inhibition by ACY-241 enhances the activity of paclitaxel in solid tumor models SO ONCOTARGET LA English DT Article DE HDAC; paclitaxel; solid tumors; mitotic spindle ID HISTONE DEACETYLASE INHIBITORS; SPINDLE ASSEMBLY CHECKPOINT; CANCER-CELLS; DYNAMIC INSTABILITY; OVARIAN-CANCER; APOPTOSIS; MICROTUBULES; MITOSIS; TAXOL; CYTOTOXICITY AB ACY-241 is a novel, orally available and selective histone deacetylase (HDAC) 6 inhibitor in Phase 1b clinical development in multiple myeloma (NCT 02400242). Like the structurally related drug ACY-1215 (ricolinostat), ACY-241 has the potential for a substantially reduced side effect profile versus current nonselective HDAC inhibitor drug candidates due to reduced potency against Class I HDACs while retaining the potential for anticancer effectiveness. We now show that combination treatment of xenograft models with paclitaxel and either ricolinostat or ACY-241 significantly suppresses solid tumor growth. In cell lines from multiple solid tumor lineages, combination treatment with ACY-241 and paclitaxel enhanced inhibition of proliferation and increased cell death relative to either single agent alone. Combination treatment with ACY-241 and paclitaxel also resulted in more frequent occurrence of mitotic cells with abnormal multipolar spindles and aberrant mitoses, consistent with the observed increase of aneuploid cells. At the molecular level, multipolar mitotic spindle formation was observed to be NuMA-dependent and gamma-tubulin independent, suggesting that treatment-induced multipolar spindle formation does not depend on centrosomal amplification. The significantly enhanced efficacy of ACY-241 plus paclitaxel observed here, in addition to the anticipated superior safety profile of a selective HDAC6 inhibitor versus pan-HDAC inhibitors, provides a strong rationale for clinical development of this combination in patients with advanced solid tumors. C1 [Huang, Pengyu; Almeciga-Pinto, Ingrid; Jarpe, Matthew; van Duzer, John H.; Yang, Min; Jones, Simon S.; Quayle, Steven N.] Acetylon Pharmaceut Inc, Boston, MA 02210 USA. [Mazitschek, Ralph] Massachusetts Gen Hosp, Harvard Med Sch, Ctr Syst Biol, Boston, MA USA. RP Jones, SS (reprint author), Acetylon Pharmaceut Inc, Boston, MA 02210 USA. EM sjones@acetylon.com NR 46 TC 1 Z9 1 U1 3 U2 3 PU IMPACT JOURNALS LLC PI ORCHARD PARK PA 6666 E QUAKER ST, STE 1, ORCHARD PARK, NY 14127 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD JAN 10 PY 2017 VL 8 IS 2 BP 2694 EP 2707 DI 10.18632/oncotarget.13738 PG 14 WC Oncology; Cell Biology SC Oncology; Cell Biology GA EH1EL UT WOS:000391506300068 PM 27926524 ER PT J AU Cheng, LC Jiang, Y Xie, Y Qiu, LL Yang, Q Lu, HY AF Cheng, Li-Chun Jiang, Yan Xie, Yu Qiu, Lu-Lu Yang, Qing Lu, Hui-Yi TI Novel amphiphilic folic acid-cholesterol-chitosan micelles for paclitaxel delivery SO ONCOTARGET LA English DT Article DE paclitaxel; folate acid; cholesterol; chitosan; micelle ID IN-VITRO; GLYCOL CHITOSAN; CARBOXYMETHYL CHITOSAN; GOLD NANOPARTICLES; DRUG-DELIVERY; ORAL DELIVERY; CO-DELIVERY; DOXORUBICIN; DERIVATIVES; LIPOSOMES AB In order to decrease the toxicity of paclitaxel (PTX) and increase the efficiency, we developed an amphiphilic PTX injection system using a biodegradable and biocompatible polymer synthesized by folic acid, cholesterol, and chitosan (FACC). This FACC-based polymer had a low critical concentration (64.13 mu g/ml) and could self-assemble in aqueous condition to form nanoscale micelles. The particle sizes of FACC-PTX micelles were 253.2+/-0.56 nm, the encapsulation efficiency and loading capacity of these FACC-PTX micelles were 65.1+/-0.23% and 9.1+/-0.16%, respectively. The cumulative release rate was about 85% at pH 5.0 which was higher than that at pH 7.4 (76%). This pH-dependent release behavior was highly suggesting that PTX release from FACC-PTX micelles might be higher in a weak acidic tumor microenvironment and lower toxic for normal cells. The anti-cancer effectiveness of FACC-PTX micelles was investigated by in vitro cytotoxicity and targeting study. The results revealed that FACC micelles have non-toxic on cells as evidenced by high cell viability found (86% to 100%) in the cells cultured with various concentrations of FACC micelles (1 to 500 mu g/ml). Targeting study indicated that the cytotoxic efficacy of FACC-PTX micelles was significantly higher than that with Taxol (R) in the Hela cells (folate receptor-positive cells). These findings indicated that the anticancer efficiency of PTX can be enhanced by adding some cancer cell positive receptor into drug carrier and the FACC micelle was a potential tumor targeting carrier for PXT delivery. C1 [Cheng, Li-Chun; Jiang, Yan; Xie, Yu; Qiu, Lu-Lu; Lu, Hui-Yi] Dalian Med Univ, Affiliated Hosp 2, Dept Pharm, Dalian 116027, Peoples R China. [Yang, Qing] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02144 USA. RP Lu, HY (reprint author), Dalian Med Univ, Affiliated Hosp 2, Dept Pharm, Dalian 116027, Peoples R China.; Yang, Q (reprint author), Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02144 USA. EM qhyang@partners.org; 15541117912@163.com FU Science and Technology Planning Project of Dalian, China [2014E14SF184] FX This work was funded by the Science and Technology Planning Project of Dalian, China (No. 2014E14SF184). NR 28 TC 0 Z9 0 U1 20 U2 20 PU IMPACT JOURNALS LLC PI ORCHARD PARK PA 6666 E QUAKER ST, STE 1, ORCHARD PARK, NY 14127 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD JAN 10 PY 2017 VL 8 IS 2 BP 3315 EP 3326 DI 10.18632/oncotarget.13757 PG 12 WC Oncology; Cell Biology SC Oncology; Cell Biology GA EH1EL UT WOS:000391506300118 PM 27926514 ER PT J AU Ysselstein, D Dehay, B Costantino, IM McCabe, GP Frosch, MP George, JM Bezard, E Rochet, JC AF Ysselstein, Daniel Dehay, Benjamin Costantino, Isabel M. McCabe, George P. Frosch, Matthew P. George, Julia M. Bezard, Erwan Rochet, Jean-Christophe TI Endosulfine-alpha inhibits membrane-induced alpha-synuclein aggregation and protects against alpha-synuclein neurotoxicity SO ACTA NEUROPATHOLOGICA COMMUNICATIONS LA English DT Article DE alpha-Synuclein; Endosulfine-alpha; Neurodegeneration; Parkinson's disease; Synucleinopathy ID ISLET AMYLOID POLYPEPTIDE; PARKINSONS-DISEASE; ALZHEIMERS-DISEASE; NMR-SPECTROSCOPY; HUMAN BRAINS; LEWY BODIES; IN-VITRO; BINDING; DISRUPTION; FIBRILLOGENESIS AB Neuropathological and genetic findings suggest that the presynaptic protein alpha-synuclein (alpha Syn) is involved in the pathogenesis of synucleinopathy disorders, including Parkinson's disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy. Evidence suggests that the self-assembly of alpha Syn conformers bound to phospholipid membranes in an aggregation-prone state plays a key role in alpha Syn neurotoxicity. Accordingly, we hypothesized that protein binding partners of lipid-associated alpha Syn could inhibit the formation of toxic alpha Syn oligomers at membrane surfaces. To address this hypothesis, we characterized the protein endosulfine-alpha (ENSA), previously shown to interact selectively with membrane-bound alpha Syn, in terms of its effects on the membrane-induced aggregation and neurotoxicity of two familial alpha Syn mutants, A30P and G51D. We found that wild-type ENSA, but not the non-alpha Syn-binding S109E variant, interfered with membrane-induced alpha Syn self-assembly, alpha Syn-mediated vesicle disruption and alpha Syn neurotoxicity. Immunoblotting analyses revealed that ENSA was down-regulated in the brains of synucleinopathy patients versus non-diseased individuals. Collectively, these results suggest that ENSA can alleviate neurotoxic effects of membrane-bound alpha Syn via an apparent chaperone-like activity at the membrane surface, and a decrease in ENSA expression may contribute to alpha Syn neuropathology in synucleinopathy disorders. More generally, our findings suggest that promoting interactions between lipid-bound, amyloidogenic proteins and their binding partners is a viable strategy to alleviate cytotoxicity in a range of protein misfolding disorders. C1 [Ysselstein, Daniel; Rochet, Jean-Christophe] Purdue Univ, Dept Med Chem & Mol Pharmacol, W Lafayette, IN 47907 USA. [Ysselstein, Daniel; Rochet, Jean-Christophe] Purdue Univ, Purdue Inst Integrat Neurosci, W Lafayette, IN 47907 USA. [Dehay, Benjamin; Bezard, Erwan] Univ Bordeaux, Inst Malad Neurodegenerat, UMR 5293, Bordeaux, France. [Dehay, Benjamin; Bezard, Erwan] CNRS, Inst Malad Neurodegenerat, UMR 5293, Bordeaux, France. [Costantino, Isabel M.; Frosch, Matthew P.] Massachusetts Gen Hosp, Massachusetts Alzheimers Dis Res Ctr, Dept Neurol, Charlestown, MA USA. [McCabe, George P.] Purdue Univ, Dept Stat, W Lafayette, IN 47907 USA. [George, Julia M.] Queen Mary Univ London, Sch Biol & Chem Sci, Dept Biol & Expt Psychol, London, England. RP Rochet, JC (reprint author), Purdue Univ, Dept Med Chem & Mol Pharmacol, W Lafayette, IN 47907 USA.; Rochet, JC (reprint author), Purdue Univ, Purdue Inst Integrat Neurosci, W Lafayette, IN 47907 USA. EM jrochet@purdue.edu FU Branfman Family Foundation; Richard F. Borch Research Enhancement Award; Purdue Research Foundation Fellowship; McKeehan Fellowship; Bilsland Dissertation Fellowship by the College of Pharmacy at Purdue University; Floss Endowment Research Award by the Department of Medicinal Chemistry and Molecular Pharmacology at Purdue University; l'Agence Nationale de la Recherche [ANR-12-BSV4-001-01-TargetPD]; LabEx BRAIN; NIH [P50 AG005134]; France Alzheimer [0033-00011]; France Parkinson [0033-00011]; ARSEP [0033-00011]; "Connaitre les Syndromes Cerebelleux" [0033-00011] FX This work was supported by a grant from the Branfman Family Foundation (J.-C. R.), a Richard F. Borch Research Enhancement Award (J.-C. R.), a Purdue Research Foundation Fellowship (J.-C. R. and D. Y.), a McKeehan Fellowship and a Bilsland Dissertation Fellowship provided by the College of Pharmacy at Purdue University (D. Y.), a Floss Endowment Research Award provided by the Department of Medicinal Chemistry and Molecular Pharmacology at Purdue University (D. Y), grants from l'Agence Nationale de la Recherche (ANR-12-BSV4-001-01-TargetPD, to E.B.) and LabEx BRAIN (E.B. and B.D.), and NIH grant P50 AG005134 (M.P.F.). The French post-mortem DLB and PD samples used in this study were obtained from the Brain Bank GIE NeuroCEB (BRIF number 0033-00011), funded by the patients' associations France Alzheimer, France Parkinson, ARSEP, and "Connaitre les Syndromes Cerebelleux" to which we express our gratitude. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 59 TC 0 Z9 0 U1 9 U2 9 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2051-5960 J9 ACTA NEUROPATHOL COM JI Acta Neuropathol. Commun. PD JAN 10 PY 2017 VL 5 AR 3 DI 10.1186/s40478-016-0403-7 PG 15 WC Neurosciences SC Neurosciences & Neurology GA EH1GK UT WOS:000391511600001 PM 28069058 ER PT J AU Dehnadi, A Cosimi, AB Smith, RN Li, XG Alonso, JL Means, TK Arnaout, MA AF Dehnadi, Abbas Cosimi, A. Benedict Smith, Rex Neal Li, Xiangen Alonso, Jose L. Means, Terry K. Arnaout, M. Amin TI Prophylactic orthosteric inhibition of leukocyte integrin CD11b/CD18 prevents long-term fibrotic kidney failure in cynomolgus monkeys SO NATURE COMMUNICATIONS LA English DT Article ID ISCHEMIA-REPERFUSION INJURY; DEPENDENT ADHESION SITE; ACUTE-RENAL-FAILURE; REGULATORY T-CELLS; MONOCLONAL-ANTIBODIES; BETA(2) INTEGRINS; GENE-EXPRESSION; GRAFT FUNCTION; UP-REGULATION; RECEPTOR AB Ischaemic acute kidney injury (AKI), an inflammatory disease process, often progresses to chronic kidney disease (CKD), with no available effective prophylaxis. This is in part due to lack of clinically relevant CKD models in non-human primates. Here we demonstrate that inhibition of the archetypal innate immune receptor CD11b/CD18 prevents progression of AKI to CKD in cynomolgus monkeys. Severe ischaemia-reperfusion injury of the right kidney, with subsequent periods of the left ureter ligation, causes irreversible right kidney failure 3, 6 or 9 months after AKI. Moreover, prophylactic inactivation of CD11b/CD18, using the orthosteric CD11b/CD18 inhibitor mAb107, improves microvascular perfusion and histopathology, reduces intrarenal pro-inflammatory mediators and salvages kidney function long term. These studies reveal an important early role of CD11b(+) leukocytes in post-ischaemic kidney fibrosis and failure, and suggest a potential early therapeutic intervention to mitigate progression of ischaemic AKI to CKD in humans. C1 [Dehnadi, Abbas; Cosimi, A. Benedict] Massachusetts Gen Hosp, Div Transplant Surg, Dept Surg, Boston, MA 02114 USA. [Cosimi, A. Benedict; Smith, Rex Neal; Li, Xiangen; Alonso, Jose L.; Means, Terry K.; Arnaout, M. Amin] Harvard Med Sch, Boston, MA 02115 USA. [Smith, Rex Neal] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Li, Xiangen; Alonso, Jose L.; Arnaout, M. Amin] Massachusetts Gen Hosp, Leukocyte Biol & Inflammat Program, Boston, MA 02114 USA. [Li, Xiangen; Alonso, Jose L.; Arnaout, M. Amin] Massachusetts Gen Hosp, Div Nephrol, Dept Med, Boston, MA 02114 USA. [Means, Terry K.] Massachusetts Gen Hosp, Div Rheumatol, Dept Med, Boston, MA 02114 USA. [Arnaout, M. Amin] Massachusetts Gen Hosp, Ctr Regenerat Med, Med Serv, Boston, MA 02114 USA. RP Arnaout, MA (reprint author), Harvard Med Sch, Boston, MA 02115 USA.; Arnaout, MA (reprint author), Massachusetts Gen Hosp, Leukocyte Biol & Inflammat Program, Boston, MA 02114 USA.; Arnaout, MA (reprint author), Massachusetts Gen Hosp, Div Nephrol, Dept Med, Boston, MA 02114 USA.; Arnaout, MA (reprint author), Massachusetts Gen Hosp, Ctr Regenerat Med, Med Serv, Boston, MA 02114 USA. EM aarnaout1@mgh.harvard.edu FU NIH grants from the National Institutes of Diabetes, Digestive and Kidney diseases (NIDDK) [DK088327, DK48549, DK007540, AI102405, AI119065, AI084884]; Allergy and Infectious Diseases (AI) of the National Institutes of Health FX We thank Drs Gilles Benichou and Dicken Ko (Massachusetts General Hospital, Boston, MA) for helpful discussions, Dr Dana N. Ashoor for technical assistance, and Drs Fabio Malavasi and Alberto Horenstein (University of Torino, Italy) for monoclonal antibody purification for use in animals. This work was supported by NIH grants DK088327, DK48549 and DK007540 (to M.A.A.), AI102405 (to A.B.C.) and AI119065 and AI084884 (to T.K.M.) from the National Institutes of Diabetes, Digestive and Kidney diseases (NIDDK) and Allergy and Infectious Diseases (AI) of the National Institutes of Health. NR 65 TC 0 Z9 0 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD JAN 10 PY 2017 VL 8 AR 13899 DI 10.1038/ncomms13899 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EH1RT UT WOS:000391545500001 PM 28071653 ER PT J AU Tsvetkov, P Sokol, E Jin, D Brune, Z Thiru, P Ghandi, M Garraway, LA Gupta, PB Santagata, S Whitesell, L Lindquist, S AF Tsvetkov, Peter Sokol, Ethan Jin, Dexter Brune, Zarina Thiru, Prathapan Ghandi, Mahmoud Garraway, Levi A. Gupta, Piyush B. Santagata, Sandro Whitesell, Luke Lindquist, Susan TI Suppression of 19S proteasome subunits marks emergence of an altered cell state in diverse cancers SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE drug resistance; epigenetic gene regulation; apoptosis; EMT; bortezomib ID EPITHELIAL-MESENCHYMAL TRANSITION; FACTOR-KAPPA-B; RAS ONCOGENE; STEM-CELLS; BORTEZOMIB; INHIBITION; RESISTANT; LYMPHOMA; PATHWAY; SYSTEM AB The use of proteasome inhibitors to target cancer's dependence on altered protein homeostasis has been greatly limited by intrinsic and acquired resistance. Analyzing data from thousands of cancer lines and tumors, we find that those with suppressed expression of one or more 19S proteasome subunits show intrinsic proteasome inhibitor resistance. Moreover, such proteasome subunit suppression is associated with poor outcome in myeloma patients, where proteasome inhibitors are a mainstay of treatment. Beyond conferring resistance to proteasome inhibitors, proteasome subunit suppression also serves as a sentinel of a more global remodeling of the transcriptome. This remodeling produces a distinct gene signature and new vulnerabilities to the proapoptotic drug, ABT-263. This frequent, naturally arising imbalance in 19S regulatory complex composition is achieved through a variety of mechanisms, including DNA methylation, and marks the emergence of a heritably altered and therapeutically relevant state in diverse cancers. C1 [Tsvetkov, Peter; Sokol, Ethan; Jin, Dexter; Brune, Zarina; Thiru, Prathapan; Gupta, Piyush B.; Whitesell, Luke; Lindquist, Susan] Whitehead Inst Biomed Res, Cambridge, MA 02142 USA. [Sokol, Ethan; Jin, Dexter; Gupta, Piyush B.; Lindquist, Susan] MIT, Dept Biol, Cambridge, MA 02139 USA. [Ghandi, Mahmoud; Garraway, Levi A.] Broad Inst, Cambridge, MA 02142 USA. [Garraway, Levi A.] Harvard Med Sch, Dana Farber Canc Inst, Boston, MA 02215 USA. [Garraway, Levi A.] Harvard Med Sch, Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Gupta, Piyush B.] Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA. [Gupta, Piyush B.] Harvard Stem Cell Inst, Cambridge, MA 02138 USA. [Santagata, Sandro] Harvard Med Sch, Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Lindquist, Susan] Howard Hughes Med Inst, Cambridge, MA 02139 USA. RP Tsvetkov, P (reprint author), Whitehead Inst Biomed Res, Cambridge, MA 02142 USA. EM petert@wi.mit.edu FU EMBO Fellowship [ALTF 739-2011]; Charles A. King Trust Postdoctoral Fellowship Program FX We thank Brad Bernstein, Anthony Letai, Jeremy Ryan, Yonatan Stelzer, Linda Clayton, Marc Mendillo, and Ruthie Scherz-Shouval for helpful discussion and comments. P. Tsvetkov was supported by EMBO Fellowship ALTF 739-2011 and by the Charles A. King Trust Postdoctoral Fellowship Program. S.L. was an investigator of the Howard Hughes Medical Institute. NR 36 TC 0 Z9 0 U1 4 U2 4 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JAN 10 PY 2017 VL 114 IS 2 BP 382 EP 387 DI 10.1073/pnas.1619067114 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EH0FR UT WOS:000391439300056 PM 28028240 ER PT J AU Singh, JA Chen, J Inacio, MCS Namba, RS Paxton, EW AF Singh, Jasvinder A. Chen, Jason Inacio, Maria C. S. Namba, Robert S. Paxton, Elizabeth W. TI An underlying diagnosis of osteonecrosis of bone is associated with worse outcomes than osteoarthritis after total hip arthroplasty SO BMC MUSCULOSKELETAL DISORDERS LA English DT Article DE Total hip replacement; Readmission; Osteoarthritis; Osteonecrosis; Arthroplasty; Joint replacement; Diagnosis; Risk factor ID RHEUMATOID-ARTHRITIS; RISK-FACTOR; REPLACEMENT; INFECTIONS; COHORT AB Background: Well-designed studies of complications and readmission rates in patients undergoing total hip arthroplasty (THA) with osteonecrosis are lacking. Our objective was to examine if a diagnosis of osteonecrosis was associated with complications, mortality and readmission rates after THA. Methods: We analyzed prospectively collected data from an integrated healthcare system's Total Joint Replacement Registry of adults with osteonecrosis vs. osteoarthritis (OA) undergoing unilateral primary THA during 2001-2012, in an observational cohort study. We examined mortality (90-day), revision (ever), deep (1 year) and superficial (30-day) surgical site infection (SSI), venous thromboembolism (VTE, 90-day), and unplanned readmission (90-day). Age, gender, race, body mass index, American Society of Anesthesiologists class, and diabetes were evaluated as confounders. We used logistic or Cox regression to calculate odds or hazard ratios (OR, HR) with 95% confidence intervals (CI). Results: Of the 47,523 primary THA cases, 45,252 (95.2%) had OA, and 2,271 (4.8%) had osteonecrosis. Compared to the OA, patients with osteonecrosis were younger (median age 55 vs. 67 years), and were less likely to be female (42.5% vs. 58.3%) or White (59.8% vs. 77.4%). Compared to the OA, the osteonecrosis cohort had higher crude incidence of 90-day mortality (0.7% vs. 0.3%), SSI (1.2% vs. 0.8%), unplanned readmission (9.6% vs. 5.2%) and revision (3.1% vs. 2.4%). After multivariable-adjustment, patients with osteonecrosis had a higher odds/hazard of mortality (OR: 2.48; 95% CI:1.31-4.72), SSI (OR: 1.67, 95% CI:1.11-2.51), unplanned 90-day readmissions (OR: 2.20; 95% CI:1.67-2.91) and a trend towards higher revision rate 1-year post-THA (HR: 1.32; 95% CI:0.94-1.84), than OA patients. Conclusions: Compared to OA, a diagnosis of osteonecrosis was associated with worse outcomes post-THA. A detailed preoperative discussion including the risk of complications is needed for informed consent from patients with osteonecrosis. C1 [Singh, Jasvinder A.] Birmingham VA Med Ctr, Med Serv, Birmingham, AL 35233 USA. [Singh, Jasvinder A.] Univ Alabama Birmingham, Dept Med, Sch Med, Fac Off Tower 805B,510 20th St S, Birmingham, AL 35294 USA. [Singh, Jasvinder A.] Univ Alabama Birmingham, Div Epidemiol, Sch Publ Hlth, Fac Off Tower 805B,510 20th St S, Birmingham, AL 35294 USA. [Singh, Jasvinder A.] Mayo Clin, Coll Med, Dept Orthoped Surg, Rochester, MN 55905 USA. [Chen, Jason; Inacio, Maria C. S.; Paxton, Elizabeth W.] Kaiser Permanente, Dept Surg Outcomes & Anal, San Diego, CA USA. [Namba, Robert S.] Kaiser Permanente, Dept Orthopaed Surg, Irvine, CA USA. RP Singh, JA (reprint author), Birmingham VA Med Ctr, Med Serv, Birmingham, AL 35233 USA.; Singh, JA (reprint author), Univ Alabama Birmingham, Dept Med, Sch Med, Fac Off Tower 805B,510 20th St S, Birmingham, AL 35294 USA.; Singh, JA (reprint author), Univ Alabama Birmingham, Div Epidemiol, Sch Publ Hlth, Fac Off Tower 805B,510 20th St S, Birmingham, AL 35294 USA.; Singh, JA (reprint author), Mayo Clin, Coll Med, Dept Orthoped Surg, Rochester, MN 55905 USA. EM Jasvinder.md@gmail.com NR 23 TC 0 Z9 0 U1 2 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2474 J9 BMC MUSCULOSKEL DIS JI BMC Musculoskelet. Disord. PD JAN 9 PY 2017 VL 18 AR 8 DI 10.1186/s12891-016-1385-0 PG 9 WC Orthopedics; Rheumatology SC Orthopedics; Rheumatology GA EM3BE UT WOS:000395188700001 PM 28068972 ER PT J AU Saladi, SV Ross, K Karaayvaz, M Tata, PR Mou, HM Rajagopal, J Ramaswamy, S Ellisen, LW AF Saladi, Srinivas Vinod Ross, Kenneth Karaayvaz, Mihriban Tata, Purushothama R. Mou, Hongmei Rajagopal, Jayaraj Ramaswamy, Sridhar Ellisen, Leif W. TI ACTL6A Is Co-Amplified with p63 in Squamous Cell Carcinoma to Drive YAP Activation, Regenerative Proliferation, and Poor Prognosis SO CANCER CELL LA English DT Article ID HIPPO PATHWAY; NECK-CANCER; STEM-CELLS; EPITHELIAL DEVELOPMENT; BAF COMPLEXES; HEAD; GENE; BIOLOGY; KIBRA; SOX2 AB Loss-of-function mutations in SWI/SNF chromatin-remodeling subunit genes are observed in many cancers, but an oncogenic role for SWI/SNF is not well established. Here, we reveal that ACTL6A, encoding an SWI/SNF subunit linked to stem cell and progenitor cell function, is frequently co-amplified and highly expressed together with the p53 family member p63 in head and neck squamous cell carcinoma (HNSCC). ACTL6A and p63 physically interact, cooperatively controlling a transcriptional program that promotes proliferation and suppresses differentiation, in part through activation of the Hippo-YAP pathway via regulators including WWC1. Ectopic ACTL6A/p63 expression promotes tumorigenesis, while ACTL6A expression and YAP activation are highly correlated in primary HNSCC and predict poor patient survival. Thus, ACTL6A and p63 collaborate as oncogenic drivers in HNSCC. C1 [Saladi, Srinivas Vinod; Ross, Kenneth; Karaayvaz, Mihriban; Ramaswamy, Sridhar; Ellisen, Leif W.] Massachusetts Gen Hosp, Ctr Canc, GRJ 904,55 Fruit St, Boston, MA 02114 USA. [Tata, Purushothama R.; Mou, Hongmei; Rajagopal, Jayaraj] Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA. [Rajagopal, Jayaraj] Massachusetts Gen Hosp, Dept Internal Med, Pulm & Crit Care Unit, Boston, MA 02114 USA. [Tata, Purushothama R.; Mou, Hongmei; Rajagopal, Jayaraj] Harvard Stem Cell Inst, Cambridge, MA 02138 USA. [Saladi, Srinivas Vinod; Karaayvaz, Mihriban; Tata, Purushothama R.; Mou, Hongmei; Rajagopal, Jayaraj; Ramaswamy, Sridhar; Ellisen, Leif W.] Harvard Med Sch, Boston, MA 02115 USA. [Ramaswamy, Sridhar] Broad Inst MIT & Harvard, Cambridge, MA 02138 USA. [Tata, Purushothama R.] Duke Univ, Sch Med, Dept Cell Biol, Durham, NC 27516 USA. RP Ellisen, LW (reprint author), Massachusetts Gen Hosp, Ctr Canc, GRJ 904,55 Fruit St, Boston, MA 02114 USA.; Ellisen, LW (reprint author), Harvard Med Sch, Boston, MA 02115 USA. EM lellisen@mgh.harvard.edu FU NIH [RO1 DE015945, R01 HL116756] FX We acknowledge the Harvard Cancer Center Specialized Histopathology Core Facility for tissue processing, and the MGH Center for Molecular Therapeutics for maintenance and validation of cell lines. We are grateful to Joan Brugge, Jose Amich, and Laura Selfors and Henry Long for input on SWI/SNF analysis, Devika Salunke for help with animal studies, and members of the Ellisen laboratory for comments on the manuscript. This work was supported by NIH grants RO1 DE015945 (LW. E., S.V.S., M.K.) and R01 HL116756 (J.R.). NR 61 TC 0 Z9 0 U1 3 U2 3 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 JAN 9 PY 2017 VL 31 IS 1 BP 35 EP 49 DI 10.1016/j.ccell.2016.12.001 PG 15 WC Oncology; Cell Biology SC Oncology; Cell Biology GA EH6RJ UT WOS:000391901300005 PM 28041841 ER PT J AU Sarosiek, KA Fraser, C Muthalagu, N Bhola, PD Chang, WT McBrayer, SK Cantlon, A Fisch, S Golomb-Mello, G Ryan, JA Deng, J Jian, B Corbett, C Goldenberg, M Madsen, JR Liao, RL Walsh, D Sedivy, J Murphy, DJ Carrasco, DR Robinson, S Moslehi, J Letai, A AF Sarosiek, Kristopher A. Fraser, Cameron Muthalagu, Nathiya Bhola, Patrick D. Chang, Weiting McBrayer, Samuel K. Cantlon, Adam Fisch, Sudeshna Golomb-Mello, Gail Ryan, Jeremy A. Deng, Jing Jian, Brian Corbett, Chris Goldenberg, Marti Madsen, Joseph R. Liao, Ronglih Walsh, Dominic Sedivy, John Murphy, Daniel J. Carrasco, Daniel Ruben Robinson, Shenandoah Moslehi, Javid Letai, Anthony TI Developmental Regulation of Mitochondria! Apoptosis by c-Myc Governs Age- and Tissue-Specific Sensitivity to Cancer Therapeutics SO CANCER CELL LA English DT Article ID CELL-DEATH; BRAIN MITOCHONDRIA; ALZHEIMERS-DISEASE; BCL-2 FAMILY; NEURAL CELL; RAT-BRAIN; IN-VIVO; BAX; EXPRESSION; THERAPY AB It is not understood why healthy tissues can exhibit varying levels of sensitivity to the same toxic stimuli. Using BH3 profiling, we find that mitochondria of many adult somatic tissues, including brain, heart, and kidneys, are profoundly refractory to pro-apoptotic signaling, leading to cellular resistance to cytotoxic chemotherapies and ionizing radiation. In contrast, mitochondria from these tissues in young mice and humans are primed for apoptosis, predisposing them to undergo cell death in response to genotoxic damage. While expression of the apoptotic protein machinery is nearly absent by adulthood, in young tissues its expression is driven by c-Myc, linking developmental growth to cell death. These differences may explain why pediatric cancer patients have a higher risk of developing treatment-associated toxicities. C1 [Sarosiek, Kristopher A.; Fraser, Cameron; Bhola, Patrick D.; McBrayer, Samuel K.; Ryan, Jeremy A.; Deng, Jing; Carrasco, Daniel Ruben; Letai, Anthony] Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave,Mayer 430, Boston, MA 02115 USA. [Sarosiek, Kristopher A.; Bhola, Patrick D.; Chang, Weiting; McBrayer, Samuel K.; Cantlon, Adam; Fisch, Sudeshna; Ryan, Jeremy A.; Deng, Jing; Madsen, Joseph R.; Liao, Ronglih; Walsh, Dominic; Carrasco, Daniel Ruben; Robinson, Shenandoah; Letai, Anthony] Harvard Med Sch, Boston, MA 02115 USA. [Muthalagu, Nathiya; Murphy, Daniel J.] Canc Res UK Beatson Inst, Glasgow G61 1BD, Lanark, Scotland. [Chang, Weiting; Cantlon, Adam; Fisch, Sudeshna; Liao, Ronglih; Walsh, Dominic] Brigham & Womens Hosp, Dept Med, Div Genet, 75 Francis St, Boston, MA 02115 USA. [Chang, Weiting; Cantlon, Adam; Fisch, Sudeshna; Liao, Ronglih; Walsh, Dominic] Brigham & Womens Hosp, Dept Med, Div Cardiovasc Med, 75 Francis St, Boston, MA 02115 USA. [Golomb-Mello, Gail; Sedivy, John] Brown Univ, Dept Mol Biol Cell Biol & Biochem, Providence, RI 02912 USA. [Jian, Brian] Kaiser Permanente, Dept Neurosurg, Sacramento, CA 95815 USA. [Corbett, Chris; Goldenberg, Marti; Madsen, Joseph R.; Robinson, Shenandoah] Boston Childrens Hosp, Dept Neurosurg, Boston, MA 02115 USA. [Murphy, Daniel J.] Univ Glasgow, Inst Canc Sci, Glasgow G61 1BD, Lanark, Scotland. [Moslehi, Javid] Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Div Cardiovasc Med, Nashville, TN 37232 USA. [Moslehi, Javid] Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Div Hematol Oncol, Nashville, TN 37232 USA. [Moslehi, Javid] Vanderbilt Univ, Dept Med, Sch Med, Cardiooncol Program,Vanderbilt Ingram Canc Ctr, Nashville, TN 37232 USA. [Sarosiek, Kristopher A.] Harvard TH Chan Sch Publ Hlth, Dept Environm Hlth, John B Little Ctr Radiat Sci, Boston, MA 02115 USA. RP Letai, A (reprint author), Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave,Mayer 430, Boston, MA 02115 USA.; Letai, A (reprint author), Harvard Med Sch, Boston, MA 02115 USA. EM anthony_letai@dfci.harvard.edu FU American Cancer Society [121360-PF-11-256-01-TBG]; Alex's Lemonade Stand Foundation for Childhood Cancers Young Investigator Award; NIH [K99CA188679, RO1CA129974, P01CA066996] FX We thank J. Sims, P. Sorger, X. Chi, L. Walensky, D. Andrews, C. Unitt, T. Bowman, O. Pozdnyakova, and S. White for providing assistance and B. Mar, J. Montero, G. Joshi, and L. Boise for critical review of our manuscript. We gratefully acknowledge funding from the American Cancer Society Postdoctoral Fellowship 121360-PF-11-256-01-TBG (K.A.S.), Alex's Lemonade Stand Foundation for Childhood Cancers Young Investigator Award (K.A.S.), as well as NIH grants K99CA188679 (K.A.S.), RO1CA129974 (A.L.), and P01CA066996 (A.L.). A.L. was a Leukemia and Lymphoma Society Scholar. NR 62 TC 2 Z9 2 U1 6 U2 6 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1535-6108 EI 1878-3686 J9 CANCER CELL JI Cancer Cell PD JAN 9 PY 2017 VL 31 IS 1 BP 142 EP 156 DI 10.1016/j.ccell.2016.11.011 PG 15 WC Oncology; Cell Biology SC Oncology; Cell Biology GA EH6RJ UT WOS:000391901300012 PM 28017613 ER PT J AU Zou, L AF Zou, Lee TI DNA Replication Checkpoint: New ATR Activator Identified SO CURRENT BIOLOGY LA English DT Editorial Material ID BINDING PROTEIN ETAA1; COMPLEXES; TOPBP1; FORKS; INITIATION; KINASE; DAMAGE; RAD17 AB The ATR kinase is a master regulator of replication stress responses. Four new studies show that the protein ETAA1 is an important activator of ATR in human cells, providing insights into how the ATR pathway reacts to replication stress. C1 [Zou, Lee] Harvard Med Sch, Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA 02129 USA. [Zou, Lee] Harvard Med Sch, Massachusetts Gen Hosp, Dept Pathol, Charlestown, MA 02129 USA. RP Zou, L (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA 02129 USA.; Zou, L (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Dept Pathol, Charlestown, MA 02129 USA. EM LZOU1@mgh.harvard.edu NR 20 TC 0 Z9 0 U1 6 U2 6 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 JAN 9 PY 2017 VL 27 IS 1 BP R33 EP R35 DI 10.1016/j.cub.2016.11.025 PG 3 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA EH6RV UT WOS:000391902500014 PM 28073021 ER PT J AU Pau, CT Mosbruger, T Saxena, R Welt, CK AF Pau, Cindy T. Mosbruger, Tim Saxena, Richa Welt, Corrine K. TI Phenotype and Tissue Expression as a Function of Genetic Risk in Polycystic Ovary Syndrome SO PLOS ONE LA English DT Article ID GENOME-WIDE ASSOCIATION; GONADOTROPIN-SECRETION; EUROPEAN ANCESTRY; HORMONE SYNTHESIS; WOMEN; VARIANTS; BETA; POPULATIONS; FEATURES; DENND1A AB Genome-wide association studies and replication analyses have identified (n = 5) or replicated (n = 10) DNA variants associated with risk for polycystic ovary syndrome (PCOS) in European women. However, the causal gene and underlying mechanism for PCOS risk at these loci have not been determined. We hypothesized that analysis of phenotype, gene expression and metformin response as a function of genotype would identify candidate genes and pathways that could provide insight into the underlying mechanism for risk at these loci. To test the hypothesis, subjects with PCOS (n = 427) diagnosed according to the NIH criteria (< 9 menses per year and clinical or biochemical hyperandrogenism) and controls (n = 407) with extensive phenotyping were studied. A subset of subjects (n = 38) underwent a subcutaneous adipose tissue biopsy for RNA sequencing and were subsequently treated with metformin for 12 weeks with standardized outcomes measured. Data were analyzed according to genotype at PCOS risk loci and adjusted for the false discovery rate. A gene variant in the THADA locus was associated with response to metformin and metformin was a predicted upstream regulator at the same locus. Genotype at the FSHB locus was associated with LH levels. Genes near the PCOS risk loci demonstrated differences in expression as a function of genotype in adipose including BLK and NEIL2 (GATA4 locus), GLIPR1 and PHLDA1 (KRR1 locus). Based on the phenotypes, expression quantitative trait loci (eQTL), and upstream regulatory and pathway analyses we hypothesize that there are PCOS subtypes. FSHB, FHSR and LHR loci may influence PCOS risk based on their relationship to gonadotropin levels. The THADA, GATA4, ERBB4, SUMO1P1, KRR1 and RAB5B loci appear to confer risk through metabolic mechanisms. The IRF1, SUMO1P1 and KRR1 loci may confer PCOS risk in development. The TOX3 and GATA4 loci appear to be involved in inflammation and its consequences. The data suggest potential PCOS subtypes and point to the need for additional studies to replicate these findings and identify personalized diagnosis and treatment options for PCOS. C1 [Pau, Cindy T.] Massachusetts Gen Hosp, Reprod Endocrine Unit, Boston, MA 02114 USA. [Mosbruger, Tim] Univ Utah, Huntsman Canc Inst Bioinformat, Salt Lake City, UT USA. [Saxena, Richa] Massachusetts Gen Hosp, Dept Anaesthesiol, Boston, MA 02114 USA. [Saxena, Richa] Massachusetts Gen Hosp, Ctr Human Genet, Boston, MA 02114 USA. [Welt, Corrine K.] Univ Utah, Div Endocrinol Metab & Diabet, Salt Lake City, UT 84112 USA. RP Welt, CK (reprint author), Univ Utah, Div Endocrinol Metab & Diabet, Salt Lake City, UT 84112 USA. EM cwelt@genetics.utah.edu FU Eunice Kennedy Shriver National Institute Of Child Health & Human Development [R01HD065029]; Harvard Clinical and Translational Science Center, from the National Center for Research Resources [1 UL1 RR025758]; American Diabetes Association [1-10-CT-57]; Partners Healthcare Center for Personalized Genetics Project Grant FX The project was supported by Award Number R01HD065029 (CKW) from the Eunice Kennedy Shriver National Institute Of Child Health & Human Development, Award Number 1 UL1 RR025758, Harvard Clinical and Translational Science Center, from the National Center for Research Resources, award 1-10-CT-57 (CKW) from the American Diabetes Association and the Partners Healthcare Center for Personalized Genetics Project Grant (CKW). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 39 TC 0 Z9 0 U1 4 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 9 PY 2017 VL 12 IS 1 AR e0168870 DI 10.1371/journal.pone.0168870 PG 17 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EH5WO UT WOS:000391843900015 PM 28068351 ER PT J AU Shirai, CL White, BS Tripathi, M Tapia, R Ley, JN Ndonwi, M Kim, S Shao, J Carver, A Saez, B Fulton, RS Fronick, C O'Laughlin, M Lagisetti, C Webb, TR Graubert, TA Walter, MJ AF Shirai, Cara Lunn White, Brian S. Tripathi, Manorama Tapia, Roberto Ley, James N. Ndonwi, Matthew Kim, Sanghyun Shao, Jin Carver, Alexa Saez, Borja Fulton, Robert S. Fronick, Catrina O'Laughlin, Michelle Lagisetti, Chandraiah Webb, Thomas R. Graubert, Timothy A. Walter, Matthew J. TI Mutant U2AF1-expressing cells are sensitive to pharmacological modulation of the spliceosome SO NATURE COMMUNICATIONS LA English DT Article ID PRE-MESSENGER-RNA; MYELODYSPLASTIC SYNDROMES; GENE-EXPRESSION; MUTATIONS; CANCER; LEUKEMIA; SRSF2; SELECTION; TARGET; U2AF1 AB Somatic mutations in spliceosome genes are detectable in similar to 50% of patients with myelo-dysplastic syndromes (MDS). We hypothesize that cells harbouring spliceosome gene mutations have increased sensitivity to pharmacological perturbation of the spliceosome. We focus on mutant U2AF1 and utilize sudemycin compounds that modulate pre-mRNA splicing. We find that haematopoietic cells expressing mutant U2AF1(S34F), including primary patient cells, have an increased sensitivity to in vitro sudemycin treatment relative to controls. In vivo sudemycin treatment of U2AF1(S34F) transgenic mice alters splicing and reverts haematopoietic progenitor cell expansion induced by mutant U2AF1 expression. The splicing effects of sudemycin and U2AF1(S34F) can be cumulative in cells exposed to both perturbations-drug and mutation-compared with cells exposed to either alone. These cumulative effects may result in downstream phenotypic consequences in sudemycin-treated mutant cells. Taken together, these data suggest a potential for treating haematological cancers harbouring U2AF1 mutations with pre-mRNA splicing modulators like sudemycins. C1 [Shirai, Cara Lunn; White, Brian S.; Tripathi, Manorama; Tapia, Roberto; Ley, James N.; Ndonwi, Matthew; Kim, Sanghyun; Shao, Jin; Carver, Alexa; Walter, Matthew J.] Washington Univ, Sch Med, Div Oncol, St Louis, MO 63110 USA. [Saez, Borja; Graubert, Timothy A.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Fulton, Robert S.; Fronick, Catrina; O'Laughlin, Michelle] Washington Univ, McDonnell Genome Inst, St Louis, MO 63108 USA. [Lagisetti, Chandraiah; Webb, Thomas R.] SRI Int, Biosci Div, Menlo Pk, CA 94025 USA. RP Walter, MJ (reprint author), Washington Univ, Sch Med, Div Oncol, St Louis, MO 63110 USA. EM mjwalter@wustl.edu FU NIH/NHLBI [T32HL007088]; Barnes-Jewish Hospital Foundation; NIH/NCI SPORE in Leukemia [P50CA171963]; NIH/NCI grant [K12CA167540, P01 CA101937]; Clinical and Translational Award from the NIH National Center for Advancing Translational Sciences [UL1 TR000448]; Edward P Evans Foundation; Lottie Caroline Hardy Trust; Leukemia and Lymphoma Society Scholar Award; Translational Research Award; NIH [CA140474]; Department of Defense [BM120018]; NCI Cancer Center Support Grant [P30CA91842] FX Support was provided by NIH/NHLBI (T32HL007088 to C.L.S.), Barnes-Jewish Hospital Foundation (B.S.W., T.A.G. and M.J.W.), an NIH/NCI SPORE in Leukemia (P50CA171963 to C.L.S., B.S.W., T.A.G. and M.J.W.), an NIH/NCI grant (K12CA167540 to C.L.S. and B.S.W.), a Clinical and Translational Award from the NIH National Center for Advancing Translational Sciences (UL1 TR000448 to B.S.W.), the Edward P Evans Foundation (T.A.G. and M.J.W.), the Lottie Caroline Hardy Trust (T.A.G. and M.J.W.), a Leukemia and Lymphoma Society Scholar Award (M.J.W.) and Translational Research Award (T.A.G.), by NIH grant CA140474 (T.R.W.) and Department of Defense (BM120018; M.J.W.). Support for procurement of human samples was provided by an NIH/NCI grant (P01 CA101937). Technical assistance was provided by the Alvin J Siteman Cancer Center High Speed Cell Sorting Core, the Tissue Procurement Core supported by an NCI Cancer Center Support Grant (P30CA91842), Carla Weinheimer and Mouse Cardiovascular Phenotyping Core in the Center for Cardiovascular Research at Washington University School of Medicine, and the McDonnell Genome Institute (Director, Richard Wilson and Co-Director, Elaine Mardis) and Chris Markovic for sequencing and NanoString experiments, respectively. E7107 and technical assistance were kindly provided by Silvia Buonamici and Peter Smith (H3 Biomedicine). We are grateful to Drs Tim Ley, Dan Link, and John DiPersio for helpful scientific discussions. NR 46 TC 0 Z9 0 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD JAN 9 PY 2017 VL 8 AR 14060 DI 10.1038/ncomms14060 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EG9GJ UT WOS:000391366600001 PM 28067246 ER PT J AU Lin, HH Yin, XY Xie, ZJ Lunetta, KL Lubitz, SA Larson, MG Ko, D Magnani, JW Mendelson, MM Liu, CY McManus, DD Levy, D Ellinor, PT Benjamin, EJ AF Lin, Honghuang Yin, Xiaoyan Xie, Zhijun Lunetta, Kathryn L. Lubitz, Steven A. Larson, Martin G. Ko, Darae Magnani, Jared W. Mendelson, Michael M. Liu, Chunyu McManus, David D. Levy, Daniel Ellinor, Patrick T. Benjamin, Emelia J. TI Methylome-wide Association Study of Atrial Fibrillation in Framingham Heart Study SO SCIENTIFIC REPORTS LA English DT Article ID SMOOTH-MUSCLE-CELLS; DNA METHYLATION; RISK-FACTORS; ALCOHOL-CONSUMPTION; GENE-EXPRESSION; FOLLOW-UP; PROTEIN; PREVALENCE; MORTALITY; DISEASE AB Atrial fibrillation (AF) is the most common cardiac arrhythmia, but little is known about the molecular mechanisms associated with AF arrhythmogenesis. DNA methylation is an important epigenetic mechanism that regulates gene expression and downstream biological processes. We hypothesize that DNA methylation might play an important role in the susceptibility to develop AF. A total of 2,639 participants from the Offspring Cohort of Framingham Heart Study were enrolled in the current study. These participants included 183 participants with prevalent AF and 220 with incident AF during up to 9 years follow up. Genome-wide methylation was profiled using the Illumina Infinium HumanMethylation450 BeadChip on blood-derived DNA collected during the eighth examination cycle (2005-2008). Two CpG sites were significantly associated with prevalent AF, and five CpGs were associated with incident AF after correction for multiple testing (FDR < 0.05). Fourteen previously reported genome-wide significant AF-related SNP were each associated with at least one CpG site; the most significant association was rs6490029 at the CUX2 locus and cg10833066 (P = 9.5 x 10(-279)). In summary, we performed genome-wide methylation profiling in a community-based cohort and identified seven methylation signatures associated with AF. Our study suggests that DNA methylation might play an important role in AF arrhythmogenesis. C1 [Lin, Honghuang; Yin, Xiaoyan; Lunetta, Kathryn L.; Larson, Martin G.; Liu, Chunyu; Levy, Daniel; Benjamin, Emelia J.] NHLBI, Framingham, MA 01702 USA. [Lin, Honghuang; Yin, Xiaoyan; Lunetta, Kathryn L.; Larson, Martin G.; Liu, Chunyu; Levy, Daniel; Benjamin, Emelia J.] Boston Univ, Framingham Heart Study, Framingham, MA 01702 USA. [Lin, Honghuang; Xie, Zhijun] Boston Univ, Sch Med, Dept Med, Sect Computat Biomed, Boston, MA 02118 USA. [Xie, Zhijun] Zhejiang Chinese Med Univ, TCM Clin Basis Inst, Hangzhou, Zhejiang, Peoples R China. [Lunetta, Kathryn L.; Liu, Chunyu] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02215 USA. [Lubitz, Steven A.; Ellinor, Patrick T.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charlestown, MA USA. [Lubitz, Steven A.; Ellinor, Patrick T.] Broad Inst Harvard & MIT, Cambridge, MA USA. [Larson, Martin G.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [Magnani, Jared W.] Univ Pittsburgh, Dept Med, UPMC Heart & Vasc Inst, Div Cardiol, Pittsburgh, PA USA. [Ko, Darae; Benjamin, Emelia J.] Boston Univ, Sch Med, Dept Med, Sect Cardiovasc Med, Boston, MA 02118 USA. [Mendelson, Michael M.; Liu, Chunyu; Levy, Daniel] NHLBI, Populat Sci Branch, Div Intramural Res, Bldg 10, Bethesda, MD 20892 USA. [Mendelson, Michael M.] Boston Childrens Hosp, Dept Cardiol, Boston, MA USA. [McManus, David D.] Univ Massachusetts, Sch Med, Med & Quantitat Hlth Sci, Worcester, MA USA. [Benjamin, Emelia J.] Boston Univ, Sch Med, Dept Med, Sect Prevent Med, Boston, MA 02118 USA. [Benjamin, Emelia J.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. RP Lin, HH (reprint author), NHLBI, Framingham, MA 01702 USA.; Lin, HH (reprint author), Boston Univ, Framingham Heart Study, Framingham, MA 01702 USA.; Lin, HH (reprint author), Boston Univ, Sch Med, Dept Med, Sect Computat Biomed, Boston, MA 02118 USA. EM hhlin@bu.edu OI Mendelson, Michael/0000-0001-7590-3958 FU National Institutes of Health [N01-HC-25195, HHSN268 201500001I, K24HL105780]; Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health; NIH [2RO1HL092577, 1R01HL128914, K23HL114724]; American Heart Association [13EIA14220013]; Fondation Leducq [14CVD01]; Doris Duke Charitable Foundation [2014105, 2015084]; Tommy Kaplan Fund, Department of Cardiology, Boston Children's Hospital FX The Framingham Heart Study is funded by National Institutes of Health contract N01-HC-25195; HHSN268 201500001I. The laboratory work for this investigation was funded by the Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health, and by a Director's Challenge Award, National Institutes of Health (DL, PI). This project also was supported by NIH grants to Drs. Ellinor, Benjamin, and Lunetta (2RO1HL092577) and Benjamin and Ellinor (1R01HL128914). Dr. Ellinor is supported by grants from the National Institutes of Health (K24HL105780), an Established Investigator Award from the American Heart Association (13EIA14220013) and by support from the Fondation Leducq (14CVD01). Dr. Lubitz is supported by NIH grants K23HL114724. This work was supported by Grant 2014105 and Grant 2015084 from the Doris Duke Charitable Foundation. Dr. Mendelson is partly supported by a family foundation award from the Tommy Kaplan Fund, Department of Cardiology, Boston Children's Hospital. The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute; the National Institutes of Health; or the U.S. Department of Health and Human Services. NR 54 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD JAN 9 PY 2017 VL 7 AR 40377 DI 10.1038/srep40377 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EG9IR UT WOS:000391372800001 PM 28067321 ER PT J AU Thondapu, V Bourantas, CV Foin, N Jang, IK Serruys, PW Barlis, P AF Thondapu, Vikas Bourantas, Christos V. Foin, Nicolas Jang, Ik-Kyung Serruys, Patrick W. Barlis, Peter TI Biomechanical stress in coronary atherosclerosis: emerging insights from computational modelling SO EUROPEAN HEART JOURNAL LA English DT Review DE Atherosclerosis; Coronary artery disease; Shear stress; Computational modelling; Plaque rupture ID ENDOTHELIAL SHEAR-STRESS; OPTICAL COHERENCE TOMOGRAPHY; SMOOTH-MUSCLE-CELLS; VULNERABLE PLAQUE RUPTURE; NITRIC-OXIDE SYNTHASE; IN-VIVO ASSESSMENT; ARTERY-DISEASE; INTRAVASCULAR ULTRASOUND; WALL SHEAR; CHOLESTEROL CRYSTALS AB Coronary plaque rupture is the most common cause of vessel thrombosis and acute coronary syndrome. The accurate early detection of plaques prone to rupture may allow prospective, preventative treatment; however, current diagnostic methods remain inadequate to detect these lesions. Established imaging features indicating vulnerability do not confer adequate specificity for symptomatic rupture. Similarly, even though experimental and computational studies have underscored the importance of endothelial shear stress in progressive atherosclerosis, the ability of shear stress to predict plaque progression remains incremental. This review examines recent advances in image-based computational modelling that have elucidated possible mechanisms of plaque progression and rupture, and potentially novel features of plaques most prone to symptomatic rupture. With further study and clinical validation, these markers and techniques may improve the specificity of future culprit plaque detection. C1 [Thondapu, Vikas; Barlis, Peter] Univ Melbourne, Fac Med Dent & Hlth Sci, Melbourne Med Sch, Melbourne, Vic 3010, Australia. [Thondapu, Vikas; Barlis, Peter] Univ Melbourne, Melbourne Sch Engn, Dept Engn Mech, Melbourne, Vic 3010, Australia. [Bourantas, Christos V.] Univ Coll London Hosp, Natl Hlth Serv Fdn Trust, London, England. [Foin, Nicolas] Natl Heart Ctr, Singapore, Singapore. [Foin, Nicolas] Duke Natl Univ Singapore, Sch Med, Singapore, Singapore. [Jang, Ik-Kyung] Massachusetts Gen Hosp, Harvard Med Sch, Cardiol Div, Boston, MA USA. [Serruys, Patrick W.] Imperial Coll, Natl Heart & Lung Inst, London, England. RP Barlis, P (reprint author), Univ Melbourne, Fac Med Dent & Hlth Sci, Melbourne Med Sch, Melbourne, Vic 3010, Australia.; Barlis, P (reprint author), Univ Melbourne, Melbourne Sch Engn, Dept Engn Mech, Melbourne, Vic 3010, Australia. EM pbarlis@unimelb.edu.au FU Australian Research Council through ARC Linkage Project [LP120100233]; Victorian Life Sciences Computation Initiative (VLSCI grant) on its Peak Computing Facility at the University of Melbourne, an initiative of the Victorian Government, Australia [VR0210] FX This work has been partially supported by the Australian Research Council through ARC Linkage Project LP120100233. This research was also supported by the Victorian Life Sciences Computation Initiative (VLSCI grant number VR0210) on its Peak Computing Facility at the University of Melbourne, an initiative of the Victorian Government, Australia. NR 137 TC 1 Z9 1 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0195-668X EI 1522-9645 J9 EUR HEART J JI Eur. Heart J. PD JAN 7 PY 2017 VL 38 IS 2 BP 81 EP 92C DI 10.1093/eurheartj/ehv689 PG 15 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EK6AI UT WOS:000394006900007 PM 28158723 ER PT J AU Balar, AV Balar, AV Rosenberg, JE Powles, T Petrylak, DP Bellmunt, J Loriot, Y Necchi, A Hoffman-Censits, J Perez-Gracia, JL Dawson, NA van der Heijden, MS Dreicer, R Srinivas, S Retz, MM Joseph, RW Drakaki, A Vaishampayan, UN Sridhar, SS Quinn, DI Duran, I Shaffer, DR Eigl, BJ Grivas, PD Yu, EY Li, S Kadel, EE Boyd, Z Bourgon, R Hegde, PS Mariathasan, S Thastrom, A Abidoye, OO Fine, GD Bajorin, DF AF Balar, Arjun V. Galsky, Matthew D. Rosenberg, Jonathan E. Powles, Thomas Petrylak, Daniel P. Bellmunt, Joaquim Loriot, Yohann Necchi, Andrea Hoffman-Censits, Jean Perez-Gracia, Jose Luis Dawson, Nancy A. van der Heijden, Michiel S. Dreicer, Robert Srinivas, Sandy Retz, Margitta M. Joseph, Richard W. Drakaki, Alexandra Vaishampayan, Ulka N. Sridhar, Srikala S. Quinn, David I. Duran, Ignacio Shaffer, David R. Eigl, Bernhard J. Grivas, Petros D. Yu, Evan Y. Li, Shi Kadel, Edward E., III Boyd, Zachary Bourgon, Richard Hegde, Priti S. Mariathasan, Sanjeev Thastrom, AnnChristine Abidoye, Oyewale O. Fine, Gregg D. Bajorin, Dean F. CA IMvigor210 Study Grp TI Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial SO LANCET LA English DT Article ID RENAL-CELL CARCINOMA; LONG-TERM-SURVIVAL; BLADDER-CANCER; CLINICAL ACTIVITY; LUNG-CANCER; CHEMOTHERAPY; UNFIT; METHOTREXATE; GEMCITABINE; VINBLASTINE AB Background First-line chemotherapy for patients with cisplatin-ineligible locally advanced or metastatic urothelial carcinoma is associated with short response duration, poor survival, and high toxicity. This study assessed atezolizumab (anti-programmed death-ligand 1 [PD-L1]) as treatment for metastatic urothelial cancer in cisplatin-ineligible patients. Methods For this single-arm, multicentre, phase 2 study, in 47 academic medical centres and community oncology practices in seven countries in North America and Europe, we recruited previously untreated patients with locally advanced or metastatic urothelial cancer who were cisplatin ineligible. Patients were given 1200 mg intravenous atezolizumab every 21 days until progression. The primary endpoint was independently confirmed objective response rate per Response Evaluation Criteria in Solid Tumors version 1.1 (central review), assessed in prespecified subgroups based on PD-L1 expression and in all patients. All participants who received one or more doses of atezolizumab were included in the primary and safety analyses. This study was registered with ClinicalTrials.gov, number NCT02108652. Findings Between June 9, 2014, and March 30, 2015, we enrolled 123 patients, of whom 119 received one or more doses of atezolizumab. At 17.2 months' median follow-up, the objective response rate was 23% (95% CI 16 to 31), the complete response rate was 9% (n=11), and 19 of 27 responses were ongoing. Median response duration was not reached. Responses occurred across all PD-L1 and poor prognostic factor subgroups. Median progression-free survival was 2.7 months (2.1 to 4.2). Median overall survival was 15.9 months (10.4 to not estimable). Tumour mutation load was associated with response. Treatment-related adverse events that occurred in 10% or more of patients were fatigue (36 [30%] patients), diarrhoea (14 [12%] patients), and pruritus (13 [11%] patients). One treatment-related death (sepsis) occurred. Nine (8%) patients had an adverse event leading to treatment discontinuation. Immune-mediated events occurred in 14 (12%) patients. Interpretation Atezolizumab showed encouraging durable response rates, survival, and tolerability, supporting its therapeutic use in untreated metastatic urothelial cancer. Funding F Hoff mann-La Roche, Genentech. C1 [Balar, Arjun V.] NYU, Perlmutter Canc Ctr, Langone Med Ctr, Genitourinary Cancers Program, New York, NY USA. [Galsky, Matthew D.] Icahn Sch Med Mt Sinai, Tisch Canc Inst, New York, NY 10029 USA. [Rosenberg, Jonathan E.; Bajorin, Dean F.] Mem Sloan Kettering Canc Ctr, Dept Med, Genitourinary Oncol Serv, 1275 York Ave, New York, NY 10021 USA. [Powles, Thomas] Queen Mary Univ London, Barts Hlth & Royal Free NHS Trust, Barts Canc Inst ECMC, London, England. [Petrylak, Daniel P.] Yale Univ, Smilow Canc Ctr, New Haven, CT USA. [Bellmunt, Joaquim] Harvard Med Sch, Dana Farber Canc Inst, Lank Ctr Genitourinary Oncol, Boston, MA USA. [Loriot, Yohann] Univ Paris Saclay, Dept Med Oncol, Villejuif, France. [Loriot, Yohann] Gustave Roussy, Villejuif, France. [Necchi, Andrea] Fdn IRCCS Ist Nazl Tumori, Dept Med Oncol, Milan, Italy. [Hoffman-Censits, Jean] Sidney Kimmel Canc Ctr Jefferson, Philadelphia, PA USA. [Perez-Gracia, Jose Luis] Univ Navarra, Clin Univ Navarra, Dept Oncol, Pamplona, Navarre, Spain. [Dawson, Nancy A.] Medstar Georgetown Univ Hosp, Lombardi Comprehens Canc Ctr, Washington, DC USA. [van der Heijden, Michiel S.] Netherlands Canc Inst, Dept Med Oncol, Amsterdam, Netherlands. [Dreicer, Robert] Univ Virginia, Sch Med, Div Hematol Oncol, Charlottesville, VA 22908 USA. [Srinivas, Sandy] Stanford Univ, Sch Med, Dept Med, Div Oncology, Stanford, CA 94305 USA. [Retz, Margitta M.] Tech Univ Munich, Klinikum Rechts Isar, Dept Urol, Munich, Germany. [Joseph, Richard W.] Mayo Clin, Dept Hematol Oncol, Jacksonville, FL 32224 USA. [Drakaki, Alexandra] Univ Calif Los Angeles, David Geffen Sch Med, Div Hematol & Oncol, Dept Med, Los Angeles, CA 90095 USA. [Drakaki, Alexandra] Univ Calif Los Angeles, David Geffen Sch Med, Inst Urol Oncol, Los Angeles, CA 90095 USA. [Vaishampayan, Ulka N.] Wayne State Univ, Karmanos Canc Inst, Detroit, MI USA. [Sridhar, Srikala S.] Princess Margaret Canc Ctr, Dept Med Oncol & Hematol, Toronto, ON, Canada. [Quinn, David I.] Univ Southern Calif, Norris Comprehens Canc Ctr, Los Angeles, CA USA. [Duran, Ignacio] Hosp Univ Virgen Rocio, Dept Med Oncol, Seville, Spain. [Duran, Ignacio] Inst Biomed Seville, Seville, Spain. [Shaffer, David R.] New York Oncol Hematol, Albany, NY USA. [Eigl, Bernhard J.] British Columbia Canc Agcy, Vancouver, BC, Canada. [Grivas, Petros D.] Cleveland Clin, Taussig Canc Inst, Dept Hematol & Med Oncol, Cleveland, OH 44106 USA. [Yu, Evan Y.] Univ Washington, Dept Med, Div Oncol, Seattle, WA USA. [Yu, Evan Y.] Fred Hutchinson Canc Res Ctr, Div Clin Res, 1124 Columbia St, Seattle, WA 98104 USA. [Li, Shi; Kadel, Edward E., III; Boyd, Zachary; Bourgon, Richard; Hegde, Priti S.; Mariathasan, Sanjeev; Thastrom, AnnChristine; Abidoye, Oyewale O.; Fine, Gregg D.] Genentech Inc, San Francisco, CA USA. RP Balar, AV (reprint author), NYU, Perlmutter Canc Ctr, New York, NY 10016 USA. EM arjun.balar@nyumc.org FU F Hoffmann-La Roche, Genentech FX F Hoffmann-La Roche, Genentech. NR 30 TC 4 Z9 4 U1 7 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 EI 1474-547X J9 LANCET JI Lancet PD JAN 7 PY 2017 VL 389 IS 10064 BP 67 EP 76 DI 10.1016/S0140-6736(16)32455-2 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA EG7VH UT WOS:000391264000039 PM 27939400 ER PT J AU Geng, CR Daartz, J Lam-Tin-Cheung, K Bussiere, M Shih, HA Paganetti, H Schuemann, J AF Geng, Changran Daartz, Juliane Lam-Tin-Cheung, Kimberley Bussiere, Marc Shih, Helen A. Paganetti, Harald Schuemann, Jan TI Limitations of analytical dose calculations for small field proton radiosurgery SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article DE proton stereotactic radiosurgery; analytical dose calculation; Monte Carlo; small field dosimetry ID RANGE UNCERTAINTIES; THERAPY; ACCURACY; BEAMS AB The purpose of the work was to evaluate the dosimetric uncertainties of an analytical dose calculation engine and the impact on treatment plans using small fields in intracranial proton stereotactic radiosurgery (PSRS) for a gantry based double scattering system. 50 patients were evaluated including 10 patients for each of 5 diagnostic indications of: arteriovenous malformation (AVM), acoustic neuroma (AN), meningioma (MGM), metastasis (METS), and pituitary adenoma (PIT). Treatment plans followed standard prescription and optimization procedures for PSRS. We performed comparisons between delivered dose distributions, determined by Monte Carlo (MC) simulations, and those calculated with the analytical dose calculation algorithm (ADC) used in our current treatment planning system in terms of dose volume histogram parameters and beam range distributions. Results show that the difference in the dose to 95% of the target (D95) is within 6% when applying measured field size output corrections for AN, MGM, and PIT. However, for AVM and METS, the differences can be as great as 10% and 12%, respectively. Normalizing the MC dose to the ADC dose based on the dose of voxels in a central area of the target reduces the difference of the D95 to within 6% for all sites. The generally applied margin to cover uncertainties in range (3.5% of the prescribed range + 1 mm) is not sufficient to cover the range uncertainty for ADC in all cases, especially for patients with high tissue heterogeneity. The root mean square of the R90 difference, the difference in the position of distal falloff to 90% of the prescribed dose, is affected by several factors, especially the patient geometry heterogeneity, modulation and field diameter. In conclusion, implementation of Monte Carlo dose calculation techniques into the clinic can reduce the uncertainty of the target dose for proton stereotactic radiosurgery. If MC is not available for treatment planning, using MC dose distributions to adjust the delivered doses level can also reduce uncertainties below 3% for mean target dose and 6% for the D95. C1 [Geng, Changran; Daartz, Juliane; Lam-Tin-Cheung, Kimberley; Bussiere, Marc; Shih, Helen A.; Paganetti, Harald; Schuemann, Jan] Harvard Med Sch, Dept Radiat Oncol, Massachusetts Gen Hosp, 30 Fruit St, Boston, MA 02114 USA. RP Geng, CR (reprint author), Harvard Med Sch, Dept Radiat Oncol, Massachusetts Gen Hosp, 30 Fruit St, Boston, MA 02114 USA. EM cgeng@mgh.harvard.edu; jschuemann@mgh.harvard.edu FU National Cancer Institute [U19 CA-21239] FX This work was funded by the National Cancer Institute under U19 CA-21239. NR 16 TC 0 Z9 0 U1 4 U2 4 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 JAN 7 PY 2017 VL 62 IS 1 BP 246 EP 257 DI 10.1088/1361-6560/62/1/246 PG 12 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA EH1ZT UT WOS:000391567700006 ER PT J AU Kim, J Park, YK Sharp, G Busse, P Winey, B AF Kim, Jihun Park, Yang-Kyun Sharp, Gregory Busse, Paul Winey, Brian TI Water equivalent path length calculations using scatter-corrected head and neck CBCT images to evaluate patients for adaptive proton therapy SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article DE adaptive proton therapy; head and neck; cone-beam CT; scatter correction; proton therapy ID CONE-BEAM CT; MODULATED RADIATION-THERAPY; CANCER RADIOTHERAPY; COMPUTED-TOMOGRAPHY; DEFORMABLE REGISTRATION; TREATMENT UNCERTAINTIES; OROPHARYNGEAL CANCER; SETUP UNCERTAINTIES; DOSE RECALCULATION; GEOMETRIC CHANGES AB Proton therapy has dosimetric advantages due to the well-defined range of the proton beam over photon radiotherapy. When the proton beams, however, are delivered to the patient in fractionated radiation treatment, the treatment outcome is affected by delivery uncertainties such as anatomic change in the patient and daily patient setup error. This study aims at establishing a method to evaluate the dosimetric impact of the anatomic change and patient setup error during head and neck proton therapy. Range variations due to the delivery uncertainties were assessed by calculating water equivalent path length (WEPL) to the distal edge of tumor volume using planning CT and weekly treatment cone-beam CT (CBCT) images. Specifically, mean difference and root mean squared deviation (RMSD) of the distal WEPLs were calculated as the weekly range variations. To accurately calculate the distal WEPLs, an existing CBCT scatter correction algorithm was used. An automatic rigid registration was used to align the planning CT and treatment CBCT images, simulating a six degree-of-freedom couch correction at treatments. The authors conclude that the dosimetric impact of the anatomic change and patient setup error was reasonably captured in the differences of the distal WEPL variation with a range calculation uncertainty of 2%. The proposed method to calculate the distal WEPL using the scatter-corrected CBCT images can be an essential tool to decide the necessity of re-planning in adaptive proton therapy. C1 [Kim, Jihun] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. Harvard Med Sch, Boston, MA 02114 USA. RP Kim, J (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. EM jkim115@mgh.harvard.edu FU NCI Federal Share of program [C06 CA059267] FX This work was supported by the NCI Federal Share of program income earned by Massachusetts General Hospital on C06 CA059267, Proton Therapy Research and Treatment Center. NR 32 TC 0 Z9 0 U1 3 U2 3 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 JAN 7 PY 2017 VL 62 IS 1 BP 59 EP 72 DI 10.1088/1361-6560/62/1/59 PG 14 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA EG8AF UT WOS:000391277100006 ER PT J AU Harshbarger, W Gondi, S Ficarro, SB Hunter, J Udayakumar, D Gurbani, D Singer, WD Liu, Y Li, LB Marto, JA Westover, KD AF Harshbarger, Wayne Gondi, Sudershan Ficarro, Scott B. Hunter, John Udayakumar, Durga Gurbani, Deepak Singer, William D. Liu, Yan Li, Lianbo Marto, Jarrod A. Westover, Kenneth D. TI Structural and Biochemical Analyses Reveal the Mechanism of Glutathione S-Transferase Pi 1 Inhibition by the Anti-cancer Compound Piperlongumine SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CANCER-CELLS; DRUG-RESISTANCE; BREAST-CANCER; GASTRIC-CANCER; TUMOR-CELLS; EXPRESSION; APOPTOSIS; POTENT; GST; JNK AB Glutathione S-transferase pi 1 (GSTP1) is frequently overexpressed in cancerous tumors and is a putative target of the plant compound piperlongumine (PL), which contains two reactive olefins and inhibits proliferation in cancer cells but not normal cells. PL exposure of cancer cells results in increased reactive oxygen species and decreased GSH. These data in tandem with other information led to the conclusion that PL inhibits GSTP1, which forms covalent bonds between GSH and various electrophilic compounds, through covalent adduct formation at the C7-C8 olefin of PL, whereas the C2-C3 olefin of PL was postulated to react with GSH. However, direct evidence for this mechanism has been lacking. To investigate, we solved the X-ray crystal structure of GSTP1 bound to PL and GSH at 1.1 angstrom resolution to rationalize previously reported structure activity relationship studies. Surprisingly, the structure showed that a hydrolysis product of PL (hPL) was conjugated to glutathione at the C7-C8 olefin, and this complex was bound to the active site of GSTP1; no covalent bond formation between hPL and GSTP1 was observed. Mass spectrometry (MS) analysis of the reactions between PL and GSTP1 confirmed that PL does not label GSTP1. Moreover, MS data also indicated that nucleophilic attack on PL at the C2-C3 olefin led to PL hydrolysis. Although hPL inhibits GSTP1 enzymatic activity in vitro, treatment of cells susceptible to PL with hPL did not have significant antiproliferative effects, suggesting that hPL is not membrane-permeable. Altogether, our data suggest a model wherein PL is a prodrug whose intracellular hydrolysis initiates the formation of the hPL-GSH conjugate, which blocks the active site of and inhibits GSTP1 and thereby cancer cell proliferation. C1 [Harshbarger, Wayne; Gondi, Sudershan; Hunter, John; Udayakumar, Durga; Gurbani, Deepak; Singer, William D.; Liu, Yan; Li, Lianbo; Westover, Kenneth D.] Univ Texas Southwestern Med Ctr Dallas, Dept Biochem, Dallas, TX 75390 USA. [Harshbarger, Wayne; Gondi, Sudershan; Hunter, John; Udayakumar, Durga; Gurbani, Deepak; Singer, William D.; Liu, Yan; Li, Lianbo; Westover, Kenneth D.] Univ Texas Southwestern Med Ctr Dallas, Dept Radiat Oncol, Dallas, TX 75390 USA. [Ficarro, Scott B.; Marto, Jarrod A.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Ficarro, Scott B.; Marto, Jarrod A.] Dana Farber Canc Inst, Blais Prote Ctr, Boston, MA 02115 USA. RP Westover, KD (reprint author), Univ Texas Southwestern Med Ctr Dallas, Dept Biochem, Dallas, TX 75390 USA.; Westover, KD (reprint author), Univ Texas Southwestern Med Ctr Dallas, Dept Radiat Oncol, Dallas, TX 75390 USA. EM kenneth.westover@utsouthwestern.edu FU U.S. Department of Energy, Office of Biological and Environmental Research [DEAC02-06CH11357] FX Results shown in this report are derived from work performed at the Argonne National Laboratory, Structural Biology Center at the Advanced Photon Source. Argonne is operated by UChicago Argonne, LLC, for the U.S. Department of Energy, Office of Biological and Environmental Research under Contract DEAC02-06CH11357. NR 46 TC 0 Z9 0 U1 7 U2 7 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD JAN 6 PY 2017 VL 292 IS 1 BP 112 EP 120 DI 10.1074/jbc.M116.750299 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EH2DQ UT WOS:000391578000010 PM 27872191 ER PT J AU Agamasu, C Ghanam, RH Xu, F Sun, Y Chen, YB Saad, JS AF Agamasu, Constance Ghanam, Ruba H. Xu, Fei Sun, Yong Chen, Yabing Saad, Jamil S. TI The Interplay between Calmodulin and Membrane Interactions with the Pleckstrin Homology Domain of Akt SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HUMAN BREAST-CANCER; PROTEIN-KINASE-B; PHOSPHOLIPID-BILAYER NANODISCS; HIGH-RESOLUTION STRUCTURE; HIV-1 MATRIX PROTEIN; TARGET RECOGNITION; PHOSPHATIDYLINOSITOL 3-KINASE; BIOPHYSICAL CHARACTERIZATION; INOSITOL PHOSPHATES; NMR-SPECTROSCOPY AB The Akt protein, a serine/threonine kinase, plays important roles in cell survival, apoptosis, and oncogenes. Akt is translocated to the plasma membrane for activation. Akt-membrane binding is mediated by direct interactions between its pleckstrin homology domain (PHD) and phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P-3). It has been shown that Akt activation in breast cancer cells is modulated by calmodulin (CaM). However, the molecular mechanism of the interplay between CaM and membrane binding is not established. Here, we employed nuclear magnetic resonance (NMR) and biochemical and biophysical techniques to characterize how PI(3,4,5)P-3, CaM, and membrane mimetics (nanodisc) bind to Akt(PHD). We show that PI(3,4,5)P-3 binding to Akt(PHD) displaces the C-terminal lobe of CaM but not the weakly binding N-terminal lobe. However, binding of a PI(3,4,5)P-3-embedded membrane nanodisc to Akt(PHD) with a 10(3)-fold tighter affinity than PI(3,4,5)P-3 is able to completely displace CaM. We also show that Akt(PHD) binds to both layers of the nanodisc, indicating proper incorporation of PI(3,4,5)P-3 on the nanodisc surface. No detectable binding has been observed between Akt(PHD) and PI(3,4,5)P-3-free nanodiscs, demonstrating that PI(3,4,5)P-3 is required for membrane binding, CaM displacement, and Akt activation. Using pancreatic cancer cells, we demonstrate that inhibition of Akt-CaM binding attenuated Akt activation. Our findings support a model by which CaM binds to Akt to facilitate its translocation to the membrane. Elucidation of the molecular details of the interplay between membrane and CaM binding to Akt may help in the development of potential targets to control the pathophysiological processes of cell survival. C1 [Agamasu, Constance; Ghanam, Ruba H.; Saad, Jamil S.] Univ Alabama Birmingham, Dept Microbiol, Birmingham, AL 35294 USA. [Xu, Fei; Sun, Yong; Chen, Yabing] Univ Alabama Birmingham, Dept Pathol, Birmingham, AL 35294 USA. [Sun, Yong; Chen, Yabing] Birmingham Vet Affairs Med Ctr, Res Dept, Birmingham, AL 35294 USA. RP Saad, JS (reprint author), 845 19th St South, Birmingham, AL 35294 USA. EM saad@uab.edu OI Saad, Jamil/0000-0001-9503-6484 FU National Institutes of Health [1S10RR026478] FX We thank the Comprehensive Cancer Center, University of Alabama at Birmingham, for supporting the High-Field NMR facility and the X-ray core facility that houses the Auto-ITC200 (acquired through National Institutes of Health Grant 1S10RR026478). NR 67 TC 0 Z9 0 U1 2 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD JAN 6 PY 2017 VL 292 IS 1 BP 251 EP 263 DI 10.1074/jbc.M116.752816 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EH2DQ UT WOS:000391578000022 PM 27872186 ER PT J AU Danielson, KM Rubio, R Abderazzaq, F Das, S Wang, YYE AF Danielson, Kirsty M. Rubio, Renee Abderazzaq, Fieda Das, Saumya Wang, Yaoyu E. TI High Throughput Sequencing of Extracellular RNA from Human Plasma SO PLOS ONE LA English DT Article ID HUMAN HEPATOCELLULAR-CARCINOMA; MICRORNA EXPRESSION PATTERNS; CHRONIC LYMPHOCYTIC-LEUKEMIA; ACUTE LYMPHOBLASTIC-LEUKEMIA; ACUTE MYELOID-LEUKEMIA; NON-TUMOROUS TISSUES; HUMAN OVARIAN-CANCER; HEART-FAILURE; GENE-EXPRESSION; LUNG-CANCER AB The presence and relative stability of extracellular RNAs (exRNAs) in biofluids has led to an emerging recognition of their promise as 'liquid biopsies' for diseases. Most prior studies on discovery of exRNAs as disease-specific biomarkers have focused on microRNAs (miRNAs) using technologies such as qRT-PCR and microarrays. The recent application of next-generation sequencing to discovery of exRNA biomarkers has revealed the presence of potential novel miRNAs as well as other RNA species such as tRNAs, snoRNAs, piRNAs and lncRNAs in biofluids. At the same time, the use of RNA sequencing for biofluids poses unique challenges, including low amounts of input RNAs, the presence of exRNAs in different compartments with varying degrees of vulnerability to isolation techniques, and the high abundance of specific RNA species (thereby limiting the sensitivity of detection of less abundant species). Moreover, discovery in human diseases often relies on archival biospecimens of varying age and limiting amounts of samples. In this study, we have tested RNA isolation methods to optimize profiling exRNAs by RNA sequencing in individuals without any known diseases. Our findings are consistent with other recent studies that detect microRNAs and ribosomal RNAs as the major exRNA species in plasma. Similar to other recent studies, we found that the landscape of biofluid microRNA transcriptome is dominated by several abundant microRNAs that appear to comprise conserved extracellular miRNAs. There is reasonable correlation of sets of conserved miRNAs across biological replicates, and even across other data sets obtained at different investigative sites. Conversely, the detection of less abundant miRNAs is far more dependent on the exact methodology of RNA isolation and profiling. This study highlights the challenges in detecting and quantifying less abundant plasma miRNAs in health and disease using RNA sequencing platforms. C1 [Danielson, Kirsty M.; Das, Saumya] Massachusetts Gen Hosp, Cardiovasc Inst, Boston, MA 02114 USA. [Rubio, Renee; Abderazzaq, Fieda; Wang, Yaoyu E.] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Ctr Canc Computat Biol, Boston, MA 02115 USA. RP Das, S (reprint author), Massachusetts Gen Hosp, Cardiovasc Inst, Boston, MA 02114 USA.; Wang, YYE (reprint author), Dana Farber Canc Inst, Dept Biostat & Computat Biol, Ctr Canc Computat Biol, Boston, MA 02115 USA. EM sdas@mgh.harvard.edu; yewang@jimmy.harvard.edu FU National Institutes of Health [UH2TR000901]; Dana-Farber Strategic Plan Initiative FX KMD and SD are supported by National Institutes of Health UH2TR000901; RR, FA, and YEW are supported by Dana-Farber Strategic Plan Initiative. NR 83 TC 0 Z9 0 U1 10 U2 10 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 6 PY 2017 VL 12 IS 1 AR e0164644 DI 10.1371/journal.pone.0164644 PG 18 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EH3AX UT WOS:000391641500004 PM 28060806 ER PT J AU Rhodes, CM Chang, YC Regan, S Triant, VA AF Rhodes, Corinne M. Chang, Yuchiao Regan, Susan Triant, Virginia A. TI Non-Communicable Disease Preventive Screening by HIV Care Model SO PLOS ONE LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; ACUTE MYOCARDIAL-INFARCTION; CARDIOVASCULAR RISK-FACTORS; QUALITY-OF-CARE; ANTIRETROVIRAL THERAPY; PHYSICIAN EXPERIENCE; ADMINISTRATIVE DATA; POSITIVE PATIENTS; INFECTED PATIENTS; SHARED CARE AB Importance The Human Immunodeficiency Virus (HIV) epidemic has evolved, with an increasing non-communicable disease (NCD) burden emerging and need for long-term management, yet there are limited data to help delineate the optimal care model to screen for NCDs for this patient population. Objective The primary aim was to compare rates of NCD preventive screening in persons living with HIV/AIDS (PLWHA) by type of HIV care model, focusing on metabolic/cardiovascular disease (CVD) and cancer screening. We hypothesized that primary care models that included generalists would have higher preventive screening rates. Design Prospective observational cohort study. Setting Partners HealthCare System (PHS) encompassing Brigham & Women's Hospital, Massachusetts General Hospital, and affiliated community health centers. Participants PLWHA age > 18 engaged in active primary care at PHS. Exposure HIV care model categorized as infectious disease (ID) providers only, generalist providers only, or ID plus generalist providers. Main Outcome(s) and Measures(s) Odds of screening for metabolic/CVD outcomes including hypertension (HTN), obesity, hyperlipidemia (HL), and diabetes (DM) and cancer including colorectal cancer (CRC), cervical cancer, and breast cancer. Results In a cohort of 1565 PLWHA, distribution by HIV care model was 875 ID (56%), 90 generalists (6%), and 600 ID plus generalists (38%). Patients in the generalist group had lower odds of viral suppression but similar CD4 counts and ART exposure as compared with ID and ID plus generalist groups. In analyses adjusting for sociodemographic and clinical covariates and clustering within provider, there were no significant differences in metabolic/CVD or cancer screening rates among the three HIV care models. Conclusions There were no notable differences in metabolic/CVD or cancer screening rates by HIV care model after adjusting for sociodemographic and clinical factors. These findings suggest that HIV patients receive similar preventive health care for NCDs independent of HIV care model. C1 [Rhodes, Corinne M.] Univ Penn, Sch Med, Div Gen Internal Med, Philadelphia, PA 19104 USA. [Chang, Yuchiao; Regan, Susan; Triant, Virginia A.] Massachusetts Gen Hosp, Div Gen Internal Med, Boston, MA 02114 USA. [Chang, Yuchiao; Regan, Susan; Triant, Virginia A.] Harvard Med Sch, Boston, MA USA. [Triant, Virginia A.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. RP Rhodes, CM (reprint author), Univ Penn, Sch Med, Div Gen Internal Med, Philadelphia, PA 19104 USA. EM corinne.rhodes@uphs.upenn.edu FU Health Resources and Service Administration [T32 HP102]; Tyoichi Sasakawa Fellowship Fund; Harvard Catalyst Disparities Enrichment Grant; National Institute of Allergy and Infectious Diseases [K01AI73109] FX This work was supported by Health Resources and Service Administration T32 HP102 (CMR), Tyoichi Sasakawa Fellowship Fund (CMR), Harvard Catalyst Disparities Enrichment Grant (CMR), National Institute of Allergy and Infectious Diseases K01AI73109 (VAT). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 55 TC 0 Z9 0 U1 4 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 6 PY 2017 VL 12 IS 1 AR e0169246 DI 10.1371/journal.pone.0169246 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EH3AX UT WOS:000391641500070 PM 28060868 ER PT J AU Ku, SY Rosario, S Wang, YQ Mu, P Seshadri, M Goodrich, ZW Goodrich, MM Labbe, DP Gomez, EC Wang, JM Long, HW Xu, B Brown, M Loda, M Sawyers, CL Ellis, L Goodrich, DW AF Ku, Sheng Yu Rosario, Spencer Wang, Yanqing Mu, Ping Seshadri, Mukund Goodrich, Zachary W. Goodrich, Maxwell M. Labbe, David P. Gomez, Eduardo Cortes Wang, Jianmin Long, Henry W. Xu, Bo Brown, Myles Loda, Massimo Sawyers, Charles L. Ellis, Leigh Goodrich, David W. TI Rb1 and Trp53 cooperate to suppress prostate cancer lineage plasticity, metastasis, and antiandrogen resistance SO SCIENCE LA English DT Article ID SMALL-CELL CARCINOMA; MOUSE MODEL; PTEN; TUMORIGENESIS; DEFICIENCY; EXPRESSION; GENERATION; DELETION; PATHWAY; EZH2 AB Prostate cancer relapsing from antiandrogen therapies can exhibit variant histology with altered lineage marker expression, suggesting that lineage plasticity facilitates therapeutic resistance. The mechanisms underlying prostate cancer lineage plasticity are incompletely understood. Studying mouse models, we demonstrate that Rb1 loss facilitates lineage plasticity and metastasis of prostate adenocarcinoma initiated by Pten mutation. Additional loss of Trp53 causes resistance to antiandrogen therapy. Gene expression profiling indicates that mouse tumors resemble human prostate cancer neuroendocrine variants; both mouse and human tumors exhibit increased expression of epigenetic reprogramming factors such as Ezh2 and Sox2. Clinically relevant Ezh2 inhibitors restore androgen receptor expression and sensitivity to antiandrogen therapy. These findings uncover genetic mutations that enable prostate cancer progression; identify mouse models for studying prostate cancer lineage plasticity; and suggest an epigenetic approach for extending clinical responses to antiandrogen therapy. C1 [Ku, Sheng Yu; Rosario, Spencer; Wang, Yanqing; Seshadri, Mukund; Goodrich, Zachary W.; Goodrich, Maxwell M.; Ellis, Leigh; Goodrich, David W.] RPCI, Dept Pharmacol & Therapeut, Buffalo, NY 14263 USA. [Mu, Ping] MSKCC, Human Oncol & Pathogenesis Program, New York, NY 10065 USA. [Labbe, David P.] Dana Farber Canc Inst, Ctr Funct Canc Epigenet, Boston, MA 02115 USA. [Goodrich, Zachary W.; Labbe, David P.; Wang, Jianmin] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Wang, Yanqing; Goodrich, Maxwell M.] RPCI, Dept Biostat & Bioinformat, Buffalo, NY 14263 USA. [Labbe, David P.; Xu, Bo] RPCI, Dept Pathol, Buffalo, NY 14263 USA. [Seshadri, Mukund; Labbe, David P.; Loda, Massimo] Dana Farber Canc Inst, Ctr Mol Oncol Pathol, Dept Med Oncol, Boston, MA 02115 USA. [Seshadri, Mukund; Gomez, Eduardo Cortes; Wang, Jianmin] Harvard Med Sch, Brigham & Womens Hosp, Boston, MA 02115 USA. [Gomez, Eduardo Cortes; Wang, Jianmin] Harvard Med Sch, Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Loda, Massimo] Kings Coll London, Div Canc Studies, London SE1 9RT, England. [Rosario, Spencer; Labbe, David P.; Xu, Bo; Loda, Massimo] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. RP Ellis, L; Goodrich, DW (reprint author), RPCI, Dept Pharmacol & Therapeut, Buffalo, NY 14263 USA. EM leigh.ellis@roswellpark.org; david.goodrich@roswellpark.org FU National Cancer Institute (NCI) [R21 CA179907, R01 CA70292, R01 CA155169, R01 CA19387, P50 CA092629]; Congressionally Directed Medical Research Programs Prostate Cancer Research Program Postdoctoral Prostate Cancer Training Award [PC141607]; Prostate Cancer Foundation; Roswell Park Alliance Foundation; Cancer Research Society; Canadian Institute of Health Research; Howard Hughes Medical Institute [SU2C/AACR DT0712]; NCI RPCI Cancer Center [P30 CA016056]; NCI MSKCC Cancer Center [P30 CA008748, P3 CA008748]; ORIC Pharmaceuticals FX RNA-seq data generated in this study are deposited in the Gene Expression Omnibus (accession no. GSE90891). We acknowledge the RPCI writing group for critical reading of the manuscript and helpful comments. We thank H. Baumann for important assistance with multispectral imaging. The work was supported by funding from the National Cancer Institute (NCI) (grants R21 CA179907 and R01 CA70292 to D.W.G.; R01 CA155169, R01 CA19387, and P50 CA092629 to C.L.S.). P.M. was supported by a Congressionally Directed Medical Research Programs Prostate Cancer Research Program Postdoctoral Prostate Cancer Training Award (PC141607). L.E. and D.P.L. were supported by Prostate Cancer Foundation Young Investigator Awards. D.W.G. and M.S. were supported by the Roswell Park Alliance Foundation. D.P.L. is a recipient of a Scholarship for the Next Generation of Scientists from the Cancer Research Society and a Canadian Institute of Health Research Fellowship. C.L.S. was supported by the Howard Hughes Medical Institute (SU2C/AACR DT0712). The study was supported by the NCI RPCI Cancer Center Support Grant (P30 CA016056) and the NCI MSKCC Cancer Center Support Grant (P30 CA008748, P3 CA008748). C.L.S. is a co-inventor of enzalutamide and may be entitled to royalties. Enzalutamide is commercially available from Selleck Chemicals. C.L.S. serves on the board of directors of Novartis and is a paid consultant to ORIC Pharmaceuticals. NR 29 TC 2 Z9 2 U1 9 U2 9 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 JAN 6 PY 2017 VL 355 IS 6320 BP 78 EP 83 DI 10.1126/science.aah4199 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EH4KK UT WOS:000391739900047 PM 28059767 ER PT J AU Ballandras-Colas, A Maskell, DP Serrao, E Locke, J Swuec, P Jonsson, SR Kotecha, A Cook, NJ Pye, VE Taylor, IA Andresdottir, V Engelman, AN Costa, A Cherepanov, P AF Ballandras-Colas, Allison Maskell, Daniel P. Serrao, Erik Locke, Julia Swuec, Paolo Jonsson, Stefan R. Kotecha, Abhay Cook, Nicola J. Pye, Valerie E. Taylor, Ian A. Andresdottir, Valgerdur Engelman, Alan N. Costa, Alessandro Cherepanov, Peter TI A supramolecular assembly mediates lentiviral DNA integration SO SCIENCE LA English DT Article ID HIV-1 INTEGRASE; CRYSTAL-STRUCTURE; RETROVIRAL INTEGRATION; IN-VITRO; PROTEIN; INTASOME; DOMAIN; BINDING AB Retroviral integrase (IN) functions within the intasome nucleoprotein complex to catalyze insertion of viral DNA into cellular chromatin. Using cryo-electron microscopy, we now visualize the functional maedi-visna lentivirus intasome at 4.9 angstrom resolution. The intasome comprises a homo-hexadecamer of IN with a tetramer-of-tetramers architecture featuring eight structurally distinct types of IN protomers supporting two catalytically competent subunits. The conserved intasomal core, previously observed in simpler retroviral systems, is formed between two IN tetramers, with a pair of C-terminal domains from flanking tetramers completing the synaptic interface. Our results explain how HIV-1 IN, which self-associates into higher-order multimers, can form a functional intasome, reconcile the bulk of early HIV-1 IN biochemical and structural data, and provide a lentiviral platform for design of HIV-1 IN inhibitors. C1 [Ballandras-Colas, Allison; Maskell, Daniel P.; Cook, Nicola J.; Pye, Valerie E.; Cherepanov, Peter] Francis Crick Inst, Chromatin Struct & Mobile DNA, London NW1 1AT, England. [Serrao, Erik; Engelman, Alan N.] Dana Farber Canc Inst, Dept Canc Immunol & Virol, Boston, MA 02215 USA. [Serrao, Erik; Engelman, Alan N.] Harvard Med Sch, Dept Med, Boston, MA 02115 USA. [Locke, Julia; Swuec, Paolo; Costa, Alessandro] Francis Crick Inst, Macromol Machines Lab, London NW1 1AT, England. [Jonsson, Stefan R.; Andresdottir, Valgerdur] Univ Iceland, Inst Expt Pathol, IS-112 Reykjavik, Iceland. [Kotecha, Abhay] Univ Oxford, Div Struct Biol, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England. [Taylor, Ian A.] Francis Crick Inst, Macromol Struct Lab, London NW1 1AT, England. [Cherepanov, Peter] Imperial Coll London, Div Med, London W2 1PG, England. [Maskell, Daniel P.] Univ Leeds, Sch Mol & Cellular Biol, Leeds LS2 9JT, W Yorkshire, England. RP Cherepanov, P (reprint author), Francis Crick Inst, Chromatin Struct & Mobile DNA, London NW1 1AT, England.; Costa, A (reprint author), Francis Crick Inst, Macromol Machines Lab, London NW1 1AT, England.; Cherepanov, P (reprint author), Imperial Coll London, Div Med, London W2 1PG, England. EM alessandro.costa@crick.ac.uk; peter.cherepanov@crick.ac.uk RI Cherepanov, Peter/F-6859-2010; OI Cherepanov, Peter/0000-0002-0634-538X; Pye, Valerie E/0000-0001-9616-2992 FU NIH [GM082251, AI070042]; Francis Crick Institute; Wellcome Trust; Icelandic Research Fund; U.K. Department for Business, Integration, and Skills [ST/K00042X/1, ST/K00087X/1, ST/K003267/1]; Wellcome Trust [060208/Z/00/Z, 093305/Z/10/Z] FX We thank G. Schoehn for help with preliminary cryo-EM; the staff of the Diamond beamlines I04 and I04-1 for assistance with x-ray data collection; P. Afonine for advice on real-space refinement; L. Collinson, R. Carzaniga, T. Pape, P. Walker, and A. Purkiss for EM, x-ray crystallography, and software support; L. Heck for expert assistance with the computer cluster; and G. Maertens for comments on the manuscript. Data presented in this manuscript are tabulated in the main paper and in the supplementary materials. The cryo-EM maps, pseudo-atomic models, and x-ray structures were deposited with the Protein Data Bank and the EM Data Bank with accessions EMD-4138, EMD-4139, PDB-5M0Q, PDB-5M0R, PDB-5LLJ, and PDB-5T3A; the integration site sequencing data were deposited with National Center of Biotechnology Information, NIH, GEO repository under accession GSE87786. This work was supported by NIH grants GM082251 and AI070042 (P.C. and A.N.E.), The Francis Crick Institute (P.C. and A.C.), The Wellcome Trust (A.K.), and Icelandic Research Fund (V.A. and S.R.J.). We acknowledge the use of the Durham University DiRAC Data Centric system, which is supported by capital grants ST/K00042X/1, ST/K00087X/1, and ST/K003267/1 from the U.K. Department for Business, Integration, and Skills. The Division of Structural Biology Particle Imaging Center EM Facility at University of Oxford was founded by The Wellcome Trust Joint Infrastructure Fund (JIF) award 060208/Z/00/Z and equipment grant 093305/Z/10/Z. NR 25 TC 2 Z9 2 U1 7 U2 7 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 JAN 6 PY 2017 VL 355 IS 6320 BP 93 EP 95 DI 10.1126/science.aah7002 PG 3 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EH4KK UT WOS:000391739900050 PM 28059770 ER PT J AU Liu, SJ Horlbeck, MA Cho, SW Birk, HS Malatesta, M He, D Attenello, FJ Villalta, JE Cho, MY Chen, YW Mandegar, MA Olvera, MP Gilbert, LA Conklin, BR Chang, HY Weissman, JS Lim, DA AF Liu, S. John Horlbeck, Max A. Cho, Seung Woo Birk, Harjus S. Malatesta, Martina He, Daniel Attenello, Frank J. Villalta, Jacqueline E. Cho, Min Y. Chen, Yuwen Mandegar, Mohammad A. Olvera, Michael P. Gilbert, Luke A. Conklin, Bruce R. Chang, Howard Y. Weissman, Jonathan S. Lim, Daniel A. TI CRISPRi-based genome-scale identification of functional long noncoding RNA loci in human cells SO SCIENCE LA English DT Article ID GENE-EXPRESSION; STEM-CELLS; DIFFERENTIATION; TRANSCRIPTION; EVOLUTION; CANCER; LNCRNA; INTERFERENCE; ACTIVATION; ENHANCERS AB The human genome produces thousands of long noncoding RNAs (lncRNAs)-transcripts >200 nucleotides long that do not encode proteins. Although critical roles in normal biology and disease have been revealed for a subset of lncRNAs, the function of the vast majority remains untested. We developed a CRISPR interference (CRISPRi) platform targeting 16,401 lncRNA loci in seven diverse cell lines, including six transformed cell lines and human induced pluripotent stem cells (iPSCs). Large-scale screening identified 499 lncRNA loci required for robust cellular growth, of which 89% showed growth-modifying function exclusively in one cell type. We further found that lncRNA knockdown can perturb complex transcriptional networks in a cell type-specific manner. These data underscore the functional importance and cell type specificity of many lncRNAs. C1 [Liu, S. John; Birk, Harjus S.; Malatesta, Martina; He, Daniel; Attenello, Frank J.; Lim, Daniel A.] Univ Calif San Francisco, Dept Neurol Surg, San Francisco, CA 94143 USA. [Liu, S. John; Birk, Harjus S.; Malatesta, Martina; He, Daniel; Attenello, Frank J.; Lim, Daniel A.] Univ Calif San Francisco, Eli & Edythe Broad Ctr Regenerat Med & Stem Cell, San Francisco, CA 94143 USA. [Horlbeck, Max A.; Villalta, Jacqueline E.; Cho, Min Y.; Chen, Yuwen; Mandegar, Mohammad A.; Olvera, Michael P.; Gilbert, Luke A.; Conklin, Bruce R.; Weissman, Jonathan S.] Univ Calif San Francisco, Dept Cellular & Mol Pharmacol, San Francisco, CA 94143 USA. [Horlbeck, Max A.; Villalta, Jacqueline E.; Cho, Min Y.; Chen, Yuwen; Gilbert, Luke A.; Weissman, Jonathan S.] Univ Calif San Francisco, Howard Hughes Med Inst, San Francisco, CA 94143 USA. [Horlbeck, Max A.; Villalta, Jacqueline E.; Cho, Min Y.; Chen, Yuwen; Gilbert, Luke A.; Weissman, Jonathan S.] Univ Calif San Francisco, Calif Inst Quantitat Biomed Res, San Francisco, CA 94143 USA. [Horlbeck, Max A.; Villalta, Jacqueline E.; Cho, Min Y.; Chen, Yuwen; Gilbert, Luke A.; Weissman, Jonathan S.] Univ Calif San Francisco, Ctr RNA Syst Biol, San Francisco, CA 94143 USA. [Conklin, Bruce R.] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. [Conklin, Bruce R.] Gladstone Inst Cardiovasc Dis, San Francisco, CA USA. [Cho, Seung Woo; Chang, Howard Y.] Stanford Univ, Ctr Personal Dynam Regulomes, Stanford, CA 94305 USA. [Lim, Daniel A.] San Francisco VA Med Ctr, San Francisco, CA USA. RP Lim, DA (reprint author), Univ Calif San Francisco, Dept Neurol Surg, San Francisco, CA 94143 USA.; Lim, DA (reprint author), Univ Calif San Francisco, Eli & Edythe Broad Ctr Regenerat Med & Stem Cell, San Francisco, CA 94143 USA.; Weissman, JS (reprint author), Univ Calif San Francisco, Dept Cellular & Mol Pharmacol, San Francisco, CA 94143 USA.; Weissman, JS (reprint author), Univ Calif San Francisco, Howard Hughes Med Inst, San Francisco, CA 94143 USA.; Weissman, JS (reprint author), Univ Calif San Francisco, Calif Inst Quantitat Biomed Res, San Francisco, CA 94143 USA.; Weissman, JS (reprint author), Univ Calif San Francisco, Ctr RNA Syst Biol, San Francisco, CA 94143 USA.; Lim, DA (reprint author), San Francisco VA Med Ctr, San Francisco, CA USA. EM jonathan.weissman@ucsf.edu; daniel.lim@ucsf.edu FU NIH [1R01NS091544-01A1, F30 NS092319-01, P50 GM102706, U01 CA168370, R01 DA036858, R35-CA209919, P50-HG007735, U01HL100406, P01HL089707, R01HL130533]; VA grant [5I01 BX000252-07]; NIH Specialized Programs of Research Excellence Developmental Research Program subaward; Shurl and Kay Curci Foundation; LoGlio Foundation; Hana Jabsheh Initiative; Howard Hughes Medical Institutes; Gladstone Institutes; NIH/NCI Pathway to Independence Award [K99CA204602] FX We thank the members of the Lim and Weissman labs, particularly A. Fields, J. Dunn, M. DeVera, M. Cui, and D. Wu, for helpful discussions and assistance; A. Truong for assistance with iPS cell culturing; N. Salomonis for iPSC RNA-seq data; E. Chow and D. Bogdanoff of the UCSF Center for Advanced Technology for sequencing assistance; and L. Bruhn, D. Ryan, L. Fairbairn, and P. Tsang of Agilent Technologies for their assistance on the design and synthesis of oligonucleotide pools. Supported by NIH grant 1R01NS091544-01A1, VA grant 5I01 BX000252-07, NIH Specialized Programs of Research Excellence Developmental Research Program subaward, the Shurl and Kay Curci Foundation, the LoGlio Foundation, and the Hana Jabsheh Initiative (D.A.L.); NIH grant F30 NS092319-01 (S.J.L.); the Howard Hughes Medical Institutes and NIH grants P50 GM102706, U01 CA168370, and R01 DA036858 (M.A.H., J.E.V., M.Y.C., Y.C., L.A.G., and J.S.W.); NIH grants R35-CA209919 and P50-HG007735 (S.W.C. and H.Y.C.); the Gladstone Institutes and NIH grants U01HL100406, P01HL089707, and R01HL130533 (B.R.C. and M.A.M.); and NIH/NCI Pathway to Independence Award K99CA204602 (L.A.G.). Oligonucleotide pools were provided courtesy of the Innovative Genomics Initiative. M.A.H., L.A.G., and J.S.W. are inventors on patent application PCT/US15/40449 submitted by UCSF that covers CRISPRi library design. The human iPSC line WTC expressing the CRISPRi system (WTC-CRISPRi Gen IC) is available from B.R.C. under material transfer agreement from the Gladstone Institutes. The parental iPSC line (WTC) is available from the Coriell Biorepository #GM25256. The CRiNCL libraries are available from J.S.W. (via Addgene for academic users) under a material transfer agreement from UCSF and Agilent Technologies. M.A.H., L.A.G., and J.S.W. are inventors on patent application PCT/US15/40449 submitted by UCSF that covers CRISPRi library design. J.S.W. is a founder of KSQ Therapeutics, a company that uses CRISPR-based screening to identify therapeutic targets. H.Y.C. is a co-founder of Epinomics Inc. and served on the scientific advisory board of RaNA Therapeutics. M.A.H. and L.A.G. are consultants for KSQ Therapeutics. NR 61 TC 0 Z9 0 U1 26 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 JAN 6 PY 2017 VL 355 IS 6320 AR aah7111 DI 10.1126/science.aah7111 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EH4KK UT WOS:000391739900002 ER PT J AU Zhou, J Wu, Z Wong, G Pectasides, E Nagaraja, A Stachler, M Zhang, HK Chen, T Zhang, HS Liu, JB Xu, XS Sicinska, E Sanchez-Vega, F Rustgi, AK Diehl, JA Wong, KK Bass, AJ AF Zhou, Jin Wu, Zhong Wong, Gabrielle Pectasides, Eirini Nagaraja, Ankur Stachler, Matthew Zhang, Haikuo Chen, Ting Zhang, Haisheng Liu, Jie Bin Xu, Xinsen Sicinska, Ewa Sanchez-Vega, Francisco Rustgi, Anil K. Diehl, J. Alan Wong, Kwok-Kin Bass, Adam J. TI CDK4/6 or MAPK blockade enhances efficacy of EGFR inhibition in oesophageal squamous cell carcinoma SO NATURE COMMUNICATIONS LA English DT Article ID GROWTH-FACTOR-RECEPTOR; MUTANT LUNG-CANCER; MESENCHYMAL TRANSITION; KINASE INHIBITORS; ACQUIRED-RESISTANCE; COLORECTAL-CANCER; GEFITINIB; SENSITIVITY; MUTATIONS; HEAD AB Oesophageal squamous cell carcinoma is a deadly disease where systemic therapy has relied upon empiric chemotherapy despite the presence of genomic alterations pointing to candidate therapeutic targets, including recurrent amplification of the gene encoding receptor tyrosine kinase epidermal growth factor receptor (EGFR). Here, we demonstrate that EGFR-targeting small-molecule inhibitors have efficacy in EGFR-amplified oesophageal squamous cell carcinoma (ESCC), but may become quickly ineffective. Resistance can occur following the emergence of epithelial-mesenchymal transition and by reactivation of the mitogen-activated protein kinase (MAPK) pathway following EGFR blockade. We demonstrate that blockade of this rebound activation with MEK (mitogen-activated protein kinase kinase) inhibition enhances EGFR inhibitor-induced apoptosis and cell cycle arrest, and delays resistance to EGFR monotherapy. Furthermore, genomic profiling shows that cell cycle regulators are altered in the majority of EGFR-amplified tumours and a combination of cyclin-dependent kinase 4/6 (CDK4/6) and EGFR inhibitors prevents the emergence of resistance in vitro and in vivo. These data suggest that upfront combination strategies targeting EGFR amplification, guided by adaptive pathway reactivation or by co-occurring genomic alterations, should be tested clinically. C1 [Zhou, Jin; Wu, Zhong; Wong, Gabrielle; Pectasides, Eirini; Nagaraja, Ankur; Stachler, Matthew; Zhang, Haikuo; Chen, Ting; Zhang, Haisheng; Liu, Jie Bin; Xu, Xinsen; Sicinska, Ewa; Wong, Kwok-Kin; Bass, Adam J.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Sicinska, Ewa] Dana Farber Canc Inst, Dept Mol Oncol Pathol, Boston, MA 02215 USA. [Sanchez-Vega, Francisco] Mem Sloan Kettering Canc Ctr, Div Computat Biol, New York, NY 10065 USA. [Rustgi, Anil K.] Univ Penn, Sch Med, Dept Med, Philadelphia, PA 19104 USA. [Diehl, J. Alan] Med Univ South Carolina, Dept Biochem & Mol Biol, Hollings Canc Ctr, Charleston, SC 29425 USA. [Wong, Kwok-Kin; Bass, Adam J.] Harvard Med Sch, Dept Med, Boston, MA 02215 USA. [Bass, Adam J.] Broad Inst MIT & Harvard, Canc Program, Cambridge, MA 02139 USA. [Bass, Adam J.] Brigham & Womens Hosp, Dept Med, 75 Francis St, Boston, MA 02115 USA. RP Bass, AJ (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA.; Bass, AJ (reprint author), Harvard Med Sch, Dept Med, Boston, MA 02215 USA.; Bass, AJ (reprint author), Broad Inst MIT & Harvard, Canc Program, Cambridge, MA 02139 USA.; Bass, AJ (reprint author), Brigham & Womens Hosp, Dept Med, 75 Francis St, Boston, MA 02115 USA. EM adam_bass@dfci.harvard.edu FU NIH [R01 CA187119, R01 CA196932, P01 CA098101, R01 DK060694, R01 DK056645]; American Cancer Society [RP-10-033-01-CCE, P30 DK050306] FX We thank N. Sethi and other members of the Bass laboratory, and X. Zhang of the Meyerson laboratory for discussions. A.J.B. was supported by the NIH Grants R01 CA187119 and R01 CA196932. A.K.R., J.A.D., K.-K.W. and A.J.B. were supported by the NIH Grant P01 CA098101 and its Molecular Pathology/Imaging and Molecular Biology/Gene Expression Core Facilities. A.K.R. was also supported by the NIH Grants R01 DK060694 and R01 DK056645, American Cancer Society RP-10-033-01-CCE and P30 DK050306. NR 42 TC 0 Z9 0 U1 5 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD JAN 6 PY 2017 VL 8 AR 13897 DI 10.1038/ncomms13897 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EG8KP UT WOS:000391306000001 PM 28059068 ER PT J AU Hai, J Zhu, CQ Wang, T Organ, SL Shepherd, FA Tsao, MS AF Hai, Josephine Zhu, Chang-Qi Wang, Tao Organ, Shawna L. Shepherd, Frances A. Tsao, Ming-Sound TI TRIM14 is a Putative Tumor Suppressor and Regulator of Innate Immune Response in Non-Small Cell Lung Cancer SO SCIENTIFIC REPORTS LA English DT Article ID NON-HODGKINS-LYMPHOMA; GENE-EXPRESSION; SQUAMOUS-CELL; SIGNALING PATHWAYS; DOWN-REGULATION; E3 LIGASE; APOPTOSIS; SIGNATURE; CARCINOMA; OVEREXPRESSION AB Non-small-cell lung carcinoma (NSCLC) accounts for 85% of malignant lung tumors and is the leading cause of cancer deaths. Our group previously identified Tripartite Motif 14 (TRIM14) as a component of a prognostic multigene expression signature for NSCLC. Little is known about the function of TRIM14 protein in normal or disease states. We investigated the functional and prognostic role of TRIM14 in NSCLC using in vitro and in vivo perturbation model systems. Firstly, a pooled RNAi screen identified TRIM14 to effect cell proliferation/survival in NSCLC cells. Secondly, silencing of TRIM14 expression significantly enhanced tumor growth in NSCLC xenograft mouse models, while exogenous TRIM14 expression attenuated tumorigenesis. In addition, differences in apoptotic activity between TRIM14-deficient and control tumors suggests that TRIM14 tumor suppressor activity may depend on cell death signaling pathways. TRIM14-deficient cell lines showed both resistance to hypoxiainduced cell death and attenuation of interferon response via STAT1 signaling. Consistent with these phenotypes, multivariate analyses on published mRNA expression datasets of over 600 primary NSCLCs demonstrated that low TRIM14 mRNA levels are significantly associated with poorer prognosis in early stage NSCLC patients. Our functional data therefore establish a novel tumor suppressive role for TRIM14 in NSCLC progression. C1 [Hai, Josephine; Zhu, Chang-Qi; Wang, Tao; Organ, Shawna L.; Shepherd, Frances A.; Tsao, Ming-Sound] Univ Hlth Network, Princess Margaret Canc Ctr, Toronto, ON, Canada. [Hai, Josephine; Tsao, Ming-Sound] Univ Toronto, Dept Med Biophys, Toronto, ON, Canada. [Hai, Josephine] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Hai, Josephine] Harvard Med Sch, Dept Med, Boston, MA USA. RP Tsao, MS (reprint author), Univ Hlth Network, Princess Margaret Canc Ctr, Toronto, ON, Canada.; Tsao, MS (reprint author), Univ Toronto, Dept Med Biophys, Toronto, ON, Canada. EM Ming.Tsao@uhn.on.ca FU Canadian Cancer Society Research Institute [020527]; Ontario Ministry of Health and Long Term Care; Princess Margaret Cancer Foundation; Terry Fox Foundation Training Program in Molecular Pathology of Cancer at CIHR; M. Qasim Choksi Chair in Lung Cancer Translational Research; Scott Taylor Chair in Lung Cancer Research FX The authors thank Drs Scott Douglas, Kevin Brown, and Jeifei Tong for helpful discussions and analyses. We thank Drs Dan Cojocari and Brad Wouters for making the HypOxygen H85 workstation available to us. This study was supported by the Canadian Cancer Society Research Institute grant #020527, the Ontario Ministry of Health and Long Term Care, and the Princess Margaret Cancer Foundation. Dr. Wang was supported by the Terry Fox Foundation Training Program in Molecular Pathology of Cancer at CIHR. Dr. Tsao holds the M. Qasim Choksi Chair in Lung Cancer Translational Research. Dr. Shepherd holds the Scott Taylor Chair in Lung Cancer Research. NR 36 TC 0 Z9 0 U1 7 U2 7 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 JAN 6 PY 2017 VL 7 AR 39692 DI 10.1038/srep39692 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EG8LH UT WOS:000391308000001 PM 28059079 ER PT J AU Cutler, CS Koreth, J Ritz, J AF Cutler, Corey S. Koreth, John Ritz, Jerome TI Mechanistic approaches for the prevention and treatment of chronic GVHD SO BLOOD LA English DT Review ID VERSUS-HOST-DISEASE; REGULATORY T-CELLS; BONE-MARROW-TRANSPLANTATION; UNRELATED DONOR TRANSPLANTATION; CHIMERIC MONOCLONAL-ANTIBODY; FOLLICULAR HELPER-CELLS; ACUTE MYELOID-LEUKEMIA; B-CELLS; POSTTRANSPLANTATION CYCLOPHOSPHAMIDE; PHASE-II AB Clinical outcomes for patients undergoing allogeneic hematopoietic stem cell transplantation continue to improve, but chronic graft-versus-host disease (GVHD) remains a common toxicity and major cause of nonrelapse morbidity and mortality. Treatment of chronic GVHD has previously relied primarily on corticosteroids and other broadly immune suppressive agents. However, conventional immune suppressive agents have limited clinical efficacy in chronic GVHD, and prolonged immune suppressive treatments result in additional toxicities that further limit clinical recovery from transplant and return to normal daily function. Recent advances in our understanding of the immune pathology of chronic GVHD offer the possibility that new therapeutic approaches can be directed in more precise ways to target specific immunologic mechanisms and pathways. In this review, we briefly summarize current standard treatment options and present new therapeutic approaches that are supported by preclinical studies and earlyphase clinical trials suggesting that these approaches may have clinical utility for treatment or prevention of chronic GVHD. Further evaluation of these new therapeutic options in well-designed prospective multicenter trials are needed to identify the most effective new agents and improve outcomes for patients with chronic GVHD. C1 [Cutler, Corey S.; Koreth, John; Ritz, Jerome] Brigham & Womens Hosp, Harvard Med Sch, Dana Farber Canc Inst, Div Hematol Malignancies, Boston, MA USA. RP Ritz, J (reprint author), Dana Farber Canc Inst, 450 Brookline Ave,M530, Boston, MA 02215 USA. EM jerome_ritz@dfci.harvard.edu FU National Institutes of Health, National Cancer Institute [P01CA142106, R01CA183559, R01CA183560] FX This study was supported by National Institutes of Health, National Cancer Institute grants P01CA142106, R01CA183559, and R01CA183560. NR 100 TC 1 Z9 1 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD JAN 5 PY 2017 VL 129 IS 1 BP 22 EP 29 DI 10.1182/blood-2016-08-686659 PG 8 WC Hematology SC Hematology GA EO2LF UT WOS:000396527300009 PM 27821505 ER PT J AU Valerio, DG Xu, HM Eisold, ME Woolthuis, CM Pandita, TK Armstrong, SA AF Valerio, Daria G. Xu, Haiming Eisold, Meghan E. Woolthuis, Carolien M. Pandita, Tej K. Armstrong, Scott A. TI Histone acetyltransferase activity of MOF is required for adult but not early fetal hematopoiesis in mice SO BLOOD LA English DT Article ID STRAND BREAK REPAIR; GROUP GENE RAE28; STEM-CELLS; DEFINITIVE HEMATOPOIESIS; H4 ACETYLATION; LYSINE 16; IN-VIVO; C-MYB; DROSOPHILA; PROTEIN AB K(lysine) acetyltransferase 8 (KAT8, also known as MOF) mediates the acetylation of histone H4 at lysine 16 (H4K16ac) and is crucial for murine embryogenesis. Lysine acetyltransferases have been shown to regulate various stages of normal hematopoiesis. However, the function of MOF in hematopoietic stem cell (HSC) development has not yet been elucidated. We set out to study the role of MOF in general hematopoiesis by using a Vav1-cre-induced conditional murine Mofknockout system and found that MOF is critical for hematopoietic cell maintenance and HSC engraftment capacity in adult hematopoiesis. Rescue experiments with a MOF histone acetyltransferase domain mutant illustrated the requirement for MOF acetyltransferase activity in the clonogenic capacity of HSCs and progenitors. In stark contrast, fetal steadystate hematopoiesis at embryonic day (E) 14.5 was not affected by homozygous Mofdeletion despite dramatic loss of global H4K16ac. Hematopoietic defects start manifesting in late gestation at E17.5. The discovery that MOF and its H4K16ac activity are required for adult but not early and midgestational hematopoiesis supports the notion that multiple chromatin regulators may be crucial for hematopoiesis at varying stages of development. MOF is therefore a developmental-stage-specific chromatin regulator found to be essential for adult but not early fetal hematopoiesis. (Blood. 2017;129(1):48-59) C1 [Valerio, Daria G.; Xu, Haiming; Eisold, Meghan E.; Armstrong, Scott A.] Mem Sloan Kettering Canc Ctr, Ctr Epigenet Res, 1275 York Ave, New York, NY 10021 USA. [Valerio, Daria G.; Xu, Haiming; Eisold, Meghan E.; Armstrong, Scott A.] Mem Sloan Kettering Canc Ctr, Canc Biol & Genet Program, 1275 York Ave, New York, NY 10021 USA. [Xu, Haiming; Armstrong, Scott A.] Harvard Med Sch, Boston Childrens Hosp, Dana Farber Canc Inst, Div Hematol Oncol,Dept Pediat Oncol, Boston, MA USA. [Woolthuis, Carolien M.] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, 1275 York Ave, New York, NY 10021 USA. [Pandita, Tej K.] Houston Methodist Res Inst, Dept Radiat Oncol, Houston, TX USA. [Armstrong, Scott A.] Mem Sloan Kettering Canc Ctr, Dept Pediat Oncol, 1275 York Ave, New York, NY 10021 USA. RP Armstrong, SA (reprint author), Harvard Med Sch, Dana Farber Canc Inst, Dept Pediat Oncol, 450 Brookline Ave, Boston, MA 02215 USA. EM scott_armstrong@dfci.harvard.edu FU CURE Childhood Cancer Research Grant (D.G.V.); National Institutes of Health (NIH); National Cancer Institute grants [P01 CA66996, R01 CA140575]; Leukemia and Lymphoma Society; Gabrielle's Angel Research Foundation; Department of Defense Bone Marrow Failure Postdoctoral Fellowship Award [W81XWH-12-1-0568]; NIH, National Cancer Institute grants [R01 CA129537, R01 CA154320]; NIH Memorial Sloan Kettering Cancer Center Support Grant [P30 CA008748] FX The authors acknowledge Z. Feng for administrative assistance. This work was supported by a CURE Childhood Cancer Research Grant (D.G.V.), National Institutes of Health (NIH), National Cancer Institute grants P01 CA66996 and R01 CA140575 (S.A.A.), the Leukemia and Lymphoma Society (S.A.A.), Gabrielle's Angel Research Foundation (S.A.A.), a Department of Defense Bone Marrow Failure Postdoctoral Fellowship Award (W81XWH-12-1-0568) (H.X.); NIH, National Cancer Institute grants R01 CA129537 and R01 CA154320 (T.K.P.); and an NIH Memorial Sloan Kettering Cancer Center Support Grant (P30 CA008748). NR 54 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD JAN 5 PY 2017 VL 129 IS 1 BP 48 EP 59 DI 10.1182/blood-2016-05-714568 PG 12 WC Hematology SC Hematology GA EO2LF UT WOS:000396527300012 PM 27827827 ER PT J AU Shen, QC Cheng, FX Song, HL Lu, WQ Zhao, JF An, XL Liu, MY Chen, GQ Zhao, ZM Zhang, J AF Shen, Qiancheng Cheng, Feixiong Song, Huili Lu, Weiqiang Zhao, Junfei An, Xiaoli Liu, Mingyao Chen, Guoqiang Zhao, Zhongming Zhang, Jian TI Proteome-Scale Investigation of Protein Allosteric Regulation Perturbed by Somatic Mutations in 7,000 Cancer Genomes SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID SIGNIFICANTLY MUTATED GENES; PHOSPHORYLATION NETWORKS; HUMAN PHOSPHODIESTERASE; MISSENSE MUTATION; DRIVER MUTATIONS; INTERACTOME; DISCOVERY; DATABASE; REVEALS; KINASE AB The allosteric regulation triggering the protein's functional activity via conformational changes is an intrinsic function of protein under many physiological and pathological conditions, including cancer. Identification of the biological effects of specific somatic variants on allosteric proteins and the phenotypes that they alter during tumor initiation and progression is a central challenge for cancer genomes in the post-genomic era. Here, we mapped more than 47,000 somatic missense mutations observed in approximately 7,000 tumor-normal matched samples across 33 cancer types into protein allosteric sites to prioritize the mutated allosteric proteins and we tested our prediction in cancer cell lines. We found that the deleterious mutations identified in cancer genomes were more significantly enriched at protein allosteric sites than tolerated mutations, suggesting a critical role for protein allosteric variants in cancer. Next, we developed a statistical approach, namely AlloDriver, and further identified 15 potential mutated allosteric proteins during pan-cancer and individual cancer-type analyses. More importantly, we experimentally confirmed that p.Pro360Ala on PDE10A played a potential oncogenic role in mediating tumorigenesis in non-small cell lung cancer (NSCLC). In summary, these findings shed light on the role of allosteric regulation during tumorigenesis and provide a useful tool for the timely development of targeted cancer therapies. C1 [Shen, Qiancheng; Song, Huili; An, Xiaoli; Chen, Guoqiang; Zhang, Jian] Shanghai Jiao Tong Univ, Sch Med, Shanghai Key Lab Tumor Microenvironm & Inflammat, Minist Educ,Dept Pathophysiol,Key Lab Cell Differ, Shanghai 200025, Peoples R China. [Cheng, Feixiong] Sichuan Univ, West China Med Sch, West China Hosp, State Key Lab Biotherapy,Collaborat Innovat Ctr B, Chengdu 610041, Peoples R China. [Cheng, Feixiong; Zhao, Junfei] Vanderbilt Univ, Sch Med, Dept Biomed Informat, Nashville, TN 37203 USA. [Lu, Weiqiang; Liu, Mingyao] East China Normal Univ, Inst Biomed Sci, Shanghai Key Lab Regulatory Biol, Shanghai 200241, Peoples R China. [Lu, Weiqiang; Liu, Mingyao] East China Normal Univ, Sch Life Sci, Shanghai 200241, Peoples R China. [Zhao, Zhongming] Univ Texas Hlth Sci Ctr Houston, Sch Biomed Informat, Ctr Precis Hlth, Houston, TX 77030 USA. [Cheng, Feixiong] Dana Farber Canc Inst, Ctr Canc Syst Biol, Boston, MA 02215 USA. [Cheng, Feixiong] Northeastern Univ, Ctr Complex Networks Res, Boston, MA 02115 USA. RP Zhang, J (reprint author), Shanghai Jiao Tong Univ, Sch Med, Shanghai Key Lab Tumor Microenvironm & Inflammat, Minist Educ,Dept Pathophysiol,Key Lab Cell Differ, Shanghai 200025, Peoples R China.; Zhao, ZM (reprint author), Univ Texas Hlth Sci Ctr Houston, Sch Biomed Informat, Ctr Precis Hlth, Houston, TX 77030 USA. EM zhongming.zhao@uth.tmc.edu; jian.zhang@sjtu.edu.cn FU National High-tech R&D Program of China (863 Program) [2015AA020108]; National Natural Science Foundation of China [81322046, 81473137, 81302698, 81573020]; NIH [R01LM011177] FX This work was partially supported by the National High-tech R&D Program of China (863 Program) (2015AA020108) and the National Natural Science Foundation of China (81322046, 81473137, and 81302698) to J.Z., the National Natural Science Foundation of China (81573020) to F.C., and the NIH (R01LM011177) to Z.Z. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 69 TC 0 Z9 0 U1 4 U2 4 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 JAN 5 PY 2017 VL 100 IS 1 BP 5 EP 20 DI 10.1016/j.ajhg.2016.09.020 PG 16 WC Genetics & Heredity SC Genetics & Heredity GA EH6UX UT WOS:000391910500001 PM 27939638 ER PT J AU Ahola-Olli, AV Wurtz, P Havulinna, AS Aalto, K Pitkanen, N Lehtimaki, T Kahonen, M Lyytikainen, LP Raitoharju, E Seppala, I Sarin, AP Ripatti, S Palotie, A Perola, M Viikari, JS Jalkanen, S Maksimow, M Salomaa, V Salmi, M Kettunen, J Raitakari, OT AF Ahola-Olli, Ari V. Wurtz, Peter Havulinna, Aki S. Aalto, Kristiina Pitkanen, Niina Lehtimaki, Terho Kahonen, Mika Lyytikainen, Leo-Pekka Raitoharju, Emma Seppala, Ilkka Sarin, Antti-Pekka Ripatti, Samuli Palotie, Aarne Perola, Markus Viikari, Jorma S. Jalkanen, Sirpa Maksimow, Mikael Salomaa, Veikko Salmi, Marko Kettunen, Johannes Raitakari, Olli T. TI Genome-wide Association Study Identifies 27 Loci Influencing Concentrations of Circulating Cytokines and Growth Factors SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID MONOCYTE CHEMOATTRACTANT PROTEIN-1; INFLAMMATORY-BOWEL-DISEASE; DUFFY ANTIGEN RECEPTOR; CROHNS-DISEASE; SUSCEPTIBILITY LOCI; ULCERATIVE-COLITIS; MONOCLONAL-ANTIBODY; INTERLEUKIN-16; METAANALYSIS; VARIANTS AB Circulating cytokines and growth factors are regulators of inflammation and have been implicated in autoimmune and metabolic diseases. In this genome-wide association study (GWAS) of up to 8,293 Finns we identified 27 genome-widely significant loci (p < 1.2 x 10(-9)) for one or more cytokines. Fifteen of the associated variants had expression quantitative trait loci in whole blood. We provide genetic instruments to clarify the causal roles of cytokine signaling and upstream inflammation in immune-related and other chronic diseases. We further link inflammatory markers with variants previously associated with autoimmune diseases such as Crohn disease, multiple sclerosis, and ulcerative colitis and hereby elucidate the molecular mechanisms underpinning these diseases and suggest potential drug targets. C1 [Ahola-Olli, Ari V.; Pitkanen, Niina; Raitakari, Olli T.] Univ Turku, Res Ctr Appl & Prevent Cardiovasc Med, FIN-20520 Turku, Finland. [Wurtz, Peter; Kettunen, Johannes] Univ Oulu, Ctr Life Course Hlth Res, Computat Med, Oulu 90014, Finland. [Havulinna, Aki S.; Sarin, Antti-Pekka; Ripatti, Samuli; Perola, Markus; Salomaa, Veikko; Kettunen, Johannes] Natl Inst Hlth & Welf, Helsinki 00271, Finland. [Aalto, Kristiina; Jalkanen, Sirpa; Maksimow, Mikael; Salmi, Marko] Univ Turku, Dept Med Microbiol & Immunol, Medic Res Lab, FIN-20520 Turku, Finland. [Lehtimaki, Terho; Lyytikainen, Leo-Pekka; Raitoharju, Emma; Seppala, Ilkka] Univ Tampere, Sch Med, Pirkanmaa Hosp Dist, Dept Clin Chem,Fimlab Labs, Tampere 33014, Finland. [Kahonen, Mika] Tampere Univ Hosp, Dept Clin Physiol, Tampere 33521, Finland. [Sarin, Antti-Pekka; Ripatti, Samuli; Palotie, Aarne; Perola, Markus] Univ Helsinki, Inst Mol Med Finland FIMM, FIN-00014 Helsinki, Finland. [Ripatti, Samuli] Univ Helsinki, Dept Publ Hlth, Helsinki 00271, Finland. [Palotie, Aarne] Massachusetts Gen Hosp, Dept Med, Analyt & Translat Genet Unit, Boston, MA 02114 USA. [Palotie, Aarne] Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA 02142 USA. [Palotie, Aarne] Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Cambridge, MA 02142 USA. [Palotie, Aarne] Massachusetts Gen Hosp, Dept Psychiat, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA. [Palotie, Aarne] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Viikari, Jorma S.] Univ Turku, Dept Med, FIN-20520 Turku, Finland. [Viikari, Jorma S.] Turku Univ Hosp, Div Med, FIN-20520 Turku, Finland. [Kettunen, Johannes] Univ Eastern Finland, Sch Pharm, NMR Metabol Lab, Kuopio 70211, Finland. [Kettunen, Johannes; Raitakari, Olli T.] Univ Oulu, Bioctr Oulu, Oulu 90014, Finland. [Raitakari, Olli T.] Turku Univ Hosp, Dept Clin Physiol & Nucl Med, FIN-20520 Turku, Finland. RP Ahola-Olli, AV (reprint author), Univ Turku, Res Ctr Appl & Prevent Cardiovasc Med, FIN-20520 Turku, Finland. EM avahol@utu.fi FU Academy of Finland [286284, 134309, 126925, 121584, 124282, 129378, 117787, 41071, 139635]; Social Insurance Institution of Finland; Kuopio, Tampere, and Turku University Hospital Medical Funds [X51001]; Juho Vainio Foundation; Paavo Nurmi Foundation; Finnish Foundation of Cardiovascular Research; Finnish Cultural Foundation; Tampere Tuberculosis Foundation; Emil Aaltonen Foundation; Yrjo Jahnsson Foundation; Finnish Diabetes Research Foundation; Novo Nordisk Foundation; Finnish Foundation for Cardiovascular Research FX The Young Finns Study has been financially supported by the Academy of Finland: grants 286284 (T.L.), 134309, 126925, 121584, 124282, 129378, 117787, and 41071; the Social Insurance Institution of Finland; Kuopio, Tampere, and Turku University Hospital Medical Funds (grant X51001 for T.L.); Juho Vainio Foundation; Paavo Nurmi Foundation; Finnish Foundation of Cardiovascular Research; Finnish Cultural Foundation; Tampere Tuberculosis Foundation (T.L.); Emil Aaltonen Foundation; and Yrjo Jahnsson Foundation. P.W. was supported by Finnish Diabetes Research Foundation, Novo Nordisk Foundation, and Yrjo Jahnsson Foundation. V.S. was supported by the Academy of Finland, grant number 139635, and the Finnish Foundation for Cardiovascular Research. We gratefully acknowledge Vine Aalto and Irina Lisinen for expert technical assistance in the data management. NR 49 TC 0 Z9 0 U1 2 U2 2 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 JAN 5 PY 2017 VL 100 IS 1 BP 40 EP 50 DI 10.1016/j.ajhg.2016.11.007 PG 11 WC Genetics & Heredity SC Genetics & Heredity GA EH6UX UT WOS:000391910500004 PM 27989323 ER PT J AU Han, S Jerome, JA Gregory, AD Mallampalli, RK AF Han, SeungHye Jerome, Jacob A. Gregory, Alyssa D. Mallampalli, Rama K. TI Cigarette smoke destabilizes NLRP3 protein by promoting its ubiquitination SO RESPIRATORY RESEARCH LA English DT Article DE NLRP3; Cigarette smoke; Ubiquitin ID NALP3 INFLAMMASOME; INDUCED EMPHYSEMA; TOBACCO-SMOKE; DEGRADATION; LUNG; ELASTASE; SYSTEM; AIRWAY; ALPHA; IL-18 AB Background: Cigarette smoke suppresses innate immunity, making smokers more susceptible to infection. The NLRP3 inflammasome is a multi-protein complex that releases interleukin (IL) -1 beta and IL -18. These cytokines are critical for a timely host response to pathogens. Whether cigarette smoke affects NLRP3 protein levels, and its ability to form an inflammasome, is not known. Methods and results: Using the human monocyte THP1 cell line and C57BL/6 mice, we show that cigarette smoke decreases NLRP3 levels in cells by increasing ubiquitin-mediated proteasomal processing. Half-life of NLRP3 is shortened with the exposure to cigarette smoke extract. Cigarette smoke extract reduces cellular NLRP3 protein abundance in the presence of lipopolysaccharide, a known inducer of NLRP3 protein, thereby decreasing the formation of NLRP3 inflammasomes. The release of IL-1 beta and IL-18 by inflammasome activation is also decreased with the exposure to cigarette smoke extract both in THP1 cells and primary human peripheral blood macrophages. Conclusions: Cigarette smoke extract decreased NLRP3 protein abundance via increased ubiquitin-mediated proteasomal processing. The release of IL-1 beta and IL-18 is also decreased with cigarette smoke extract. Our findings may provide mechanistic insights on immunosuppression in smokers and unique opportunities to develop a strategy to modulate immune function. C1 [Han, SeungHye; Jerome, Jacob A.; Mallampalli, Rama K.] Univ Pittsburgh, Dept Med, Acute Lung Injury Ctr Excellence, Pittsburgh, PA 15260 USA. [Gregory, Alyssa D.; Mallampalli, Rama K.] Univ Pittsburgh, Dept Med, Div Pulm Allergy & Crit Care Med, 930 Scaife Hall, Pittsburgh, PA 15213 USA. [Mallampalli, Rama K.] Vet Affairs Pittsburgh Healthcare Syst, Med Specialty Serv Line, Pittsburgh, PA 15240 USA. RP Mallampalli, RK (reprint author), Univ Pittsburgh, Dept Med, Acute Lung Injury Ctr Excellence, Pittsburgh, PA 15260 USA.; Mallampalli, RK (reprint author), Univ Pittsburgh, Dept Med, Div Pulm Allergy & Crit Care Med, 930 Scaife Hall, Pittsburgh, PA 15213 USA.; Mallampalli, RK (reprint author), Vet Affairs Pittsburgh Healthcare Syst, Med Specialty Serv Line, Pittsburgh, PA 15240 USA. EM mallampallirk@upmc.edu FU Merit Review Award from the US Department of Veterans Affairs, National Institutes of Health R01 grants [HL096376, HL097376, HL098174, HL081784, 1UH2HL123502, P01HL114453]; American Heart Association Award [15POST25700096]; Breathe Pennsylvania Lung Health Research Grant; Flight Attendant Medical Research Institute FX This work was supported by a Merit Review Award from the US Department of Veterans Affairs, National Institutes of Health R01 grants HL096376, HL097376, HL098174, HL081784, 1UH2HL123502, P01HL114453 (to R.K.M.); an American Heart Association Award 15POST25700096, Breathe Pennsylvania Lung Health Research Grant (to S.H.); and Flight Attendant Medical Research Institute (to A. D.G.). The contents presented do not represent the views of the Department of Veterans Affairs or the United States Government. NR 31 TC 0 Z9 0 U1 1 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1465-993X EI 1465-9921 J9 RESP RES JI Respir. Res. PD JAN 5 PY 2017 VL 18 AR 2 DI 10.1186/s12931-016-0485-6 PG 8 WC Respiratory System SC Respiratory System GA EG9UP UT WOS:000391405300001 PM 28056996 ER PT J AU Pequito, S Preciado, VM Barabasi, AL Pappas, GJ AF Pequito, Sergio Preciado, Victor M. Barabasi, Albert-Laszlo Pappas, George J. TI Trade-offs between driving nodes and time-to-control in complex networks SO SCIENTIFIC REPORTS LA English DT Article ID CONTROLLABILITY; SYSTEMS AB Recent advances in control theory provide us with efficient tools to determine the minimum number of driving (or driven) nodes to steer a complex network towards a desired state. Furthermore, we often need to do it within a given time window, so it is of practical importance to understand the trade-offs between the minimum number of driving/driven nodes and the minimum time required to reach a desired state. Therefore, we introduce the notion of actuation spectrum to capture such trade-offs, which we used to find that in many complex networks only a small fraction of driving (or driven) nodes is required to steer the network to a desired state within a relatively small time window. Furthermore, our empirical studies reveal that, even though synthetic network models are designed to present structural properties similar to those observed in real networks, their actuation spectra can be dramatically different. Thus, it supports the need to develop new synthetic network models able to replicate controllability properties of real-world networks. C1 [Pequito, Sergio; Preciado, Victor M.; Pappas, George J.] Univ Penn, Sch Engn & Appl Sci, Dept Elect & Syst Engn, Philadelphia, PA 19104 USA. [Barabasi, Albert-Laszlo] Northeastern Univ, Ctr Complex Network Res, Boston, MA 02115 USA. [Barabasi, Albert-Laszlo] Northeastern Univ, Dept Phys, Boston, MA 02115 USA. [Barabasi, Albert-Laszlo] Northeastern Univ, Dept Comp Sci, Boston, MA 02115 USA. [Barabasi, Albert-Laszlo] Northeastern Univ, Dept Biol, Boston, MA 02115 USA. [Barabasi, Albert-Laszlo] Dana Farber Canc Inst, Ctr Canc Syst Biol, Boston, MA 02115 USA. [Barabasi, Albert-Laszlo] Harvard Med Sch, Brighamand Womens Hosp, Dept Med, Boston, MA 02115 USA. RP Pequito, S (reprint author), Univ Penn, Sch Engn & Appl Sci, Dept Elect & Syst Engn, Philadelphia, PA 19104 USA. EM sergo@seas.upenn.edu FU MARCO; DARPA; NSF [CNS-1302222, IIS-1447470]; John Templeton Foundation: Mathematical and Physical Sciences [PFI-777]; European Commission [641191] FX S.P. and G.J.P. supported in part by the TerraSwarm Research Center, one of six centers supported by the STARnet phase of the Focus Center Research Program (FCRP) a Semiconductor Research Corporation program sponsored by MARCO and DARPA. V.M.P. is supported by the NSF under grants CNS-1302222 and IIS-1447470. A.-L.B is supported by the John Templeton Foundation: Mathematical and Physical Sciences grant number PFI-777; European Commission grant 641191 (CIMPLEX). NR 26 TC 0 Z9 0 U1 8 U2 8 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 JAN 5 PY 2017 VL 7 AR 39978 DI 10.1038/srep39978 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EG6WS UT WOS:000391187600001 PM 28054597 ER PT J AU Clark, JW Chabner, BA AF Clark, Jeffrey W. Chabner, Bruce A. TI Limits to Precision Cancer Medicine SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [Clark, Jeffrey W.; Chabner, Bruce A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Clark, JW (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. EM jclark@partners.org NR 4 TC 0 Z9 0 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JAN 5 PY 2017 VL 376 IS 1 BP 96 EP 96 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA EG6SS UT WOS:000391177100027 PM 28052223 ER PT J AU Ben-Ari, A Chansky, H Rozet, I AF Ben-Ari, Alon Chansky, Howard Rozet, Irene TI Preoperative Opioid Use Is Associated with Early Revision After Total Knee Arthroplasty A Study of Male Patients Treated in the Veterans Affairs System SO JOURNAL OF BONE AND JOINT SURGERY-AMERICAN VOLUME LA English DT Article ID CONTROLLED-TRIAL; GLYCEMIC CONTROL; PAIN MANAGEMENT; UNITED-STATES; RISK-FACTORS; REPLACEMENT; OUTCOMES; IMPACT; HIP AB Background: Opioid use is endemic in the U.S. and is associated with morbidity and mortality. The impact of long-term opioid use on joint-replacement outcomes remains unknown. We tested the hypothesis that use of opioids is associated with adverse outcomes after total knee arthroplasty (TKA). Methods: We performed a retrospective analysis of patients who had had TKA within the U.S. Veterans Affairs (VA) system over a 6-year period and had been followed for 1 year postoperatively. The length of time for which an opioid had been prescribed and the morphine equivalent dose were calculated for each patient. Patients for whom opioids had been prescribed for >3 months in the year prior to the TKA were assigned to the long-term opioid group. A natural language processing-based machine-learning classifier was developed to classify revisions due to infectious and non-infectious causes on the basis of the postoperative note. Survival curves for the time to knee revision or manipulation were used to compare the long-term opioid group with the patients who did not take opioids long-term. Hazard and odds ratios for knee revision and manipulation were obtained as well. Results: Of 32,636 patients (94.4% male; mean age [and standard deviation], 64.45 +/- 9.41 years) who underwent TKA, 12,772 (39.1%) were in the long-term opioid group and 734 (2.2%) had a revision within a year after the TKA. Chronic kidney disease, diabetes, and long-term opioid use were associated with revision within 1 year-with odds ratios (95% confidence intervals [CIs]) of 1.76 (1.37 to 2.22), 1.11 (0.93 to 1.31), and 1.40 (1.19 to 1.64), respectively-and were also the leading factors associated with a revision at any time after the index TKA-with odds ratios (95% CIs) of 1.61 (1.34 to 1.92), 1.21 (1.08 to 1.36), and 1.28 (1.15 to 1.43), respectively. Long-term opioid use had a hazard ratio of 1.19 (95% CI = 1.10 to 0.24) in the analysis of its relationship with knee revision, but the hazard was not significant in the analysis of its association with knee manipulation. The accuracy of the text classifier was 0.94, with the area under the receiver operating characteristic curve being 0.99. There was no association between long-term use of opioids and the specific cause for knee revision. Conclusions: Long-term opioid use prior to TKA was associated with an increased risk of knee revision during the first year after TKA among predominantly male patients treated in the VA system. C1 [Ben-Ari, Alon; Chansky, Howard; Rozet, Irene] Univ Washington, Dept Anesthesiol & Pain Med, Seattle, WA USA. [Ben-Ari, Alon; Chansky, Howard; Rozet, Irene] Univ Washington, Dept Orthopaed Surg & Sports Med, VA Puget Sound Hlth Care Syst, Seattle, WA USA. RP Ben-Ari, A (reprint author), Univ Washington, Dept Anesthesiol & Pain Med, Seattle, WA USA.; Ben-Ari, A (reprint author), Univ Washington, Dept Orthopaed Surg & Sports Med, VA Puget Sound Hlth Care Syst, Seattle, WA USA. EM alon.benari@gmail.com; chansky@uw.edu; irozet@uw.edu NR 38 TC 0 Z9 0 U1 0 U2 0 PU JOURNAL BONE JOINT SURGERY PI NEEDHAM PA 20 PICKERING ST, NEEDHAM, MA 02492 USA SN 0021-9355 EI 1535-1386 J9 J BONE JOINT SURG AM JI J. Bone Joint Surg.-Am. Vol. PD JAN 4 PY 2017 VL 99 IS 1 BP 1 EP 9 DI 10.2106/JBJS.16.00167 PG 9 WC Orthopedics; Surgery SC Orthopedics; Surgery GA EP0HM UT WOS:000397067900005 PM 28060227 ER PT J AU Karczewski, KJ Weisburd, B Thomas, B Solomonson, M Ruderfer, DM Kavanagh, D Hamamsy, T Lek, M Samocha, KE Cummings, BB Birnbaum, D Daly, MJ MacArthur, DG AF Karczewski, Konrad J. Weisburd, Ben Thomas, Brett Solomonson, Matthew Ruderfer, Douglas M. Kavanagh, David Hamamsy, Tymor Lek, Monkol Samocha, Kaitlin E. Cummings, Beryl B. Birnbaum, Daniel Daly, Mark J. MacArthur, Daniel G. CA Exome Aggregation Consortium TI The ExAC browser: displaying reference data information from over 60 000 exomes SO NUCLEIC ACIDS RESEARCH LA English DT Article ID FUNCTIONAL PREDICTIONS; VARIANTS; DBNSFP AB Worldwide, hundreds of thousands of humans have had their genomes or exomes sequenced, and access to the resulting data sets can provide valuable information for variant interpretation and understanding gene function. Here, we present a lightweight, flexible browser framework to display large population datasets of genetic variation. We demonstrate its use for exome sequence data from 60 706 individuals in the Exome Aggregation Consortium (ExAC). The ExAC browser provides gene- and transcript-centric displays of variation, a critical view for clinical applications. Additionally, we provide a variant display, which includes population frequency and functional annotation data as well as short read support for the called variant. This browser is open-source, freely available at http://exac.broadinstitute.org, and has already been used extensively by clinical laboratories worldwide. C1 [Karczewski, Konrad J.; Weisburd, Ben; Thomas, Brett; Solomonson, Matthew; Lek, Monkol; Samocha, Kaitlin E.; Cummings, Beryl B.; Birnbaum, Daniel; Daly, Mark J.; MacArthur, Daniel G.] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA. [Karczewski, Konrad J.; Weisburd, Ben; Thomas, Brett; Solomonson, Matthew; Lek, Monkol; Samocha, Kaitlin E.; Cummings, Beryl B.; Birnbaum, Daniel; Daly, Mark J.; MacArthur, Daniel G.] MIT, Broad Inst Harvard, Med & Populat Genet, Cambridge, MA 02142 USA. [Ruderfer, Douglas M.; Kavanagh, David; Hamamsy, Tymor] Icahn Sch Med Mt Sinai, Div Psychiat Genom, Dept Psychiat, New York, NY 10029 USA. RP Karczewski, KJ (reprint author), Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA.; Karczewski, KJ (reprint author), MIT, Broad Inst Harvard, Med & Populat Genet, Cambridge, MA 02142 USA. EM konradjkarczewski@gmail.com FU NIGMS Fellowship [F32GM115208]; Australian National Health and Medical Research Council C.J. Martin Fellowship; Australian American Association Sir Keith Murdoch Fellowship; MDA/AANEM Development Grant; NIGMS [R01 GM104371]; NIDDK [U54 DK105566] FX NIGMS Fellowship [F32GM115208 to K.J.K.]; Australian National Health and Medical Research Council C.J. Martin Fellowship, Australian American Association Sir Keith Murdoch Fellowship and the MDA/AANEM Development Grant (to M.L.); NIGMS [R01 GM104371 and NIDDK U54 DK105566 to D.G.M.]. Funding for open access charge: Daniel MacArthur, Analytic and Translational Genetics Unit. NR 17 TC 1 Z9 1 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 EI 1362-4962 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD JAN 4 PY 2017 VL 45 IS D1 BP D840 EP D845 DI 10.1093/nar/gkw971 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EO3DQ UT WOS:000396575500117 PM 27899611 ER PT J AU Li, P Tompkins, RG Xiao, WZ AF Li, Peng Tompkins, Ronald G. Xiao, Wenzhong CA Inflammation Host Response TI KERIS: kaleidoscope of gene responses to inflammation between species SO NUCLEIC ACIDS RESEARCH LA English DT Article ID SET ENRICHMENT ANALYSIS; HUMANS; EXPRESSION; MOUSE; GENOME; MICE; DATABASE; MODELS; ANNOTATION; INJURY AB A cornerstone of modern biomedical research is the use of animal models to study disease mechanisms and to develop new therapeutic approaches. In order to help the research community to better explore the similarities and differences of genomic response between human inflammatory diseases and murine models, we developed KERIS: kaleidoscope of gene responses to inflammation between species (available at http://www.igenomed.org/keris/). As of June 2016, KERIS includes comparisons of the genomic response of six human inflammatory diseases (burns, trauma, infection, sepsis, endotoxin and acute respiratory distress syndrome) and matched mouse models, using 2257 curated samples from the Inflammation and the Host Response to Injury Glue Grant studies and other representative studies in Gene Expression Omnibus. A researcher can browse, query, visualize and compare the response patterns of genes, pathways and functional modules across different diseases and corresponding murine models. The database is expected to help biologists choosing models when studying the mechanisms of particular genes and pathways in a disease and prioritizing the translation of findings from disease models into clinical studies. C1 [Li, Peng; Tompkins, Ronald G.; Xiao, Wenzhong; Inflammation Host Response] Harvard Med Sch, Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. RP Xiao, WZ (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. EM wenzhong.xiao@mgh.harvard.edu FU National Institutes of Health (NIH) [R24-GM102656, R01-GM101401, P50-GM021700]; Shriners Research Grant [85500-BOS]; NIH FX National Institutes of Health (NIH) [R24-GM102656, R01-GM101401, P50-GM021700]; Shriners Research Grant [85500-BOS]. Funding for open access charge: NIH. NR 33 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 EI 1362-4962 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD JAN 4 PY 2017 VL 45 IS D1 BP D908 EP D914 DI 10.1093/nar/gkw974 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EO3DQ UT WOS:000396575500126 PM 27789704 ER PT J AU Mei, SL Qin, Q Wu, Q Sun, HF Zheng, RB Zang, CZ Zhu, MY Wu, JX Shi, XH Taing, L Liu, T Brown, M Meyer, CA Liu, XS AF Mei, Shenglin Qin, Qian Wu, Qiu Sun, Hanfei Zheng, Rongbin Zang, Chongzhi Zhu, Muyuan Wu, Jiaxin Shi, Xiaohui Taing, Len Liu, Tao Brown, Myles Meyer, Clifford A. Liu, X. Shirley TI Cistrome Data Browser: a data portal for ChIP-Seq and chromatin accessibility data in human and mouse SO NUCLEIC ACIDS RESEARCH LA English DT Article ID TRANSCRIPTIONAL REGULATION; GENE-EXPRESSION; QUALITY-CONTROL; HUMAN GENOME; LANDSCAPE; PROFILES; ARCHIVE; UPDATE; ENCODE; CELLS AB Chromatin immunoprecipitation, DNase I hypersensitivity and transposase-accessibility assays combined with high-throughput sequencing enable the genome-wide study of chromatin dynamics, transcription factor binding and gene regulation. Although rapidly accumulating publicly available ChIP-seq, DNase-seq and ATAC-seq data are a valuable resource for the systematic investigation of gene regulation processes, a lack of standardized curation, quality control and analysis procedures have hindered extensive reuse of these data. To overcome this challenge, we built the Cistrome database, a collection of ChIP-seq and chromatin accessibility data (DNase-seq and ATAC-seq) published before January 1, 2016, including 13 366 human and 9953 mouse samples. All the data have been carefully curated and processed with a streamlined analysis pipeline and evaluated with comprehensive quality control metrics. We have also created a user-friendly web server for data query, exploration and visualization. The resulting Cistrome DB (Cistrome Data Browser), available online at http://cistrome.org/db, is expected to become a valuable resource for transcriptional and epigenetic regulation studies. C1 [Mei, Shenglin; Qin, Qian; Wu, Qiu; Liu, X. Shirley] Tongji Univ, Shanghai Pulm Hosp, Clin Translat Res Ctr, Shanghai 200433, Peoples R China. [Mei, Shenglin; Qin, Qian; Wu, Qiu; Sun, Hanfei; Zheng, Rongbin; Zhu, Muyuan; Shi, Xiaohui; Liu, X. Shirley] Tongji Univ, Sch Life Sci & Technol, Dept Bioinformat, Shanghai 200092, Peoples R China. [Zang, Chongzhi; Taing, Len; Meyer, Clifford A.; Liu, X. Shirley] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02215 USA. [Zang, Chongzhi; Taing, Len; Meyer, Clifford A.; Liu, X. Shirley] Harvard TH Chan Sch Publ Hlth, Boston, MA 02215 USA. [Zang, Chongzhi; Brown, Myles; Meyer, Clifford A.; Liu, X. Shirley] Dana Farber Canc Inst, Ctr Funct Canc Epigenet, Boston, MA 02215 USA. [Brown, Myles] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Brown, Myles] Harvard Med Sch, Dept Med Oncol, Boston, MA 02215 USA. [Wu, Jiaxin] Tsinghua Univ, MOE Key Lab Bioinformat, Bioinformat Div, Beijing 100084, Peoples R China. [Wu, Jiaxin] Tsinghua Univ, Ctr Synthet & Syst Biol, TNLIST, Beijing 100084, Peoples R China. [Wu, Jiaxin] Tsinghua Univ, Dept Automat, Beijing 100084, Peoples R China. [Liu, Tao] SUNY Buffalo, Dept Biochem, Buffalo, NY 14214 USA. RP Liu, XS (reprint author), Tongji Univ, Shanghai Pulm Hosp, Clin Translat Res Ctr, Shanghai 200433, Peoples R China.; Liu, XS (reprint author), Tongji Univ, Sch Life Sci & Technol, Dept Bioinformat, Shanghai 200092, Peoples R China.; Meyer, CA; Liu, XS (reprint author), Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02215 USA.; Meyer, CA; Liu, XS (reprint author), Harvard TH Chan Sch Publ Hlth, Boston, MA 02215 USA.; Meyer, CA; Liu, XS (reprint author), Dana Farber Canc Inst, Ctr Funct Canc Epigenet, Boston, MA 02215 USA. EM cliff@jimmy.harvard.edu; xsliu@jimmy.harvard.edu FU National Institutes of Health [U01 CA180980]; National Natural Science Foundation of China [31329003]; Campaign Technology Fund of Dana-Farber Cancer Institute FX National Institutes of Health [U01 CA180980]; National Natural Science Foundation of China [31329003]; Campaign Technology Fund of Dana-Farber Cancer Institute. Funding for open access charge: National Natural Science Foundation of China [31329003]. NR 28 TC 1 Z9 1 U1 1 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 EI 1362-4962 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD JAN 4 PY 2017 VL 45 IS D1 BP D658 EP D662 DI 10.1093/nar/gkw983 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EO3DQ UT WOS:000396575500092 PM 27789702 ER PT J AU Mandelblat-Cerf, Y Kim, A Burgess, CR Subramanian, S Tannous, BA Lowell, BB Andermann, ML AF Mandelblat-Cerf, Yael Kim, Angela Burgess, Christian R. Subramanian, Siva Tannous, Bakhos A. Lowell, Bradford B. Andermann, Mark L. TI Bidirectional Anticipation of Future Osmotic Challenges by Vasopressin Neurons SO NEURON LA English DT Article ID PLASMA VASOPRESSIN; COLLECTING DUCT; SECRETION; DRINKING; SIGNALS; THIRST; HYPOTHALAMUS; INHIBITION; AMYGDALA; HUNGER AB Ingestion of water and food are major hypo-and hyperosmotic challenges. To protect the body from osmotic stress, posterior pituitary-projecting, vasopressin- secreting neurons (VPpp neurons) counter osmotic perturbations by altering their release of vasopressin, which controls renal water excretion. Vasopressin levels begin to fall within minutes of water consumption, even prior to changes in blood osmolality. To ascertain the precise temporal dynamics by which water or food ingestion affect VPpp neuron activity, we directly recorded the spiking and calcium activity of genetically defined VPpp neurons. In states of elevated osmolality, water availability rapidly decreased VPpp neuron activity within seconds, beginning prior to water ingestion, upon presentation of water-predicting cues. In contrast, food availability following food restriction rapidly increased VPpp neuron activity within seconds, but only following feeding onset. These rapid and distinct changes in activity during drinking and feeding suggest diverse neural mechanisms underlying anticipatory regulation of VPpp neurons. C1 [Mandelblat-Cerf, Yael; Kim, Angela; Burgess, Christian R.; Subramanian, Siva; Lowell, Bradford B.; Andermann, Mark L.] Beth Israel Deaconess Med Ctr, Div Endocrinol Diabet & Metab, Boston, MA 02215 USA. [Kim, Angela; Tannous, Bakhos A.; Lowell, Bradford B.; Andermann, Mark L.] Harvard Med Sch, Program Neurosci, Boston, MA 02115 USA. [Tannous, Bakhos A.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Neurol, Charlestown, MA 02129 USA. RP Lowell, BB; Andermann, ML (reprint author), Beth Israel Deaconess Med Ctr, Div Endocrinol Diabet & Metab, Boston, MA 02215 USA.; Lowell, BB; Andermann, ML (reprint author), Harvard Med Sch, Program Neurosci, Boston, MA 02115 USA. EM blowell@bidmc.harvard.edu; manderma@bidmc.harvard.edu FU A. King Trust Postdoctoral Fellowship; Davis Family Foundation Postdoctoral Fellowship; Pew Scholars Program in the Biomedical Sciences; Smith Family Foundation; Klarman Family Foundation; NIH [R01 DK075632, R01 DK096010, R01 DK089044, P30 DK046200, P30 DK057521, R01 DK109930, DP2 DK105570] FX We would like to thank Dr. A. Sugden for assistance with breakpoint analysis experiments and members of the M.L.A. and B.B.L.labs and Drs.C.Saper, J. Majzoub, S. Liberles, J. Geerling, and Y. Livneh for helpful discussion. We thank Drs. Jayaraman, Kerr, Kim, Looger, and Svoboda and the GENIE Project at JFRC (HHMI) for distribution of GCaMP6s. Support was provided by a Charles A. King Trust Postdoctoral Fellowship (Y.M.-C.), a Davis Family Foundation Postdoctoral Fellowship (C. R. B.), NIH R01 DK075632, R01 DK096010, R01 DK089044, P30 DK046200, and P30 DK057521 (B. B. L.), NIH R01 DK109930, DP2 DK105570, the Pew Scholars Program in the Biomedical Sciences, the Klarman Family Foundation, and the Smith Family Foundation (M. L. A.). NR 36 TC 1 Z9 1 U1 1 U2 1 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 JAN 4 PY 2017 VL 93 IS 1 BP 57 EP 65 DI 10.1016/j.neuron.2016.11.021 PG 9 WC Neurosciences SC Neurosciences & Neurology GA EO0ZR UT WOS:000396427800009 PM 27989461 ER PT J AU Hudry, E AF Hudry, Eloise TI New Therapeutic Avenue for ALS: Avoiding a Fatal Encounter of TDP-43 at the Mitochondria SO MOLECULAR THERAPY LA English DT Editorial Material ID AMYOTROPHIC-LATERAL-SCLEROSIS; MUTATIONS; COGNITION; DISEASE; FUS/TLS C1 [Hudry, Eloise] Harvard Med Sch, Alzheimers Dis Res Unit, 114 16th St, Charlestown, MA 02129 USA. [Hudry, Eloise] Massachusetts Gen Hosp, 114 16th St, Charlestown, MA 02129 USA. RP Hudry, E (reprint author), Harvard Med Sch, Alzheimers Dis Res Unit, 114 16th St, Charlestown, MA 02129 USA.; Hudry, E (reprint author), Massachusetts Gen Hosp, 114 16th St, Charlestown, MA 02129 USA. EM ehudry@mgh.harvard.edu NR 16 TC 0 Z9 0 U1 2 U2 2 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1525-0016 EI 1525-0024 J9 MOL THER JI Mol. Ther. PD JAN 4 PY 2017 VL 25 IS 1 BP 10 EP 11 DI 10.1016/j.ymthe.2016.12.001 PG 2 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA EH6RM UT WOS:000391901600004 PM 28129105 ER PT J AU Bassi, R Niewczas, MA Biancone, L Bussolino, S Merugumala, S Tezzal, S D'Addio, F Ben Nasr, M Valderrama-Vasquez, A Usuelli, V De Zan, V El Essawy, B Venturini, M Secchi, A De Cobelli, F Lie, A Chandraker, A Fiorina, P AF Bassi, Roberto Niewczas, Monika A. Biancone, Luigi Bussolino, Stefania Merugumala, Sai Tezzal, Sara D'Addio, Francesca Ben Nasr, Moufida Valderrama-Vasquez, Alessandro Usuelli, Vera De Zan, Valentina El Essawy, Basset Venturini, Massimo Secchi, Antonio De Cobelli, Francesco Lie, Alexander Chandraker, Anil Fiorina, Paolo TI Metabolomic Profiling in Individuals with a Failing Kidney Allograft SO PLOS ONE LA English DT Article ID MAGNETIC-RESONANCE-SPECTROSCOPY; STAGE RENAL-DISEASE; ENERGY PHOSPHATE-METABOLISM; TYPE-1 DIABETIC-PATIENTS; PANCREAS TRANSPLANTATION; AMINO-ACID; URINARY METABOLOMICS; PLASMA; INJURY; RECIPIENTS AB Background Alteration of certain metabolites may play a role in the pathophysiology of renal allograft disease. Methods To explore metabolomic abnormalities in individuals with a failing kidney allograft, we analyzed by liquid chromatography-mass spectrometry (LC-MS/MS; for ex vivo profiling of serum and urine) and two dimensional correlated spectroscopy (2D COSY; for in vivo study of the kidney graft) 40 subjects with varying degrees of chronic allograft dysfunction stratified by tertiles of glomerular filtration rate (GFR; T1, T2, T3). Ten healthy non-allograft individuals were chosen as controls. Results LC-MS/MS analysis revealed a dose-response association between GFR and serum concentration of tryptophan, glutamine, dimethylarginine isomers (asymmetric [A]DMA and symmetric [S] DMA) and short-chain acylcarnitines (C4 and C12), (test for trend: T1-T3 = p<0.05; p = 0.01; p<0.001; p = 0.01; p = 0.01; p<0.05, respectively). The same association was found between GFR and urinary levels of histidine, DOPA, dopamine, carnosine, SDMA and ADMA (test for trend: T1-T3 = p<0.05; p< 0.01; p = 0.001; p<0.05; p = 0.001; p<0.001; p< 0.01, respectively). In vivo 2D COSY of the kidney allograft revealed significant reduction in the parenchymal content of choline, creatine, taurine and threonine (all: p<0.05) in individuals with lower GFR levels. Conclusions We report an association between renal function and altered metabolomic profile in renal transplant individuals with different degrees of kidney graft function. C1 [Bassi, Roberto; Tezzal, Sara; D'Addio, Francesca; Ben Nasr, Moufida; Fiorina, Paolo] Harvard Med Sch, Div Nephrol, Boston Childrens Hosp, Boston, MA 02115 USA. [Bassi, Roberto; D'Addio, Francesca; Valderrama-Vasquez, Alessandro; Usuelli, Vera; Secchi, Antonio; Fiorina, Paolo] IRCCS Osped San Raffaele, Transplant Med, Milan, Italy. [Niewczas, Monika A.] Harvard Med Sch, Sect Genet & Epidemiol, Joslin Diabet Ctr, Boston, MA USA. [Biancone, Luigi; Bussolino, Stefania] San Giovanni Battista Hosp, Turin, Italy. [Biancone, Luigi; Bussolino, Stefania] Univ Turin, Div Nephrol Dialysis & Transplantat, Turin, Italy. [Merugumala, Sai] Univ Texas Austin, Biomed Engn, Austin, TX 78712 USA. [De Zan, Valentina; Secchi, Antonio; De Cobelli, Francesco] Univ Vita Salute San Raffaele, Milan, Italy. [El Essawy, Basset] Al Azhar Univ, Med, Cairo, Egypt. [Venturini, Massimo; De Cobelli, Francesco] Ist Sci San Raffaele, Radiol, Milan, Italy. [Lie, Alexander] Harvard Med Sch, Brigham & Womens Hosp, Dept Radiol, Ctr Clin Spect, Boston, MA USA. [Chandraker, Anil] Harvard Med Sch, Brigham & Womens Hosp, Transplantat Res Ctr, Boston, MA USA. RP Fiorina, P (reprint author), Harvard Med Sch, Div Nephrol, Boston Childrens Hosp, Boston, MA 02115 USA.; Fiorina, P (reprint author), IRCCS Osped San Raffaele, Transplant Med, Milan, Italy. EM paolo.fiorina@childrens.harvard.edu RI D'Addio, Francesca/F-3417-2017 OI D'Addio, Francesca/0000-0002-0345-0694 FU AST Genentech/Novartis Clinical Science Fellowship; Italian Society of Diabetes (AMD-SID) Pasquale di Coste Award; JDRF [5-CDA-2015-89-A-B]; American Heart Association (AHA); Italian Ministry of Health [RF-2010-2303119]; EFSD/Sanofi European Research Programme FX This work was supported by a AST Genentech/Novartis Clinical Science Fellowship grant to RB and an Italian Society of Diabetes (AMD-SID) Pasquale di Coste Award to RB. RB was supported by a JDRF Post-Doctoral Research Fellowship grant. MAN received a JDRF Career Development Award (5-CDA-2015-89-A-B). PF was supported by an American Heart Association (AHA) Grant-In-Aid and the Italian Ministry of Health (grant RF-2010-2303119). PF also received support from the EFSD/Sanofi European Research Programme. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 50 TC 0 Z9 0 U1 6 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 JAN 4 PY 2017 VL 12 IS 1 AR e0169077 DI 10.1371/journal.pone.0169077 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EH2TP UT WOS:000391621500031 PM 28052095 ER PT J AU Beliveau, V Ganz, M Feng, L Ozenne, B Hojgaard, L Fisher, PM Svarer, C Greve, DN Knudsen, GM AF Beliveau, Vincent Ganz, Melanie Feng, Ling Ozenne, Brice Hojgaard, Liselotte Fisher, Patrick M. Svarer, Claus Greve, Douglas N. Knudsen, Gitte M. TI A High-Resolution In Vivo Atlas of the Human Brain's Serotonin System SO JOURNAL OF NEUROSCIENCE LA English DT Article DE 5-HT; atlas; autoradiography; MRI; mRNA; PET ID POSITRON-EMISSION-TOMOGRAPHY; RECEPTOR MESSENGER-RNA; MEDIAN RAPHE NUCLEI; CORTICAL SURFACE; 5-HT1B RECEPTORS; PET RADIOLIGAND; CEREBRAL-CORTEX; TRANSPORTERS; BINDING; MRI AB The serotonin (5-hydroxytryptamine, 5-HT) system modulates many important brain functions and is critically involved in many neuropsychiatric disorders. Here, we present a high-resolution, multidimensional, in vivo atlas of four of the human brain's 5-HT receptors (5-HT1A, 5-HT1B, 5-HT2A, and 5-HT4) and the 5-HT transporter (5-HTT). The atlas is created from molecular and structural high-resolution neuroimaging data consisting of positron emission tomography (PET) and magnetic resonance imaging (MRI) scans acquired in a total of 210 healthy individuals. Comparison of the regional PET binding measures with postmortem human brain autoradiography outcomes showed a high correlation for the five 5-HT targets and this enabled us to transform the atlas to represent protein densities (in picomoles per milliliter). We also assessed the regional association between protein concentration and mRNA expression in the human brain by comparing the 5-HT density across the atlas with data from the Allen Human Brain atlas and identified receptor-and transporter-specific associations that show the regional relation between the two measures. Together, these data provide unparalleled insight into the serotonin system of the human brain. C1 [Beliveau, Vincent; Ganz, Melanie; Feng, Ling; Ozenne, Brice; Fisher, Patrick M.; Svarer, Claus; Knudsen, Gitte M.] Rigshosp, Neurobiol Res Unit, 9 Blegdamsvej,Sect 6931, DK-2100 Copenhagen, Denmark. [Beliveau, Vincent; Ganz, Melanie; Feng, Ling; Ozenne, Brice; Fisher, Patrick M.; Svarer, Claus; Knudsen, Gitte M.] Rigshosp, Ctr Integrated Mol Brain Imaging, DK-2100 Copenhagen, Denmark. [Beliveau, Vincent; Hojgaard, Liselotte; Knudsen, Gitte M.] Rigshosp, Copenhagen Univ Hosp, Fac Hlth & Med Sci, DK-2100 Copenhagen, Denmark. [Ozenne, Brice] Rigshosp, Copenhagen Univ Hosp, Dept Publ Hlth, Sect Biostat, DK-2100 Copenhagen, Denmark. [Hojgaard, Liselotte] Rigshosp, Copenhagen Univ Hosp, PET & Cyclotron Unit, DK-2100 Copenhagen, Denmark. [Greve, Douglas N.] Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Boston, MA 02129 USA. [Greve, Douglas N.] Harvard Med Sch, Boston, MA 02115 USA. RP Knudsen, GM (reprint author), Rigshosp, Neurobiol Res Unit, 9 Blegdamsvej,Sect 6931, DK-2100 Copenhagen, Denmark. EM gmk@nru.dk RI Knudsen, Gitte/C-1368-2013; OI Knudsen, Gitte/0000-0003-1508-6866; Ozenne, Brice Maxime Hugues/0000-0001-9694-2956; Beliveau, Vincent/0000-0001-7805-279X FU Lundbeck Foundation Center Cimbi [R90-A7722]; Danish Council for Independent Research-Medical Sciences [4183-00627]; Research Council of Rigshospitalet [R84-A3300]; Carlsberg Foundation [2013-01-0502]; National Institutes of Health [5R21EB018964-02]; European Union [HEALTH-F2-2011-278850 IN-MiND]; National Institutes of Health (Multimodal Brain Imaging of Serotonin Grant) [5R21EB018964-02]; MGH Shared Instrumentation Grant [S10RR023043] FX Collection of data included in the study was supported by the Lundbeck Foundation Center Cimbi (Grant R90-A7722). V.B. was supported by the Danish Council for Independent Research-Medical Sciences (Grant 4183-00627) and the Research Council of Rigshospitalet (R84-A3300). M.G. was supported by the Carlsberg Foundation (Grant 2013-01-0502) and the National Institutes of Health (Grant 5R21EB018964-02). L.F. was supported by the European Union's Seventh Framework Programme (Grant FP7/2007-2013 under Agreement HEALTH-F2-2011-278850 IN-MiND). D.N.G.'s research was supported by the National Institutes of Health (Multimodal Brain Imaging of Serotonin Grant 5R21EB018964-02) and the MGH Shared Instrumentation Grant S10RR023043). We thank the John and Birthe Meyer Foundation for providing the PET HRRT scanner. NR 55 TC 0 Z9 0 U1 4 U2 4 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 JAN 4 PY 2017 VL 37 IS 1 BP 120 EP 128 DI 10.1523/JNEUROSCI.2830-16.2017 PG 9 WC Neurosciences SC Neurosciences & Neurology GA EG6GV UT WOS:000391143500011 PM 28053035 ER PT J AU Sarma, AA Nkonde-Price, C Gulati, M Duvernoy, CS Lewis, SJ Wood, MJ AF Sarma, Amy A. Nkonde-Price, Chileshe Gulati, Martha Duvernoy, Claire S. Lewis, Sandra J. Wood, Malissa J. CA Amer Coll Cardiology Women TI Cardiovascular Medicine and Society The Pregnant Cardiologist SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE pregnancy; training; women in cardiology ID RESIDENT PHYSICIANS; RADIATION SAFETY; CAREER; EXPERIENCES; KNOWLEDGE; EDUCATION; PERSONNEL; MOTHERS; WOMEN AB Women are a consistent minority in the field of cardiology, with concerns regarding balancing career and parenting responsibilities often cited as a contributing factor to this under-representation. To investigate the impact that a career in cardiology may have on the family planning decisions of female cardiologists, the Women in Cardiology section of the American College of Cardiology conducted a voluntary anonymous survey. The following perspective highlights lessons learned from the survey, and potential solutions to the issues surrounding maternity leave, radiation exposure during pregnancy, and breastfeeding accommodations raised by these data. Given that most female cardiologists are pregnant at some point during their careers, particularly during the vulnerable periods of training and early career, improving the experience of pregnancy and early parenthood for all cardiologists may secure the best possible candidates to the field of cardiology. (C) 2017 by the American College of Cardiology Foundation. Published by Elsevier. All rights reserved. C1 [Sarma, Amy A.; Wood, Malissa J.] Massachusetts Gen Hosp, Dept Cardiol, 55 Fruit St, Boston, MA 02114 USA. [Nkonde-Price, Chileshe] Southern Calif Permanente Med Grp, Dept Cardiol, Pasadena, CA USA. [Gulati, Martha] Univ Arizona, Dept Cardiol, Phoenix, AZ USA. [Duvernoy, Claire S.] Univ Michigan Hlth Syst, Dept Cardiol, VA Ann Arbor Healthcare Syst, Ann Arbor, MI USA. [Lewis, Sandra J.] Oregon Hlth & Sci Univ, Dept Cardiol, Northwest Cardiovasc Inst, Portland, OR 97201 USA. RP Sarma, AA (reprint author), Massachusetts Gen Hosp, Dept Cardiol, 55 Fruit St, Boston, MA 02114 USA. EM Asarma1@partners.org NR 25 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD JAN 3 PY 2017 VL 69 IS 1 BP 92 EP 101 DI 10.1016/j.jacc.2016.09.978 PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EJ1TD UT WOS:000392992200013 PM 28057255 ER PT J AU Janjua, SA Triant, VA Addison, D Szilveszter, B Regan, S Staziaki, PV Grinspoon, SA Hoffmann, U Zanni, MV Neilan, TG AF Janjua, Sumbal A. Triant, Virginia A. Addison, Daniel Szilveszter, Balint Regan, Susan Staziaki, Pedro V. Grinspoon, Steven A. Hoffmann, Udo Zanni, Markella V. Neilan, Tomas G. TI HIV Infection and Heart Failure Outcomes in Women SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Letter C1 [Neilan, Tomas G.] Massachusetts Gen Hosp, Div Cardiol, Cardiac MR PET CT Program, 165 Cambridge St,Suite 400, Boston, MA 02114 USA. [Neilan, Tomas G.] Massachusetts Gen Hosp, Dept Radiol, 165 Cambridge St,Suite 400, Boston, MA 02114 USA. RP Neilan, TG (reprint author), Massachusetts Gen Hosp, Div Cardiol, Cardiac MR PET CT Program, 165 Cambridge St,Suite 400, Boston, MA 02114 USA.; Neilan, TG (reprint author), Massachusetts Gen Hosp, Dept Radiol, 165 Cambridge St,Suite 400, Boston, MA 02114 USA. EM tneilan@partners.org NR 2 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD JAN 3 PY 2017 VL 69 IS 1 BP 107 EP 108 DI 10.1016/j.jacc.2016.11.013 PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EJ1TD UT WOS:000392992200017 PM 28057235 ER PT J AU Goldfine, AB Shoelson, SE AF Goldfine, Allison B. Shoelson, Steven E. TI Therapeutic approaches targeting inflammation for diabetes and associated cardiovascular risk SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Review ID C-REACTIVE PROTEIN; PLACEBO-CONTROLLED TRIAL; NECROSIS-FACTOR-ALPHA; FACTOR-KAPPA-B; IMPAIRED GLUCOSE-TOLERANCE; LIFE-STYLE INTERVENTION; NONSTEROIDAL ANTIINFLAMMATORY DRUGS; INTERLEUKIN-1 RECEPTOR ANTAGONIST; RANDOMIZED CONTROLLED-TRIAL; BLOOD-CELL COUNT AB Obesity-related sub-acute chronic inflammation has been associated with incident type 2 diabetes and atherosclerotic cardiovascular disease. Inflammation is increasingly considered to be a pathologic mediator of these commonly co-occurring diseases. A growing number of preclinical and clinical studies support the inflammatory hypothesis, but clinical trials to confirm the therapeutic potential to target inflammation to treat or prevent cardiometabolic conditions are still ongoing. There are multiple inflammatory signaling pathways. Regulation is complex, with substantial crosstalk across these multiple pathways. The activity of select pathways may be differentially regulated in different tissues. Pharmacologic approaches to diabetes management may have direct or indirect antiinflammatory effects, the latter potentially attributable to an improved metabolic state. Conversely, some antiinflammatory approaches may affect glucose metabolism and cardiovascular health. To date, clinical trials suggest that targeting one portion of the inflammatory cascade may differentially affect dysglycemia and atherothrombosis. Understanding the underlying biological processes may contribute to the development of safe and effective therapies, although a single approach may not be sufficient for optimal management of both metabolic and athrothrombotic disease states. C1 [Goldfine, Allison B.] Joslin Diabet Ctr, One Joslin Pl, Boston, MA 02215 USA. Harvard Med Sch, Boston, MA USA. EM allison.goldfine@joslin.harvard.edu FU NIH [DK045943, DK051729, DK073547, DK090792, DK095327, DK108936, HL133329, DK074556, HL083813, HL101422, P30DK036836]; American Diabetes Association [1-06-RA-126, 7-04-MN-47, 7-06-CVD-31, 7-08-MN-55, 7-09-CVD-08, 1-12-CT-71, 7-12-MN-77, 7-13-CE-17]; Helen and Morton Adler Chair FX This work was supported by NIH grants DK045943, DK051729, DK073547, DK090792, DK095327, DK108936 and HL133329 (to SES); DK074556, and HL083813 (to ABG and SES); and HL101422 (ABG); American Diabetes Association grants 1-06-RA-126, 7-04-MN-47, 7-06-CVD-31, 7-08-MN-55, 7-09-CVD-08, 1-12-CT-71, and 7-12-MN-77 (to SES) and 7-13-CE-17 (to ABG); and the Helen and Morton Adler Chair (to SES). We gratefully acknowledge use of core facilities of the Joslin Diabetes Center, which are supported by NIH P30DK036836. NR 209 TC 1 Z9 1 U1 3 U2 3 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 2015 MANCHESTER RD, ANN ARBOR, MI 48104 USA SN 0021-9738 EI 1558-8238 J9 J CLIN INVEST JI J. Clin. Invest. PD JAN 3 PY 2017 VL 127 IS 1 BP 83 EP 93 DI 10.1172/JCI88884 PG 11 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EI1UK UT WOS:000392271300010 PM 28045401 ER PT J AU Cunningham, TJ Tabacchi, M Eliane, JP Tuchayi, SM Manivasagam, S Mirzaalian, H Turkoz, A Kopan, R Schaffer, A Saavedra, AP Wallendorf, M Cornelius, LA Demehri, S AF Cunningham, Trevor J. Tabacchi, Mary Eliane, Jean-Pierre Tuchayi, Sara Moradi Manivasagam, Sindhu Mirzaalian, Hengameh Turkoz, Ahu Kopan, Raphael Schaffer, Andras Saavedra, Arturo P. Wallendorf, Michael Cornelius, Lynn A. Demehri, Shadmehr TI Randomized trial of calcipotriol combined with 5-fluorouracil for skin cancer precursor immunotherapy SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID THYMIC STROMAL LYMPHOPOIETIN; ACTINIC KERATOSIS TREATMENT; ATOPIC-DERMATITIS; MOUSE SKIN; T-CELLS; KERATINOCYTES; CARCINOGENESIS; 2.5-PERCENT; VITAMIN-D3; INDUCTION AB BACKGROUND. Actinic keratosis is a precursor to cutaneous squamous cell carcinoma. Long treatment durations and severe side effects have limited the efficacy of current actinic keratosis treatments. Thymic stromal lymphopoietin (TSLP) is an epithelium-derived cytokine that induces a robust antitumor immunity in barrier-defective skin. Here, we investigated the efficacy of calcipotriol, a topical TSLP inducer, in combination with 5-fluorouracil (5-FU) as an immunotherapy for actinic keratosis. METHODS. The mechanism of calcipotriol action against skin carcinogenesis was examined in genetically engineered mouse models. The efficacy and safety of 0.005% calcipotriol ointment combined with 5% 5-FU cream were compared with Vaseline plus 5-FU for the field treatment of actinic keratosis in a randomized, double-blind clinical trial involving 131 participants. The assigned treatment was self-applied to the entirety of the qualified anatomical sites (face, scalp, and upper extremities) twice daily for 4 consecutive days. The percentage of reduction in the number of actinic keratoses (primary outcome), local skin reactions, and immune activation parameters were assessed. RESULTS. Calcipotriol suppressed skin cancer development in mice in a TSLP-dependent manner. Four-day application of calcipotriol plus 5-FU versus Vaseline plus 5-FU led to an 87.8% versus 26.3% mean reduction in the number of actinic keratoses in participants (P < 0.0001). Importantly, calcipotriol plus 5-FU treatment induced TSLP, HLA class II, and natural killer cell group 2D (NKG2D) ligand expression in the lesional keratinocytes associated with a marked CD4+ T cell infiltration, which peaked on days 10-11 after treatment, without pain, crusting, or ulceration. CONCLUSION. Our findings demonstrate the synergistic effects of calcipotriol and 5-FU treatment in optimally activating a CD4+ T cell-mediated immunity against actinic keratoses and, potentially, cancers of the skin and other organs. C1 [Cunningham, Trevor J.; Tuchayi, Sara Moradi; Saavedra, Arturo P.; Demehri, Shadmehr] Massachusetts Gen Hosp, Ctr Canc Immunobiol, Boston, MA 02114 USA. [Cunningham, Trevor J.; Tuchayi, Sara Moradi; Saavedra, Arturo P.; Demehri, Shadmehr] Massachusetts Gen Hosp, Dept Dermatol, Cutaneous Biol Res Ctr, Boston, MA 02114 USA. [Cunningham, Trevor J.; Tuchayi, Sara Moradi; Saavedra, Arturo P.; Demehri, Shadmehr] Massachusetts Gen Hosp, Ctr Canc Res, Boston, MA 02114 USA. [Cunningham, Trevor J.; Eliane, Jean-Pierre; Tuchayi, Sara Moradi; Mirzaalian, Hengameh; Saavedra, Arturo P.; Demehri, Shadmehr] Harvard Med Sch, Boston, MA USA. [Cunningham, Trevor J.; Tabacchi, Mary; Manivasagam, Sindhu; Cornelius, Lynn A.; Demehri, Shadmehr] Washington Univ, Sch Med, Dept Med, Div Dermatol, St Louis, MO 63110 USA. [Eliane, Jean-Pierre] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Mirzaalian, Hengameh] Boston Childrens Hosp, Dept Radiol, Boston, MA USA. [Turkoz, Ahu; Kopan, Raphael] Cincinnati Childrens Hosp Med Ctr, Div Dev Biol, Cincinnati, OH 45229 USA. [Schaffer, Andras] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO USA. [Wallendorf, Michael] Washington Univ, Sch Med, Div Biostat, St Louis, MO 63110 USA. EM sdemehri1@mgh.harvard.edu FU American Skin Association; Dermatology Foundation; Burroughs Wellcome Fund; American Philosophical Society; La Roche-Posay Research Foundation; NIH [1DP5OD021353, RO1GM055479] FX We thank Caroline Mann, Milan Anadkat, Amy Musiek, Ian Hornstra, David Sheinbein, Guadalupe Sanches, Laurin Council, and Eva Hurst at Washington University for referring patients to this study. We thank Ethan Lerner, David Fisher, Barbara Gilchrest, Nir Hacohen, and Keith Flaherty (Massachusetts General Hospital, Boston, MA, USA) for critically reading the manuscript. We also thank Warren Leonard (NIH, Bethesda, MD, USA) for the TSLPR-/- mice. SD and TJC were supported by grants from the American Skin Association, the Dermatology Foundation, the Burroughs Wellcome Fund, the American Philosophical Society, the La Roche-Posay Research Foundation, and the NIH (1DP5OD021353). RK, AT, and SM were supported by NIH grant RO1GM055479 (to RK). NR 35 TC 1 Z9 1 U1 3 U2 3 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 2015 MANCHESTER RD, ANN ARBOR, MI 48104 USA SN 0021-9738 EI 1558-8238 J9 J CLIN INVEST JI J. Clin. Invest. PD JAN 3 PY 2017 VL 127 IS 1 BP 106 EP 116 DI 10.1172/JCI89820 PG 11 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EI1UK UT WOS:000392271300015 PM 27869649 ER PT J AU Ostrem, JL San Luciano, M Dodenhoff, KA Ziman, N Markun, LC Racine, CA de Hemptinne, C Volz, MM Heath, SL Starr, PA AF Ostrem, Jill L. San Luciano, Marta Dodenhoff, Kristen A. Ziman, Nathan Markun, Leslie C. Racine, Caroline A. de Hemptinne, Coralie Volz, Monica M. Heath, Susan L. Starr, Philip A. TI Subthalamic nucleus deep brain stimulation in isolated dystonia A 3-year follow-up study SO NEUROLOGY LA English DT Article ID PRIMARY GENERALIZED DYSTONIA; CRANIAL-CERVICAL DYSTONIA; SEGMENTAL DYSTONIA; BILATERAL PALLIDOTOMY; SECONDARY DYSTONIA; PARKINSON-DISEASE; IMPLANTATION; DURATION; TRIAL AB Objective: To report long-term safety and efficacy outcomes of a large cohort of patients with medically refractory isolated dystonia treated with subthalamic nucleus (STN) deep brain stimulation (DBS). Methods: Twenty patients (12 male, 8 female; mean age 49 +/- 16.3 years) with medically refractory isolated dystonia were studied (14 were followed for 36 months). The primary endpoints were change in Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) motor score and Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) total score at 36 months compared to preoperative baseline. Multiple secondary outcomes were also assessed (ClinicalTrials.gov NCT00773604). Results: Eighteen of 20 patients showed improvement 12 months after STN DBS with sustained benefit persisting for 3 years (n = 14). At 36 months, BFMDRS motor scores improved 70.4% from a mean 17.9 +/- 8.5 to 5.3 +/- 5.6 (p = 0.0002) and total TWSTRS scores improved 66.6% from a mean 41.0 +/- 18.9 to 13.7 +/- 17.9 (p = 0.0002). Improvement at 36 months was equivalent to that seen at 6 months. Disability and quality of life measures were also improved. Three hardware-related and 24 stimulation-related nonserious adverse events occurred between years 1 and 3 (including 4 patients with dyskinesia). Conclusions: This study offers support for long-term tolerability and sustained effectiveness of STN DBS in the treatment of severe forms of isolated dystonia. Classification of evidence: This study provides Class IV evidence that STN DBS decreases long-term dystonia severity in patients with medically refractory isolated dystonia. C1 [Ostrem, Jill L.; San Luciano, Marta; Dodenhoff, Kristen A.; Ziman, Nathan; Markun, Leslie C.; Volz, Monica M.] Univ Calif San Francisco, Dept Neurol, Movement Disorders & Neuromodulat Ctr, San Francisco, CA 94143 USA. [Racine, Caroline A.; de Hemptinne, Coralie; Starr, Philip A.] Univ Calif San Francisco, Dept Neurol Surg, San Francisco, CA USA. [Ostrem, Jill L.; Markun, Leslie C.; Heath, Susan L.; Starr, Philip A.] San Francisco VA Med Ctr, Parkinsons Dis Res Educ & Clin Ctr, San Francisco, CA USA. RP Ostrem, JL (reprint author), Univ Calif San Francisco, Dept Neurol, Movement Disorders & Neuromodulat Ctr, San Francisco, CA 94143 USA.; Ostrem, JL (reprint author), San Francisco VA Med Ctr, Parkinsons Dis Res Educ & Clin Ctr, San Francisco, CA USA. EM jill.ostrem@ucsf.edu FU Bachmann Strauss Dystonia; Parkinson's Disease Foundation; Benign Essential Blepharospasm Research Foundation FX Supported by Bachmann Strauss Dystonia and Parkinson's Disease Foundation and the Benign Essential Blepharospasm Research Foundation. NR 36 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD JAN 3 PY 2017 VL 88 IS 1 BP 25 EP 35 PG 11 WC Clinical Neurology SC Neurosciences & Neurology GA EI1OE UT WOS:000392246100009 PM 27903810 ER PT J AU Huynh, E Coroller, TP Narayan, V Agrawal, V Romano, J Franco, I Parmar, C Hou, Y Mak, RH Aerts, HJWL AF Huynh, Elizabeth Coroller, Thibaud P. Narayan, Vivek Agrawal, Vishesh Romano, John Franco, Idalid Parmar, Chintan Hou, Ying Mak, Raymond H. Aerts, Hugo J. W. L. TI Associations of Radiomic Data Extracted from Static and Respiratory-Gated CT Scans with Disease Recurrence in Lung Cancer Patients Treated with SBRT SO PLOS ONE LA English DT Article ID STEREOTACTIC BODY RADIOTHERAPY; PROSPECTIVE PHASE-II; RADIATION-THERAPY; EARLY-STAGE; COMPUTED-TOMOGRAPHY; FEATURES; OUTCOMES; VARIABILITY; CARCINOMA; TEXTURE AB Radiomics aims to quantitatively capture the complex tumor phenotype contained in medical images to associate them with clinical outcomes. This study investigates the impact of different types of computed tomography (CT) images on the prognostic performance of radiomic features for disease recurrence in early stage non-small cell lung cancer (NSCLC) patients treated with stereotactic body radiation therapy (SBRT). 112 early stage NSCLC patients treated with SBRT that had static free breathing (FB) and average intensity projection (AIP) images were analyzed. Nineteen radiomic features were selected from each image type (FB or AIP) for analysis based on stability and variance. The selected FB and AIP radiomic feature sets had 6 common radiomic features between both image types and 13 unique features. The prognostic performances of the features for distant metastasis (DM) and locoregional recurrence (LRR) were evaluated using the concordance index (CI) and compared with two conventional features (tumor volume and maximum diameter). P-values were corrected for multiple testing using the false discovery rate procedure. None of the FB radiomic features were associated with DM, however, seven AIP radiomic features, that described tumor shape and heterogeneity, were (CI range: 0.638-0.676). Conventional features from FB images were not associated with DM, however, AIP conventional features were (CI range: 0.643-0.658). Radiomic and conventional multivariate models were compared between FB and AIP images using cross validation. The differences between the models were assessed using a permutation test. AIP radiomic multivariate models (median CI = 0.667) outperformed all other models (median CI range: 0.601-0.630) in predicting DM. None of the imaging features were prognostic of LRR. Therefore, image type impacts the performance of radiomic models in their association with disease recurrence. AIP images contained more information than FB images that were associated with disease recurrence in early stage NSCLC patients treated with SBRT, which suggests that AIP images may potentially be more optimal for the development of an imaging biomarker. C1 [Huynh, Elizabeth; Coroller, Thibaud P.; Narayan, Vivek; Agrawal, Vishesh; Romano, John; Franco, Idalid; Parmar, Chintan; Hou, Ying; Mak, Raymond H.; Aerts, Hugo J. W. L.] Harvard Med Sch, Brigham & Womens Hosp, Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA. [Aerts, Hugo J. W. L.] Harvard Med Sch, Brigham & Womens Hosp, Dana Farber Canc Inst, Dept Radiol, Boston, MA USA. RP Huynh, E (reprint author), Harvard Med Sch, Brigham & Womens Hosp, Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA. EM ehuynh@lroc.harvard.edu RI Aerts, Hugo/P-6350-2015 OI Aerts, Hugo/0000-0002-2122-2003 FU National Institute of Health [NIH-USA U24CA194354, NIH-USA U01CA190234]; Kaye Scholar Award; Brigham and Women's Hospital Department of Radiation Oncology Clinical Translational Grant; Varian Medical Research Collaborations FX Authors acknowledge financial support from the National Institute of Health (NIH-USA U24CA194354, and NIH-USA U01CA190234). This project was partially funded by the Kaye Scholar Award, the Brigham and Women's Hospital Department of Radiation Oncology Clinical Translational Grant and Varian Medical Research Collaborations. The study sponsors had no role in study design data collection and analysis, decision to publish, or preparation of the manuscript. NR 46 TC 0 Z9 0 U1 2 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 3 PY 2017 VL 12 IS 1 AR e0169172 DI 10.1371/journal.pone.0169172 PG 17 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EH2QJ UT WOS:000391612300135 PM 28046060 ER PT J AU Garcia-Albeniz, X Hsu, J Bretthauer, M Hernan, MA AF Garcia-Albeniz, Xabier Hsu, John Bretthauer, Michael Hernan, Miguel A. TI Effectiveness of Screening Colonoscopy to Prevent Colorectal Cancer Among Medicare Beneficiaries Aged 70 to 79 Years A Prospective Observational Study SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID FECAL OCCULT BLOOD; RANDOMIZED CONTROLLED-TRIAL; CORONARY-HEART-DISEASE; CLINICAL-TRIAL; LOWER ENDOSCOPY; TASK-FORCE; FOLLOW-UP; POPULATION; MORTALITY; SIGMOIDOSCOPY AB Background: No randomized, controlled trials of screening colonoscopy have been completed, and ongoing trials exclude persons aged 75 years or older. The Medicare program, however, reimburses screening colonoscopy without an upper age limit. Objective: To evaluate the effectiveness and safety of screening colonoscopy to prevent colorectal cancer (CRC) in persons aged 70 to 74 and those aged 75 to 79 years. Design: Large-scale, population-based, prospective study. The observational data were used to emulate a target trial with 2 groups: colonoscopy screening and no screening. Setting: United States. Participants: 1 355 692 Medicare beneficiaries (2004 to 2012) aged 70 to 79 years at average risk for CRC who used Medicare preventive services and had no previous diagnostic or surveillance colonoscopies in the past 5 years. Measurements: 8-year risk for CRC and 30-day risk for adverse events. Results: In beneficiaries aged 70 to 74 years, the 8-year risk for CRC was 2.19% (95% CI, 2.00% to 2.37%) in the screening colonoscopy group and 2.62% (CI, 2.56% to 2.67%) in the no-screening group (absolute risk difference, - 0.42% [CI, -0.24% to -0.63%]). Among those aged 75 to 79 years, the 8-year risk for CRC was 2.84% (CI, 2.54% to 3.13%) in the screening colonoscopy group and 2.97% (CI, 2.92% to 3.03%) in the no-screening group (risk difference, -0.14% [CI, -0.41 to 0.16]). The excess 30-day risk for any adverse event in the colonoscopy group was 5.6 events per 1000 individuals (CI, 4.4 to 6.8) in the 70- to 74-year age group and 10.3 per 1000 (CI, 8.6 to 11.1) in the 75- to 79-year age group. Limitation: CRC-specific mortality was not available, but CRC incidence and stage were studied at diagnosis. Conclusion: Screening colonoscopy may have had a modest benefit in preventing CRC in beneficiaries aged 70 to 74 years and a smaller benefit in older beneficiaries. The risk for adverse events was low but greater among older persons. C1 [Garcia-Albeniz, Xabier; Hernan, Miguel A.] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, 677 Huntington Ave, Boston, MA 02115 USA. [Hsu, John] Massachusetts Gen Hosp, Mongan Inst, 50 Staniford St,9th Floor, Boston, MA 02114 USA. [Bretthauer, Michael] Univ Oslo, Inst Hlth & Soc, POB 1089, N-0318 Oslo, Norway. RP Garcia-Albeniz, X (reprint author), Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, 677 Huntington Ave, Boston, MA 02115 USA. EM xabi@post.harvardedu FU National Institutes of Health (NIH) [P01-AG032952, P01-CA134294, R01-CA164023, R01-HS023128] FX By National Institutes of Health (NIH) grants P01-AG032952, P01-CA134294, R01-CA164023, and R01-HS023128. NR 50 TC 1 Z9 1 U1 4 U2 4 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 JAN 3 PY 2017 VL 166 IS 1 BP 18 EP + DI 10.7326/M16-0758 PG 13 WC Medicine, General & Internal SC General & Internal Medicine GA EH0QD UT WOS:000391467900005 PM 27669524 ER PT J AU Weinrauch, LA D'Elia, JA AF Weinrauch, Larry A. D'Elia, John A. TI The Fight Against Multidrug-Resistant Bacteria SO ANNALS OF INTERNAL MEDICINE LA English DT Letter ID CALCIUM-CHANNEL BLOCKERS C1 [Weinrauch, Larry A.] Harvard Med Sch, Boston, MA 02115 USA. [D'Elia, John A.] Joslin Diabet Ctr, Boston, MA 02215 USA. RP Weinrauch, LA (reprint author), Harvard Med Sch, Boston, MA 02115 USA. NR 5 TC 0 Z9 0 U1 1 U2 1 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 EI 1539-3704 J9 ANN INTERN MED JI Ann. Intern. Med. PD JAN 3 PY 2017 VL 166 IS 1 BP 77 EP 78 DI 10.7326/L16-0583 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA EH0QD UT WOS:000391467900018 PM 28030673 ER PT J AU Burstein, HJ Schrag, D AF Burstein, Harold J. Schrag, Deborah TI Biosimilar Therapy for ERBB2 (HER2)-Positive Breast Cancer Close Enough? SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material ID PLUS; CHEMOTHERAPY; DOCETAXEL; HER2 C1 [Burstein, Harold J.; Schrag, Deborah] Harvard Med Sch, Brigham & Womens Hosp, Dana Farber Canc Inst, Boston, MA USA. RP Schrag, D (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. EM deb_schrag@dfci.harvard.edu NR 11 TC 0 Z9 0 U1 1 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JAN 3 PY 2017 VL 317 IS 1 BP 30 EP 32 DI 10.1001/jama.2016.18979 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA EG4JE UT WOS:000391009100015 PM 27918782 ER PT J AU Zangi, L Oliveira, MS Ye, LY Ma, Q Sultana, N Hadas, Y Chepurko, E Spater, D Zhou, B Chew, WL Ebina, W Abrial, M Wang, QD Pu, WT Chien, KR AF Zangi, Lior Oliveira, Marcela S. Ye, Lillian Y. Ma, Qing Sultana, Nishat Hadas, Yoav Chepurko, Elena Spater, Daniela Zhou, Bin Chew, Wei Leong Ebina, Wataru Abrial, Maryline Wang, Qing-Dong Pu, William T. Chien, Kenneth R. TI Insulin-Like Growth Factor 1 Receptor-Dependent Pathway Drives Epicardial Adipose Tissue Formation After Myocardial Injury SO CIRCULATION LA English DT Article DE epicardial adipose tissue; epicardium; insulin-like growth factor-1; myocardial infarction; Wt1 ID MODIFIED MESSENGER-RNA; MESENCHYMAL TRANSFORMATION; PROGENITORS CONTRIBUTE; STEM-CELLS; IN-VIVO; HEART; FATE; ADULT; WT1; ADIPOGENESIS AB BACKGROUND: Epicardial adipose tissue volume and coronary artery disease are strongly associated, even after accounting for overall body mass. Despite its pathophysiological significance, the origin and paracrine signaling pathways that regulate epicardial adipose tissue's formation and expansion are unclear. METHODS: We used a novel modified mRNA-based screening approach to probe the effect of individual paracrine factors on epicardial progenitors in the adult heart. RESULTS: Using 2 independent lineage-tracing strategies in murine models, we show that cells originating from the Wt1+ mesothelial lineage, which includes epicardial cells, differentiate into epicardial adipose tissue after myocardial infarction. This differentiation process required Wt1 expression in this lineage and was stimulated by insulin-like growth factor 1 receptor (IGF1R) activation. IGF1R inhibition within this lineage significantly reduced its adipogenic differentiation in the context of exogenous, IGF1modified mRNA stimulation. Moreover, IGF1R inhibition significantly reduced Wt1 lineage cell differentiation into adipocytes after myocardial infarction. CONCLUSIONS: Our results establish IGF1R signaling as a key pathway that governs epicardial adipose tissue formation in the context of myocardial injury by redirecting the fate of Wt1+ lineage cells. Our study also demonstrates the power of modified mRNA-based paracrine factor library screening to dissect signaling pathways that govern progenitor cell activity in homeostasis and disease. C1 [Zangi, Lior; Sultana, Nishat; Hadas, Yoav] Icahn Sch Med Mt Sinai, Cardiovasc Res Ctr, Dept Genet & Genom Sci, New York, NY 10029 USA. [Zangi, Lior; Sultana, Nishat; Hadas, Yoav] Icahn Sch Med Mt Sinai, Black Family Stem Cell Inst, New York, NY USA. [Zangi, Lior; Oliveira, Marcela S.; Ye, Lillian Y.; Ma, Qing; Pu, William T.] Boston Childrens Hosp, Dept Cardiol, Boston, MA USA. [Spater, Daniela; Wang, Qing-Dong] AstraZeneca, Cardiovasc & Metab Dis Innovat Med Biotech Unit, Molndal, Sweden. [Zhou, Bin] Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Biochem & Cell Biol, State Key Lab Cell Biol, Beijing 100864, Peoples R China. [Chew, Wei Leong] Harvard Med Sch, Dept Genet, Boston, MA USA. [Ebina, Wataru; Pu, William T.] Harvard Med Sch, Harvard Stem Cell Inst, Boston, MA USA. [Abrial, Maryline] Harvard Med Sch, Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA USA. [Chien, Kenneth R.] Karolinska Inst, Dept Cell & Mol Biol & Med, Stockholm, Sweden. RP Zangi, L (reprint author), Icahn Sch Med, One Gustave L Levy Pl,Box 1030, New York, NY 10029 USA.; Pu, WT (reprint author), Boston Childrens Hosp, Enders 1254,300 Longwood Ave, Boston, MA 02115 USA.; Chien, KR (reprint author), Karolinska Inst, 35 Berzelius Vag, S-17117 Stockholm, Sweden. EM lior.zangi@mssm.edu; wpu@pulab.org; kenneth.chien@ki.se FU National Institutes of Health [R01 HL094683, U01 HL100401]; American Heart Association; Wallenberg Foundation; Karolinska Institute-AstraZeneca Integrated Cardio Metabolic Center; Distinguished Professorship of the Swedish Research Council; Cardiovascular Research Center, Icahn School of Medicine at Mt. Sinai, New York FX Dr Pu was supported by National Institutes of Health grants R01 HL094683 and U01 HL100401, an Established Investigator Award from the American Heart Association, and charitable contributions from Dr and Mrs Edwin A. Boger. Dr Zangi was supported by a postdoctoral fellowship from the American Heart Association. Dr Chien was supported by the Wallenberg Foundation, the Karolinska Institute-AstraZeneca Integrated Cardio Metabolic Center, and a Distinguished Professorship of the Swedish Research Council. Dr Zangi was also supported by seed package funds from the Cardiovascular Research Center, Icahn School of Medicine at Mt. Sinai, New York. NR 40 TC 1 Z9 1 U1 2 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD JAN 3 PY 2017 VL 135 IS 1 BP 59 EP + DI 10.1161/CIRCULATIONAHA.116.022064 PG 38 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA EF8ED UT WOS:000390560700011 PM 27803039 ER PT J AU Rooks, MG Veiga, P Reeves, AZ Lavoie, S Yasuda, K Asano, Y Yoshihara, K Michaud, M Wardwell-Scott, L Gallini, CA Glickman, JN Sudo, N Huttenhower, C Lesser, CF Garrett, WS AF Rooks, Michelle G. Veiga, Patrick Reeves, Analise Z. Lavoie, Sydney Yasuda, Koji Asano, Yasunari Yoshihara, Kazufumi Michaud, Monia Wardwell-Scott, Leslie Gallini, Carey Ann Glickman, Jonathan N. Sudo, Nobuyuki Huttenhower, Curtis Lesser, Cammie F. Garrett, Wendy S. TI QseC inhibition as an antivirulence approach for colitis-associated bacteria SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE colitis; Escherichia coli; QseC; antivirulence; gut microbiome ID INVASIVE ESCHERICHIA-COLI; INFLAMMATORY-BOWEL-DISEASE; CROHNS-DISEASE; ILEAL MUCOSA; HOST COMMUNICATION; GUT MICROBIOTA; VIRULENCE; MOTILITY; PATIENT; FLORA AB Hosts and their microbes have established a sophisticated communication system over many millennia. Within mammalian hosts, this dynamic cross-talk is essential for maintaining intestinal homeostasis. In a genetically susceptible host, dysbiosis of the gut microbiome and dysregulated immune responses are central to the development of inflammatory bowel disease (IBD). Previous surveys of stool from the T-bet(-/-)Rag2(-/-) IBD mouse model revealed microbial features that discriminate between health and disease states. Enterobacteriaceae expansion and increased gene abundances for benzoate degradation, two-component systems, and bacterial motility proteins pointed to the potential involvement of a catecholamine-mediated bacterial signaling axis in colitis pathogenesis. Enterobacteriaceae sense and respond tomicrobiota-generated signals and host-derived catecholamines through the two-component quorum-sensing Escherichia coli regulators B and C (QseBC) system. On signal detection, QseC activates a cascade to induce virulence gene expression. Although a single pathogen has not been identified as a causative agent in IBD, adherent-invasive Escherichia coli (AIEC) have been implicated. Flagellar expression is necessary for the IBD-associated AIEC strain LF82 to establish colonization. Thus, we hypothesized that qseC inactivation could reduce LF82's virulence, and found that an absence of qseC leads to down-regulated flagellar expression and motility in vitro and reduced colonization in vivo. We extend these findings on the potential of QseC-based IBD therapeutics to three preclinical IBD models, wherein we observe that QseC blockade can effectively modulate colitogenic microbiotas to reduce intestinal inflammation. Collectively, our data support a role for QseC-mediated bacterial signaling in IBD pathogenesis and indicate that QseC inhibition may be a useful microbiota-targeted approach for disease management. C1 [Rooks, Michelle G.; Veiga, Patrick; Lavoie, Sydney; Michaud, Monia; Wardwell-Scott, Leslie; Gallini, Carey Ann; Garrett, Wendy S.] Harvard TH Chan Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. [Rooks, Michelle G.; Veiga, Patrick; Lavoie, Sydney; Michaud, Monia; Wardwell-Scott, Leslie; Gallini, Carey Ann; Garrett, Wendy S.] Harvard TH Chan Sch Publ Hlth, Dept Genet & Complex Dis, Boston, MA 02115 USA. [Veiga, Patrick] Danone Nutricia Res, F-91767 Palaiseau, France. [Reeves, Analise Z.; Lesser, Cammie F.] Massachusetts Gen Hosp, Dept Med, Div Infect Dis, Boston, MA 02139 USA. [Reeves, Analise Z.; Lesser, Cammie F.] Harvard Med Sch, Dept Microbiol & Immunobiol, Boston, MA 02115 USA. [Yasuda, Koji; Huttenhower, Curtis] Harvard TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Yasuda, Koji; Huttenhower, Curtis; Garrett, Wendy S.] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. [Asano, Yasunari; Yoshihara, Kazufumi; Sudo, Nobuyuki] Kyushu Univ, Grad Sch Med Sci, Dept Psychosomat Med, Fukuoka 8128582, Japan. [Wardwell-Scott, Leslie; Garrett, Wendy S.] Harvard Med Sch, Div Med Sci, Boston, MA 02115 USA. [Glickman, Jonathan N.] Beth Israel Deaconess Med Ctr, Dept Pathol, 330 Brookline Ave, Boston, MA 02215 USA. [Glickman, Jonathan N.] Harvard Med Sch, Dept Pathol, Boston, MA 02115 USA. [Garrett, Wendy S.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. RP Garrett, WS (reprint author), Harvard TH Chan Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA.; Garrett, WS (reprint author), Harvard TH Chan Sch Publ Hlth, Dept Genet & Complex Dis, Boston, MA 02115 USA.; Garrett, WS (reprint author), Broad Inst MIT & Harvard, Cambridge, MA 02142 USA.; Garrett, WS (reprint author), Harvard Med Sch, Div Med Sci, Boston, MA 02115 USA.; Garrett, WS (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. EM wgarrett@hsph.harvard.edu RI Veiga, Patrick/A-9862-2011 OI Veiga, Patrick/0000-0001-6318-8547 FU National Institutes of Health [R01 CA154426, R01 GM099531] FX We thank members of the W.S.G. laboratory for discussions, M. Ericsson for TEM assistance, Dr. A. Darfeuille-Michaud for providing LF82, and Drs. A. Ramer-Tait, M. Wannemuehler, and G. Phillips for providing ASF strains. This study was supported by National Institutes of Health Grants R01 CA154426 and R01 GM099531 (to W.S.G.). NR 58 TC 0 Z9 0 U1 12 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 JAN 3 PY 2017 VL 114 IS 1 BP 142 EP 147 DI 10.1073/pnas.1612836114 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EG5OM UT WOS:000391093700041 PM 27980034 ER PT J AU Chandrasekaran, A Ellett, F Jorgensen, J Irimia, D AF Chandrasekaran, Arvind Ellett, Felix Jorgensen, Julianne Irimia, Daniel TI Temporal gradients limit the accumulation of neutrophils toward sources of chemoattractant SO MICROSYSTEMS & NANOENGINEERING LA English DT Article DE chemotaxis; leukocyte; microfluidic; relay signaling; scavenging ID CHEMOTAXIS; INFLAMMATION; RESPONSES AB Neutrophil trafficking during inflammation is a highly orchestrated process, coordinating neutrophil recruitment, sterilization of the wound, and inflammation resolution. Although the chemotactic signals guiding neutrophil recruitment to sites of inflammation are relatively well understood, our knowledge of mechanisms controlling cessation of neutrophil recruitment and return to normal tissue physiology remains incomplete. To gain insights into these processes, we designed a microfluidic device with an array of chemoattractant reservoirs, which mimics the microenvironment in infected tissues, when multiple clusters of microbes are present. We monitored the temporal dynamics of neutrophil recruitment toward the chemoattractant reservoirs at single cell resolution, for 3 h. We observed robust neutrophil recruitment that reached a plateau after 1.5 h, despite the continuous presence of strong chemoattractant gradients around the reservoirs. The timing of the plateau was dependent on the geometry of the devices and was independent from the number of neutrophils. On the basis of these observations, we ruled out sub-population sensitivity, chemoattractant scavenging, and production of a self-limiting stop signal as potential mechanisms underpinning the plateau in neutrophil recruitment. We found a strong correlation between the temporal stabilization of concentration changes and the plateau in neutrophils recruitment. These results suggest that dynamic aspects of chemoattractant gradients are key for maximizing recruitment during the acute phase of infections and limiting the accumulation of neutrophils as soon as the infection is contained. C1 [Chandrasekaran, Arvind; Ellett, Felix; Jorgensen, Julianne; Irimia, Daniel] Massachusetts Gen Hosp, Shriners Burns Hosp, BioMEMS Resource Ctr, Harvard Med Sch,Dept Surg, Boston, MA 02129 USA. RP Irimia, D (reprint author), Massachusetts Gen Hosp, Shriners Burns Hosp, BioMEMS Resource Ctr, Harvard Med Sch,Dept Surg, Boston, MA 02129 USA. EM dirimia@mgh.harvard.edu NR 24 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 2055-7434 J9 MICROSYST NANOENG JI Microsyst. Nanoeng. PD JAN 2 PY 2017 VL 3 AR UNSP 16067 DI 10.1038/micronano.2016.67 PG 8 WC Instruments & Instrumentation SC Instruments & Instrumentation GA EL9QC UT WOS:000394954100002 ER PT J AU Haberer, JE Musinguzi, N Tsai, AC Boum, Y Bwana, BM Muzoora, C Hunt, PW Martin, JN Bangsberg, DR AF Haberer, Jessica E. Musinguzi, Nicholas Tsai, Alexander C. Boum, Yap, II Bwana, Bosco M. Muzoora, Conrad Hunt, Peter W. Martin, Jeffrey N. Bangsberg, David R. TI Real-time electronic adherence monitoring plus follow-up improves adherence compared with standard electronic adherence monitoring SO AIDS LA English DT Letter ID ANTIRETROVIRAL THERAPY ADHERENCE; RURAL UGANDA; SMS REMINDERS; DEPRESSION AB The impact of real-time electronic monitoring on antiretroviral therapy adherence warrants further study. We conducted an analysis of cohort participants that initially involved standard electronic adherence monitoring (EAM), followed by real-time EAM and home visits for sustained at least 48-h adherence interruptions. Immediately after switching between the two types of EAM, mean adherence among 112 participants increased from 84% to 93% and remained elevated for 6 months (P<0.001). Real-time EAM is a promising approach for improving adherence. C1 [Haberer, Jessica E.; Tsai, Alexander C.; Bangsberg, David R.] Massachusetts Gen Hosp Global Hlth, 125 Nashua St,Suite 722, Boston, MA 02114 USA. [Haberer, Jessica E.; Tsai, Alexander C.; Bangsberg, David R.] Harvard Med Sch, Boston, MA USA. [Musinguzi, Nicholas; Bwana, Bosco M.; Muzoora, Conrad] Mbarara Univ Sci & Technol, Mbarara, Uganda. [Boum, Yap, II] Epicentre Mbarara Res Ctr, Mbarara, Uganda. [Hunt, Peter W.; Martin, Jeffrey N.] Univ Calif San Francisco, San Francisco, CA 94143 USA. RP Haberer, JE (reprint author), Massachusetts Gen Hosp Global Hlth, 125 Nashua St,Suite 722, Boston, MA 02114 USA.; Haberer, JE (reprint author), Harvard Med Sch, Boston, MA USA. EM jhaberer@mgh.harvard.edu FU NIMH NIH HHS [R01 MH054907] NR 18 TC 1 Z9 1 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0269-9370 EI 1473-5571 J9 AIDS JI Aids PD JAN 2 PY 2017 VL 31 IS 1 BP 169 EP 171 DI 10.1097/QAD.0000000000001310 PG 3 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA EF3QY UT WOS:000390240700019 PM 27835622 ER PT J AU Cozma, C Kramp, G Giese, AK Zielke, S Rolfs, A AF Cozma, Claudia Kramp, Guido Giese, Anne-Katrin Zielke, Susanne Rolfs, Arndt TI Lyso-SM-509 is an easy-measurable and sensitive biomarker for Niemann-Pick disease: a two year study SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT 13th Annual Research Meeting on We're Organizing Research for Lysosomal Diseases (WORLD) CY FEB 13-17, 2017 CL San Diego, CA C1 [Cozma, Claudia; Kramp, Guido; Rolfs, Arndt] Centogene AG, Rostock, Germany. [Giese, Anne-Katrin; Zielke, Susanne; Rolfs, Arndt] Univ Rostock, Rostock, Germany. [Giese, Anne-Katrin] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 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 1096-7192 EI 1096-7206 J9 MOL GENET METAB JI Mol. Genet. Metab. PD JAN-FEB PY 2017 VL 120 IS 1-2 MA 64 BP S38 EP S38 DI 10.1016/j.ymgme.2016.11.073 PG 1 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA EK2CC UT WOS:000393734000066 ER PT J AU Kovach, AE Brunner, AM Fathi, AT Chen, YB Hasserjian, RP AF Kovach, Alexandra E. Brunner, Andrew M. Fathi, Amir T. Chen, Yi-Bin Hasserjian, Robert P. TI Prognostic Significance of Residual Acute Myeloid Leukemia in Bone Marrow Samples Taken Prior to Allogeneic Hematopoietic Cell Transplantation SO AMERICAN JOURNAL OF CLINICAL PATHOLOGY LA English DT Article DE Acute myeloid leukemia; Allogeneic hematopoietic cell transplantation; Bone marrow biopsy; Minimal residual disease ID 1ST COMPLETE REMISSION; MYELODYSPLASTIC SYNDROMES; DISEASE BURDEN; NECROSIS; AML; SURVIVAL; RELAPSE; ADULTS; RISK; RECOMMENDATIONS AB Objectives: We sought to identify features in routine evaluation of pre-hematopoietic cell transplantation (HCT) bone marrow samples from patients with acute myeloid leukemia (AML) that influenced patient outcome. Methods: Of 140 patients, evidence of residual leukemia (RL) was identified in 38 (27%) of pre-HCT samples, as defined by 5% or more aspirate blasts, increased blood blasts, clustered or necrotic blasts on biopsy specimens, and/or leukemia-associated karyotypic abnormalities. Results: Morphologic or karyotypic evidence of RL was significantly associated with shorter leukemia-free survival (LFS) compared with cases without identifiable RL (median, 7.1 vs 28.3 months; P<. 0001). Upon multivariable analysis, RL, prior relapse, age, high-risk karyotype, and alternate donor source were each independently associated with shorter LFS. RL in pre-HCT samples was more strongly associated with shorter LFS in patients with intermediate or favorable-risk AML karyotype (P =.001) than secondary or adverse karyotype-risk AML (P =.04). Conclusions: Rigorous morphologic and karyotypic evaluation of pretransplant marrows is practical and important for posttransplant prognosis. C1 [Kovach, Alexandra E.] Vanderbilt Univ, Med Ctr, Dept Pathol Microbiol & Immunol, Nashville, TN USA. [Brunner, Andrew M.; Fathi, Amir T.; Chen, Yi-Bin] Massachusetts Gen Hosp, Dept Hematol Oncol, Boston, MA 02114 USA. [Hasserjian, Robert P.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. RP Hasserjian, RP (reprint author), Massachusetts Gen Hosp, Dept Pathol, Div Hematopathol, 55 Fruit St,Warren 225, Boston, MA 02114 USA. EM rhasserjian@mgh.harvard.edu NR 42 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9173 EI 1943-7722 J9 AM J CLIN PATHOL JI Am. J. Clin. Pathol. PD JAN PY 2017 VL 147 IS 1 BP 50 EP 59 DI 10.1093/AJCP/AQW203 PG 10 WC Pathology SC Pathology GA EP0QI UT WOS:000397091400006 ER PT J AU Su, YH Goncalves, T Dias-Santagata, D Hoang, MP AF Su, Yuhua Goncalves, Theodore Dias-Santagata, Dora Hoang, Mai P. TI Immunohistochemical Detection of ROS1 Fusion SO AMERICAN JOURNAL OF CLINICAL PATHOLOGY LA English DT Article DE ROS1; Immunohistochemistry; Lung carcinoma; Colorectal carcinoma; Translocation ID CELL LUNG-CANCER; ALK FUSIONS; REARRANGEMENTS; ADENOCARCINOMAS; IDENTIFICATION; TUMORS AB Objectives: Patients whose tumors harbor ROS1 translocation may benefit from targeted therapy. Detection of ROS1 rearrangement can be done by three methods: immunohistochemistry, fluorescence in situ hybridization, and molecular assays. Immunohistochemistry would be a cost-effective means to screen for ROS1 translocation, which is uncommon. Methods: ROS1 immunostain was performed on cases with known ROS1 translocation status detected either by fluorescence in situ hybridization or next-generation sequencing. Results: Fifty-seven cases, 10 lung carcinomas with ROS1 rearrangement and 47 cases without ROS1 rearrangement (25 lung carcinomas, 13 gastrointestinal carcinomas, three brain tumors, and six miscellaneous tumors), were included. ROS1 immunostain exhibited 100% sensitivity and 85% specificity, with staining seen in 10 (100%) of 10 cases with ROS1 rearrangement and in seven (15%) of 47 lung cases without ROS1 rearrangement. Weak or 1+ staining of reactive pneumocytes was seen in eight (14%) of 57 cases, and strong staining of osteoclast giant cells was seen in one case. Conclusions: Since ROS1 rearrangement is an infrequent event, immunohistochemistry is a cost-effective screening method. Confirmation of all positive and equivocal/weak staining with molecular assays would exclude the false positive cases. C1 [Hoang, Mai P.] Massachusetts Gen Hosp, Dept Pathol, 55 Fruit St,Warren 820, Boston, MA 02114 USA. Harvard Med Sch, Boston, MA USA. RP Hoang, MP (reprint author), Massachusetts Gen Hosp, Dept Pathol, 55 Fruit St,Warren 820, Boston, MA 02114 USA. EM mhoang@mgh.harvard.edu NR 22 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9173 EI 1943-7722 J9 AM J CLIN PATHOL JI Am. J. Clin. Pathol. PD JAN PY 2017 VL 147 IS 1 BP 77 EP 82 DI 10.1093/AJCP/AQW201 PG 6 WC Pathology SC Pathology GA EP0QI UT WOS:000397091400009 ER PT J AU Datta, M Via, L Chen, W Baish, J Xu, L Barry, C Jain, R AF Datta, Meenal Via, Laura Chen, Wei Baish, James Xu, Lei Barry, Clfton Jain, Rakesh TI Mathematical Model of Oxygen Transport in Tuberculosis Granulomas SO CANCER RESEARCH LA English DT Meeting Abstract CT AACR Special Conference on Engineering and Physical Sciences in Oncology CY JUN 25-28, 2016 CL Boston, MA SP Amer Assoc Canc Res C1 [Datta, Meenal; Chen, Wei; Xu, Lei; Jain, Rakesh] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Via, Laura; Barry, Clfton] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Baish, James] Bucknell Univ, Lewisburg, PA 17837 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 JAN PY 2017 VL 77 SU 2 MA B59 DI 10.1158/1538-7445.EPSO16-B59 PG 2 WC Oncology SC Oncology GA EQ1WJ UT WOS:000397860000093 ER PT J AU Emblem, KE Gerstner, ER Sorensen, AG Rosen, BR Wen, PY Batchelor, TT Jain, RK AF Emblem, Kyrre E. Gerstner, Elizabeth R. Sorensen, A. Gregory Rosen, Bruce R. Wen, Patrick Y. Batchelor, Tracy T. Jain, Rakesh K. TI Adding angiotensin-system inhibitors to anti-angiogenic therapy reduces vasogenic edema in newly diagnosed glioblastomas but not in recurrent disease SO CANCER RESEARCH LA English DT Meeting Abstract CT AACR Special Conference on Engineering and Physical Sciences in Oncology CY JUN 25-28, 2016 CL Boston, MA SP Amer Assoc Canc Res C1 [Emblem, Kyrre E.] Oslo Univ Hosp, Oslo, Norway. [Gerstner, Elizabeth R.; Rosen, Bruce R.; Batchelor, Tracy T.; Jain, Rakesh K.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Sorensen, A. Gregory] Siemens Healthcare, Malvern, PA USA. [Wen, Patrick Y.] Dana Farber Canc Inst, Boston, MA 02115 USA. NR 7 TC 0 Z9 0 U1 0 U2 0 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 JAN PY 2017 VL 77 SU 2 MA B12 DI 10.1158/1538-7445.EPSO16-B12 PG 2 WC Oncology SC Oncology GA EQ1WJ UT WOS:000397860000061 ER PT J AU Jain, RK AF Jain, Rakesh K. TI Reengineering the tumor microenvironment to improve cancer treatment: Bench to bedside SO CANCER RESEARCH LA English DT Meeting Abstract CT AACR Special Conference on Engineering and Physical Sciences in Oncology CY JUN 25-28, 2016 CL Boston, MA SP Amer Assoc Canc Res C1 [Jain, Rakesh K.] Harvard Med Sch, Boston, MA USA. [Jain, Rakesh K.] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 JAN PY 2017 VL 77 SU 2 MA IA01 PG 2 WC Oncology SC Oncology GA EQ1WJ UT WOS:000397860000096 ER PT J AU Kumar, R Ngwa, W Joshi, V Kunjachan, S Berbeco, R Makrigiorgos, M Sridhar, S AF Kumar, Rajiv Ngwa, Wilfred Joshi, Vinit Kunjachan, Sijumon Berbeco, Ross Makrigiorgos, Mike Sridhar, Srinivas TI Gold nanoparticles based platforms for localized radiosensitization in cancer radiation therapy SO CANCER RESEARCH LA English DT Meeting Abstract CT AACR Special Conference on Engineering and Physical Sciences in Oncology CY JUN 25-28, 2016 CL Boston, MA SP Amer Assoc Canc Res C1 [Kumar, Rajiv; Joshi, Vinit; Sridhar, Srinivas] Northeastern Univ, Boston, MA USA. [Ngwa, Wilfred; Kunjachan, Sijumon; Berbeco, Ross; Makrigiorgos, Mike] Dana Farber Canc Inst, Boston, MA USA. FU NSF [DGE 0965843, HHS/5U54CA151881-02]; NCI [R03CA164645, 1 K01CA17247801]; Electronics Materials Research Institute at Northeastern University; Brigham and Women's Hospital; [ARMY/ W81XWH-12-1-0154] FX This work is supported by ARMY/ W81XWH-12-1-0154, NSF DGE 0965843, HHS/5U54CA151881-02, NCI R03CA164645, NCI1 K01CA17247801, the Electronics Materials Research Institute at Northeastern University, and Brigham and Women's Hospital. NR 0 TC 0 Z9 0 U1 0 U2 0 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 JAN PY 2017 VL 77 SU 2 MA B41 DI 10.1158/1538-7445.EPSO16-B41 PG 2 WC Oncology SC Oncology GA EQ1WJ UT WOS:000397860000081 ER PT J AU Rahbari, NN Kedrin, D Incio, J Liu, H Ho, WT Nia, HT Edrich, CM Jung, K Daubriac, J Chen, I Heishi, T Martin, J Uang, YH Maimon, N Reissfelder, C Weitz, J Boucher, Y Clark, JW Grodzinsky, AJ Duda, DG Jain, RK Fukumura, D AF Rahbari, Nuh N. Kedrin, Dmitriy Incio, Joao Liu, Hao Ho, William T. Nia, Hadi T. Edrich, Christina M. Jung, Keehoon Daubriac, Julien Chen, Ivy Heishi, Takahiro Martin, John Uang, Yuhui H. Maimon, Nir Reissfelder, Christoph Weitz, Juergen Boucher, Yves Clark, Jeffrey W. Grodzinsky, Alan J. Duda, Dan G. Jain, Rakesh K. Fukumura, Dai TI VEGF-targeted therapy induces extracellular matrix remodeling and increases mechanical barriers to therapy in colorectal cancer liver metastases SO CANCER RESEARCH LA English DT Meeting Abstract CT AACR Special Conference on Engineering and Physical Sciences in Oncology CY JUN 25-28, 2016 CL Boston, MA SP Amer Assoc Canc Res C1 [Rahbari, Nuh N.; Kedrin, Dmitriy; Incio, Joao; Liu, Hao; Ho, William T.; Nia, Hadi T.; Edrich, Christina M.; Jung, Keehoon; Daubriac, Julien; Chen, Ivy; Heishi, Takahiro; Martin, John; Uang, Yuhui H.; Maimon, Nir; Boucher, Yves; Clark, Jeffrey W.; Duda, Dan G.; Jain, Rakesh K.; Fukumura, Dai] Massachusetts Gen Hosp, Harvard Med Sch, Boston, MA USA. [Reissfelder, Christoph; Weitz, Juergen] Univ Hosp Carl Gustav Carus, Dresden, Germany. [Grodzinsky, Alan J.] MIT, Cambridge, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 JAN PY 2017 VL 77 SU 2 MA PR06 DI 10.1158/1538-7445.EPSO16-PR06 PG 3 WC Oncology SC Oncology GA EQ1WJ UT WOS:000397860000114 ER PT J AU ven de Ven, ALV Tangutoori, S Baldwin, P Qiao, J Gharagouzloo, C Seitzer, N Clohessy, J Korideck, H Makrigiorgos, GM Cormack, R Pandolfi, PP Sridhar, S AF van de Ven, Anne L. Tangutoori, Shifalika Baldwin, Paige Qiao, Ju Gharagouzloo, Codi Seitzer, Nina Clohessy, John Korideck, Houari Makrigiorgos, G. Mike Cormack, Robert Pandolfi, Pier Paolo Sridhar, Srinivas TI Prostate cancer pre-treatment with nanoformulated Olaparib overcomes radiation resistance SO CANCER RESEARCH LA English DT Meeting Abstract CT AACR Special Conference on Engineering and Physical Sciences in Oncology CY JUN 25-28, 2016 CL Boston, MA SP Amer Assoc Canc Res C1 [van de Ven, Anne L.; Tangutoori, Shifalika; Baldwin, Paige; Qiao, Ju; Gharagouzloo, Codi; Sridhar, Srinivas] Northeastern Univ, Boston, MA USA. [Seitzer, Nina; Clohessy, John; Korideck, Houari; Makrigiorgos, G. Mike; Cormack, Robert] Dana Farber Canc Inst, Boston, MA USA. [Pandolfi, Pier Paolo] Beth Israel Deaconess Canc Ctr, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 JAN PY 2017 VL 77 SU 2 MA B48 DI 10.1158/1538-7445.EPSO16-B48 PG 1 WC Oncology SC Oncology GA EQ1WJ UT WOS:000397860000087 ER PT J AU Weissleder, R AF Weissleder, Ralph TI Imaging drug delivery and nanotherapeutics SO CANCER RESEARCH LA English DT Meeting Abstract CT AACR Special Conference on Engineering and Physical Sciences in Oncology CY JUN 25-28, 2016 CL Boston, MA SP Amer Assoc Canc Res C1 [Weissleder, Ralph] Massachusetts Gen Hosp, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 JAN PY 2017 VL 77 SU 2 MA IA13 DI 10.1158/1538-7445.EPSO16-IA13 PG 1 WC Oncology SC Oncology GA EQ1WJ UT WOS:000397860000104 ER PT J AU Zervantonakis, IK Iavarone, C Chen, HY Leverson, J Sampath, D Palakurthi, S Drapkin, R Liu, JF Matulonis, U Mills, G Brugge, JS AF Zervantonakis, Ioannis K. Iavarone, Claudia Chen, Hsing-Yu Leverson, Joel Sampath, Deepak Palakurthi, Sangeetha Drapkin, Ronny Liu, Joyce F. Matulonis, Ursula Mills, Gordon Brugge, Joan S. TI Systems analysis of signaling pathway adaptation to design effective PI3K-based combination therapies using ovarian cancer patient-derived xenografts SO CANCER RESEARCH LA English DT Meeting Abstract CT AACR Special Conference on Engineering and Physical Sciences in Oncology CY JUN 25-28, 2016 CL Boston, MA SP Amer Assoc Canc Res C1 [Zervantonakis, Ioannis K.; Iavarone, Claudia; Chen, Hsing-Yu; Brugge, Joan S.] Harvard Med Sch, Boston, MA USA. [Leverson, Joel] AbbVie, Chicago, IL USA. [Sampath, Deepak] Genentech Inc, San Francisco, CA USA. [Palakurthi, Sangeetha] Belfer Ctr, Dana Farber Canc Inst, Boston, MA USA. [Drapkin, Ronny] Univ Pennsylvania Med Sch, Philadelphia, PA USA. [Liu, Joyce F.; Matulonis, Ursula] Dana Farber Canc Inst, Boston, MA USA. [Mills, Gordon] MD Anderson Canc Ctr, Houston, TX USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 JAN PY 2017 VL 77 SU 2 MA PR01 DI 10.1158/1538-7445.EPSO16-PR01 PG 3 WC Oncology SC Oncology GA EQ1WJ UT WOS:000397860000111 ER PT J AU Gunter, J Berardinelli, P Blakeney, B Cronenwett, L Gurvis, J AF Gunter, June Berardinelli, Paula Blakeney, Barbara Cronenwett, Linda Gurvis, Joan TI Working with horses to develop shared leadership skills for nursing executives SO ORGANIZATIONAL DYNAMICS LA English DT Editorial Material C1 [Gunter, June] TeachingHorse LLC, 4063 NC Highway 39, Selma, NC 27576 USA. [Berardinelli, Paula] North Carolina State Univ, Hlth Promot Wellness & Adult Educ, Raleigh, NC USA. [Berardinelli, Paula] Paradigms Practices LLC, Raleigh, NC USA. [Blakeney, Barbara] Massachusetts Gen Hosp, Ctr Innovat Care Delivery, Boston, MA 02114 USA. [Blakeney, Barbara] Amer Nurses Assoc, Silver Spring, MD USA. [Blakeney, Barbara] Ctr Medicare & Medicaid Innovat, Washington, DC USA. [Cronenwett, Linda] Univ North Carolina Chapel Hill, Nursing, Sthool Nursing, Chapel Hill, NC USA. [Cronenwett, Linda; Gurvis, Joan] RWJF Execut Nurse Fellows Program, Princeton, NJ USA. [Cronenwett, Linda] Josiah Macy Jr Fdn, New York, NY USA. [Cronenwett, Linda] Spectrum Hlth Ludington Hosp, Ludington, MI USA. [Cronenwett, Linda] Univ North Carolina Chapel Hill, Sch Nursing, RWJF Execut Nurse Fellows Program, Chapel Hill, NC USA. [Gurvis, Joan] RWJF Execut Nurse Fellows Program, Ctr Creat Leadership, Princeton, NJ USA. [Gurvis, Joan] RWJF Execut Nurse Fellows Program, Program Designer, Princeton, NJ USA. RP Gunter, J (reprint author), TeachingHorse LLC, 4063 NC Highway 39, Selma, NC 27576 USA. EM junegunter@teachinghorse.com; paula@paradigmstorpractices.com; bablakeney@aol.com; lincron@email.unc.edu; gurvisj@ccl.org NR 3 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0090-2616 EI 1873-3530 J9 ORGAN DYN JI Organ. Dyn. PD JAN-MAR PY 2017 VL 46 IS 1 BP 57 EP 63 DI 10.1016/j.orgdyn.2016.06.001 PG 7 WC Business; Psychology, Applied; Management SC Business & Economics; Psychology GA EP9JE UT WOS:000397689100007 ER PT J AU Kovach, AE Brunner, AM Fathi, AT Chen, YB Hasserjian, RP AF Kovach, Alexandra E. Brunner, Andrew M. Fathi, Amir T. Chen, Yi-Bin Hasserjian, Robert P. TI Prognostic Significance of Residual Acute Myeloid Leukemia in Bone Marrow Samples Taken Prior to Allogeneic Hematopoietic Cell Transplantation SO AMERICAN JOURNAL OF CLINICAL PATHOLOGY LA English DT Article DE Acute myeloid leukemia; Allogeneic hematopoietic cell transplantation; Bone marrow biopsy; Minimal residual disease ID 1ST COMPLETE REMISSION; MYELODYSPLASTIC SYNDROMES; FLOW-CYTOMETRY; DISEASE BURDEN; AML; NECROSIS; RELAPSE; RISK; SURVIVAL; ADULTS AB Objectives: We sought to identify features in routine evaluation of pre-hematopoietic cell transplantation (HCT) bone marrow samples from patients with acute myeloid leukemia (AML) that influenced patient outcome. Methods: Of 140 patients, evidence of residual leukemia (RL) was identified in 38 (27%) of pre-HCT samples, as defined by 5% or more aspirate blasts, increased blood blasts, clustered or necrotic blasts on biopsy specimens, and/ or leukemia-associated karyotypic abnormalities. Results: Morphologic or karyotypic evidence of RL was significantly associated with shorter leukemia-free survival (LFS) compared with cases without identifiable RL (median, 7.1 vs 28.3 months; P < .0001). Upon multivariable analysis, RL, prior relapse, age, high-risk karyotype, and alternate donor source were each independently associated with shorter LFS. RL in pre-HCT samples was more strongly associated with shorter LFS in patients with intermediate or favorable-risk AML karyotype (P = .001) than secondary or adverse karyotype-risk AML (P = .04). Conclusions: Rigorous morphologic and karyotypic evaluation of pretransplant marrows is practical and important for posttransplant prognosis. C1 [Kovach, Alexandra E.] Vanderbilt Univ, Med Ctr, Dept Pathol Microbiol & Immunol, Nashville, TN USA. [Brunner, Andrew M.; Fathi, Amir T.; Chen, Yi-Bin] Massachusetts Gen Hosp, Dept Hematol Oncol, 55 Fruit St,Warren 225, Boston, MA 02114 USA. [Hasserjian, Robert P.] Massachusetts Gen Hosp, Dept Pathol, 55 Fruit St,Warren 225, Boston, MA 02114 USA. RP Hasserjian, RP (reprint author), Massachusetts Gen Hosp, Dept Pathol, Div Hematopathol, 55 Fruit St,Warren 225, Boston, MA 02114 USA. EM rhasserjian@mgh.harvard.edu NR 42 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9173 EI 1943-7722 J9 AM J CLIN PATHOL JI Am. J. Clin. Pathol. PD JAN PY 2017 VL 147 IS 1 BP 50 EP 59 DI 10.1093/AJCP/AQW203 PG 10 WC Pathology SC Pathology GA EP2PV UT WOS:000397226500006 ER PT J AU Young, MRI AF Young, M. Rita I. TI Cancer Immunology with a Focus on Understudied Cancers as Targets for Immunotherapy SO INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES LA English DT Editorial Material ID CELLS; IMMUNOGENICITY; GLIOMAS C1 [Young, M. Rita I.] Ralph H Johnson Vet Affairs Med Ctr, Res Serv 151, 109 Bee St, Charleston, SC 29401 USA. [Young, M. Rita I.] Med Univ South Carolina, Dept Otolaryngol Head & Neck Surg, 173 Ashley Ave, Charleston, SC 29425 USA. RP Young, MRI (reprint author), Ralph H Johnson Vet Affairs Med Ctr, Res Serv 151, 109 Bee St, Charleston, SC 29401 USA.; Young, MRI (reprint author), Med Univ South Carolina, Dept Otolaryngol Head & Neck Surg, 173 Ashley Ave, Charleston, SC 29425 USA. EM rita.young@va.gov NR 18 TC 0 Z9 0 U1 0 U2 0 PU MDPI AG PI BASEL PA ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND SN 1422-0067 J9 INT J MOL SCI JI Int. J. Mol. Sci. PD JAN PY 2017 VL 18 IS 1 AR 127 DI 10.3390/ijms18010127 PG 4 WC Biochemistry & Molecular Biology; Chemistry, Multidisciplinary SC Biochemistry & Molecular Biology; Chemistry GA EJ2HL UT WOS:000393030600126 ER PT J AU Rasmussen, DD Kincaid, CL Froehlich, JC AF Rasmussen, Dennis D. Kincaid, Carrie L. Froehlich, Janice C. TI Prazosin Prevents Increased Anxiety Behavior That Occurs in Response to Stress During Alcohol Deprivations SO ALCOHOL AND ALCOHOLISM LA English DT Article ID CORTICOTROPIN-RELEASING-FACTOR; CHRONIC DAILY ETHANOL; PREFERRING P RATS; DEPENDENT INDIVIDUALS; NORADRENERGIC SYSTEM; WITHDRAWAL; ABSTINENCE; DISORDERS; MODEL; NOREPINEPHRINE AB Aims: Stress-induced anxiety is a risk factor for relapse to alcohol drinking. The aim of this study was to test the hypothesis that the central nervous system (CNS)-active a1-adrenergic receptor antagonist, prazosin, would block the stress-induced increase in anxiety that occurs during alcohol deprivations. Methods: Selectively bred male alcohol-preferring (P) rats were given three cycles of 5 days of ad libitum voluntary alcohol drinking interrupted by 2 days of alcohol deprivation, with or without 1 h of restraint stress 4 h after the start of each of the first two alcohol deprivation cycles. Prazosin (1.0 or 1.5 mg/kg, IP) or vehicle was administered before each restraint stress. Anxiety-like behavior during alcohol deprivation following the third 5-day cycle of alcohol drinking (7 days after the most recent restraint stress similar to prazosin treatment) was measured by performance in an elevated plus-maze and in social approach/avoidance testing. Results: Rats that received constant alcohol access, or alcohol access and deprivations without stress or prazosin treatments in the first two alcohol deprivations did not exhibit augmented anxiety-like behavior during the third deprivation. In contrast, rats that had been stressed during the first two alcohol deprivations exhibited increased anxiety-like behavior (compared with control rats) in both anxiety tests during the third deprivation. Prazosin given before stresses in the first two cycles of alcohol withdrawal prevented increased anxiety-like behavior during the third alcohol deprivation. Conclusion: Prazosin treatment before stresses experienced during alcohol deprivations may prevent the increased anxiety during subsequent deprivation/abstinence that is a risk factor for relapse to alcohol drinking. Short summary: Administration of prazosin before stresses during repetitive alcohol deprivations in male alcohol-preferring (P) rats prevents increased anxiety during a subsequent deprivation without further prazosin treatment. Prazosin treatment during repeated alcohol deprivations may prevent the increased anxiety that is a risk factor for relapse to alcohol drinking. C1 [Rasmussen, Dennis D.; Kincaid, Carrie L.] VA Puget Sound Hlth Care Syst, VISN Mental Illness Res Educ & Clin Ctr MIRECC 20, Mental Hlth Serv, Seattle, WA USA. [Rasmussen, Dennis D.] Univ Washington, Dept Psychiat, Seattle, WA 98108 USA. [Froehlich, Janice C.] Indiana Univ Sch Med, Dept Med, Indinapolis, IN 46202 USA. RP Rasmussen, DD (reprint author), VA Med Ctr, MIRECC 116, 1660 S Columbian Way, Seattle, WA 98108 USA. EM drasmuss@u.washington.edu FU National Institutes of Health [AA018604, AA017839, AA007611] FX Supported by resources from VA Puget Sound Health Care System Mental Health Service, VISN 20 MIRECC and National Institutes of Health Grants AA018604 and AA017839 (Rasmussen); AA018604 and AA007611 (Froehlich). NR 37 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0735-0414 EI 1464-3502 J9 ALCOHOL ALCOHOLISM JI Alcohol Alcohol. PD JAN 1 PY 2017 VL 52 IS 1 BP 5 EP 11 DI 10.1093/alcalc/agw082 PG 7 WC Substance Abuse SC Substance Abuse GA EP2ML UT WOS:000397217200002 PM 27797712 ER PT J AU Bexkens, R Washburn, FJ Eygendaal, D van den Bekerom, MPJ Oh, LS AF Bexkens, Rens Washburn, Frederic J. Eygendaal, Denise van den Bekerom, Michel P. J. Oh, Luke S. TI Effectiveness of reduction maneuvers in the treatment of nursemaid's elbow: A systematic review and meta-analysis SO AMERICAN JOURNAL OF EMERGENCY MEDICINE LA English DT Review DE Nursemaid's elbow; Radial head subluxation; Reduction; Hyperpronation; Supination-flexion ID RADIAL HEAD SUBLUXATION; SUPINATION-FLEXION; PULLED ELBOW; HYPERPRONATION; PRONATION; CHILDREN AB Background/Aim: Nursemaid's elbow usually occurs in young children when longitudinal traction is placed on the arm. Several manipulative maneuvers have been described, although, the most effective treatment technique is yet unclear. The aim of this systematic review and meta-analysis was to compare the two most commonly performed maneuvers (supination-flexion and hyperpronation) in the treatment of nursemaid's elbow. Methods: A literature search was performed in PubMed, Embase, and Cochrane databases to identify randomized controlled trials comparing supination-flexion and hyperpronation. Data were extracted and pooled independently by two authors. Methodological quality assessment of included studies was performed. Meta-analysis was performed using a fixed-effect model in case of homogeneity across studies, and using a random-effect model in case of heterogeneity. Heterogeneity was calculated with the chi(2) test and inconsistency in study effects across trials was quantified by I-2 values. Results: Seven randomized trials, including 701 patients (62% female), were included. A total of 350 patients were treated with the hyperpronation maneuver versus 351 patients who underwent the supination-flexion maneuver. Meta-analysis showed that hyperpronation was more effective than supination-flexion (risk ratio, 0.34; 95% confidence interval, 0.23 to 0.49; I-2, 35%). The absolute risk difference between maneuvers was 26% in favor of hyperpronation, resulting in a number needed to treat of 4 patients. Trials lacked blinding of assessors and universal pain measures. Conclusions: Hyperpronation was more effective in terms of success rate and seems to be less painful compared to the supination-flexion maneuver in children with nursemaid's elbow. (C) 2016 Elsevier Inc. All rights reserved. C1 [Bexkens, Rens; Washburn, Frederic J.; Oh, Luke S.] Massachusetts Gen Hosp, Dept Orthopaed Surg, Sports Med Serv, 175 Cambridge St, Boston, MA 02114 USA. [Eygendaal, Denise] Amphia Hosp, Dept Orthopaed Surg, Molengracht 21, NL-4818 CK Breda, Netherlands. [Bexkens, Rens; Eygendaal, Denise] Acad Med Ctr, Dept Orthopaed Surg, Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands. [van den Bekerom, Michel P. J.] Onze Lieve Vrouw Hosp, Dept Orthopaed Surg, Shoulder & Elbow Unit, Oosterpk 9, NL-1091 AC Amsterdam, Netherlands. RP Bexkens, R (reprint author), Massachusetts Gen Hosp, Dept Orthopaed Surg, Sports Med Serv, 175 Cambridge St, Boston, MA 02114 USA.; Bexkens, R (reprint author), Acad Med Ctr, Dept Orthopaed Surg, Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands. EM rbexkens@mgh.harvard.edu; frederic.washburn@gmail.com; deygendaal@amphia.nl; bekerom@gmail.com; loh@mgh.harvard.edu NR 21 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0735-6757 EI 1532-8171 J9 AM J EMERG MED JI Am. J. Emerg. Med. PD JAN PY 2017 VL 35 IS 1 BP 159 EP 163 DI 10.1016/j.ajem.2016.10.059 PG 5 WC Emergency Medicine SC Emergency Medicine GA EP5KE UT WOS:000397416600032 PM 27836316 ER PT J AU Wallwork, RS Colicino, E Zhong, J Kloog, I Coull, BA Vokonas, P Schwartz, JD Baccarelli, AA AF Wallwork, Rachel S. Colicino, Elena Zhong, Jia Kloog, Itai Coull, Brent A. Vokonas, Pantel Schwartz, Joel D. Baccarelli, Andrea A. TI Ambient Fine Particulate Matter, Outdoor Temperature, and Risk of Metabolic Syndrome SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE air pollution; blood glucose; high-density lipoprotein cholesterol; hypertension; metabolic syndrome; obesity; temperature; triglycerides ID BODY-FAT DISTRIBUTION; BROWN ADIPOSE-TISSUE; AIR-POLLUTION; OXIDATIVE STRESS; INSULIN-RESISTANCE; ADULT HUMANS; NHANES-III; OBESITY; PREVALENCE; MORTALITY AB Ambient air pollution and temperature have been linked with cardiovascular morbidity and mortality. Metabolic syndrome and its components-abdominal obesity, elevated fasting blood glucose concentration, low highdensity lipoprotein cholesterol concentration, hypertension, and hypertriglyceridemia-predict cardiovascular disease, but the environmental causes are understudied. In this study, we prospectively examined the long-term associations of air pollution, defined as particulate matter with an aerodynamic diameter less than or equal to 2.5 mu m (PM2.5), and temperature with the development of metabolic syndrome and its components. Using covariate-adjustment Cox proportional hazards models, we estimated associations of mean annual PM2.5 concentration and temperature with risk of incident metabolic dysfunctions between 1993 and 2011 in 587 elderly (mean = 70 (standard deviation, 7) years of age) male participants in the Normative Aging Study. A 1-mu g/m3 increase in mean annual PM2.5 concentration was associated with a higher risk of developing metabolic syndrome (hazard ratio (HR) = 1.27, 95% confidence interval (CI): 1.06, 1.52), an elevated fasting blood glucose level (HR = 1.20, 95% CI: 1.03, 1.39), and hypertriglyceridemia (HR = 1.14, 95% CI: 1.00, 1.30). Our findings for metabolic syndrome and high fasting blood glucose remained significant for PM2.5 levels below the Environmental Protection Agency's health-safety limit (12 mu g/m3). A 1 degrees C increase in mean annual temperature was associated with a higher risk of developing elevated fasting blood glucose (HR = 1.33, 95% CI: 1.14, 1.56). Men living in neighborhoods with worse air quality-with higher PM2.5 levels and/or temperatures than average-showed increased risk of developing metabolic dysfunctions. C1 [Colicino, Elena] Columbia Univ, Mailman Sch Publ Hlth, Dept Environm Hlth Sci, Bldg P&S 16-416,722 W 168th St, New York, NY 10032 USA. [Wallwork, Rachel S.] Harvard Univ, Harvard Med Sch, Dept Environm Hlth, Boston, MA 02115 USA. [Colicino, Elena; Zhong, Jia; Coull, Brent A.; Schwartz, Joel D.; Baccarelli, Andrea A.] Harvard Univ, Harvard TH Chan Sch Publ Hlth, Dept Environm Hlth, Boston, MA 02115 USA. [Kloog, Itai] Ben Gurion Univ Negev, Fac Humanities & Social Sci, Dept Geog & Environm Dev, Beer Sheva, Israel. [Vokonas, Pantel] VA Boston Healthcare Syst, Dept Epidemiol, Boston, MA USA. [Vokonas, Pantel] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Vokonas, Pantel] Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA. RP Colicino, E (reprint author), Columbia Univ, Mailman Sch Publ Hlth, Dept Environm Hlth Sci, Bldg P&S 16-416,722 W 168th St, New York, NY 10032 USA. EM elena.colicino@columbia.edu FU National Institute of Environmental Health Sciences [R01ES021733, R01ES015172]; Cooperative Studies Program, Massachusetts Veterans Epidemiology Research and Information Center; US Department of Agriculture, Agricultural Research Service [53-K06-510] FX This work was supported by the National Institute of Environmental Health Sciences (grants R01ES021733 and R01ES015172). The Normative Aging Study (NAS) is supported by the Cooperative Studies Program, Massachusetts Veterans Epidemiology Research and Information Center. Additional support for the NAS was provided by the US Department of Agriculture, Agricultural Research Service (contract 53-K06-510). NR 48 TC 0 Z9 0 U1 2 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 EI 1476-6256 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JAN 1 PY 2017 VL 185 IS 1 BP 30 EP 39 DI 10.1093/aje/kww157 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA EP2RY UT WOS:000397232100005 PM 27927620 ER PT J AU Lin, BM Curhan, SG Wang, M Eavey, R Stankovic, KM Curhan, GC AF Lin, Brian M. Curhan, Sharon G. Wang, Molin Eavey, Roland Stankovic, Konstantina M. Curhan, Gary C. TI Duration of Analgesic Use and Risk of Hearing Loss in Women SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE acetaminophen; aspirin; hearing loss; nonsteroidal antiinflammatory drug ID FOOD FREQUENCY QUESTIONNAIRE; NUTRITION EXAMINATION SURVEY; SALICYLATE OTOTOXICITY; INCIDENT HYPERTENSION; NATIONAL-HEALTH; UNITED-STATES; POPULATION; IMPAIRMENT; VALIDITY; ADULTS AB Aspirin, nonsteroidal antiinflammatory drugs (NSAID), and acetaminophen are commonly used. Frequent use of analgesics has been associated with a higher risk of hearing loss. However, the association between duration of analgesic use and the risk of hearing loss is unclear. We investigated the relationship between duration of analgesic use and self-reported hearing loss among 55,850 women in the Nurses' Health Study. Cox proportional hazards regression was used to adjust for potential confounders. During 873,376 personyears of follow-up (1990-2012), longer durations of NSAID use (for > 6 years of use compared with < 1 year, multivariable-adjusted relative risk = 1.10, 95% confidence interval: 1.06, 1.15; P for trend < 0.001) and acetaminophen use (for > 6 years of use compared with < 1 year, multivariable-adjusted relative risk = 1.09, 95% confidence interval: 1.04, 1.14; P for trend < 0.001) were associated with higher risks of hearing loss. Duration of aspirin use was not associated with hearing loss (for > 6 years of use compared with < 1 year, multivariableadjusted relative risk = 1.01, 95% confidence interval: 0.97, 1.05; P for trend = 0.35). In this cohort of women, longer durations of NSAID and acetaminophen use were associated with slightly higher risks of hearing loss, but duration of aspirin use was not. Considering the high prevalence of analgesic use, this may be an important modifiable contributor to hearing loss. C1 [Lin, Brian M.; Stankovic, Konstantina M.] Massachusetts Eye & Ear Infirm, Dept Otolaryngol, 243 Charles St, Boston, MA 02114 USA. [Lin, Brian M.; Curhan, Sharon G.; Wang, Molin; Curhan, Gary C.] Brigham & Womens Hosp, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA. [Lin, Brian M.; Curhan, Sharon G.; Wang, Molin; Stankovic, Konstantina M.; Curhan, Gary C.] Harvard Med Sch, Boston, MA USA. [Wang, Molin] Harvard TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Eavey, Roland] Vanderbilt Univ, Sch Med, Vanderbilt Bill Wilkerson Ctr Otolaryngol & Commu, Nashville, TN 37212 USA. [Curhan, Gary C.] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Curhan, Gary C.] Brigham & Womens Hosp, Dept Med, Div Renal, Boston, MA 02115 USA. RP Lin, BM (reprint author), Brigham & Womens Hosp, Channing Div Network Med, 181 Longwood Ave, Boston, MA 02115 USA. EM brian_lin@meei.harvard.edu FU National Institutes of Health [U01 DC010811, UM1 CA176726] FX This work was supported by grants U01 DC010811 and UM1 CA176726 from the National Institutes of Health. NR 54 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 EI 1476-6256 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JAN 1 PY 2017 VL 185 IS 1 BP 40 EP 47 DI 10.1093/aje/kww154 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA EP2RY UT WOS:000397232100006 PM 27974293 ER PT J AU Sultzer, DL Marder, SR AF Sultzer, David L. Marder, Stephen R. TI Older Brains are Different: Brain-Behavior Studies and Their Clinical Utility SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Editorial Material C1 [Sultzer, David L.; Marder, Stephen R.] VA Greater Angeles Healthcare Syst, Psychiat Serv, Los Angeles, CA USA. [Sultzer, David L.; Marder, Stephen R.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90095 USA. RP Sultzer, DL (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Psychiat Serv,Dept Psychiat & Biobehav Sci, VA Greater Los Angeles Healthcare Syst, Los Angeles, CA 90095 USA. EM dsultzer@ucla.edu FU U.S. Department of Veterans Affairs; Eli Lilly and Company; Transition Therapeutics; Avanir; Otsuka; Astellas; Acadia; Insys; Neurocrine; Forum; Allergan; Teva; Lundbeck; Takeda; Roche FX This work was supported in part by the U.S. Department of Veterans Affairs.; Dr. Sultzer has received research support from Eli Lilly and Company, Transition Therapeutics, and Avanir and has received payment for research consultation from Otsuka, Astellas, Acadia, and Insys. Dr. Marder has received research support from Neurocrine and Forum and has received payment for consultation or other services from Allergan, Teva, Lundbeck, Otsuka, Takeda, Forum, and Roche. NR 4 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1064-7481 EI 1545-7214 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD JAN PY 2017 VL 25 IS 1 BP 11 EP 12 DI 10.1016/j.jagp.2016.10.002 PG 2 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA EO1UV UT WOS:000396484300002 PM 28231870 ER PT J AU Monin, JK Mota, N Levy, B Pachankis, J Pietrzak, RH AF Monin, Joan K. Mota, Natalie Levy, Becca Pachankis, John Pietrzak, Robert H. TI Older Age Associated with Mental Health Resiliency in Sexual Minority US Veterans SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Article DE Sexual minority status; veterans; mental health; aging ID POSTTRAUMATIC-STRESS-DISORDER; NATIONAL-HEALTH; UNITED-STATES; CARE UTILIZATION; TRAUMA EXPOSURE; ADULTS; ORIENTATION; RISK; GAY; DEPRESSION AB Objectives: Objectives were to: (a) identify the mental health needs of older and younger sexual minority and heterosexual U.S. veterans and (b) examine whether sexual minority status confers vulnerability or resiliency in older adulthood. Support and trauma exposure were examined as potential mechanisms for age by sexual orientation differences. Methods: Participants were a nationally representative sample of 3,095 U.S. veterans (ages 21 to 96 years). Measures included demographics, military characteristics, sexual orientation (lesbian, gay, or bisexual; LGB), social support, trauma, and mental health indicators (lifetime and present depression and post-traumatic stress disorder (PTSD); lifetime anxiety and suicidal ideation). Results: Younger LGB veterans were most likely to report lifetime depression and/or PTSD and current depression compared with older LGB and younger and older heterosexual veterans. Older LGB veterans had low levels of mental health problems, but they reported the smallest social support networks. Conclusions: Older and younger LGB veterans have different mental health challenges. Younger LGB veterans are more vulnerable to mental health problems than their older LGB peers. Older LGB veterans are resilient, but they may be at greater risk of social isolation than their younger LGB peers. C1 [Monin, Joan K.; Levy, Becca; Pachankis, John] Yale Sch Publ Hlth, Social & Behav Sci Div, New Haven, CT 06520 USA. [Mota, Natalie] Univ Manitoba, Dept Clin Hlth Psychol, Winnipeg, MB, Canada. [Pietrzak, Robert H.] VA Connecticut Healthcare Syst, US Dept Vet Affairs, Natl Ctr Posttraumat Stress Disorder, West Haven, CT USA. [Pietrzak, Robert H.] Yale Sch Med, Dept Psychiat, New Haven, CT USA. RP Monin, JK (reprint author), Yale Sch Publ Hlth, Social & Behav Sci Div, New Haven, CT 06520 USA. EM joan.monin@yale.edu FU Department of Veterans Affairs National Center for Post-traumatic Stress Disorder; Claude D. Pepper Older Americans Independence Center at Yale University School of Medicine (NIA) [P30AG21342]; National Institutes of Health [R01AG032284, R01HL089314, K01 AG042450] FX This study was funded by the Department of Veterans Affairs National Center for Post-traumatic Stress Disorder. Preparation of this report was supported in part by a Research Career Development Award to Dr. Pietrzak from the Claude D. Pepper Older Americans Independence Center at Yale University School of Medicine (NIA grant P30AG21342) and in part by National Institutes of Health grants (R01AG032284, R01HL089314) and to Dr. Monin from the Claude D. Pepper Older Americans Independence Center at Yale University School of Medicine (NIA grant P30AG21342) and in part by National Institutes of Health grant (K01 AG042450). There are no disclosures to report. NR 40 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 1064-7481 EI 1545-7214 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD JAN PY 2017 VL 25 IS 1 BP 81 EP 90 DI 10.1016/j.jagp.2016.09.006 PG 10 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA EO1UV UT WOS:000396484300013 PM 27769835 ER PT J AU Cardoso, F Costa, A Senkus, E Aapro, M Andre, F Barrios, CH Bergh, J Bhattacharyya, G Biganzoli, L Cardoso, MJ Carey, L Corneliussen-James, D Curigliano, G Dieras, V El Saghir, N Eniu, A Fallowfield, L Fenech, D Francis, P Gelmon, K Gennari, A Harbeck, N Hudis, C Kaufman, B Krop, I Mayer, M Meijer, H Mertz, S Ohno, S Pagani, O Papadopoulos, E Peccatori, F Penault-Llorca, F Piccart, MJ Pierga, JY Rugo, H Shockney, L Sledge, G Swain, S Thomssen, C Tutt, A Vorobiof, D Xu, B Norton, L Winer, E AF Cardoso, F. Costa, A. Senkus, E. Aapro, M. Andre, F. Barrios, C. H. Bergh, J. Bhattacharyya, G. Biganzoli, L. Cardoso, M. J. Carey, L. Corneliussen-James, D. Curigliano, G. Dieras, V. El Saghir, N. Eniu, A. Fallowfield, L. Fenech, D. Francis, P. Gelmon, K. Gennari, A. Harbeck, N. Hudis, C. Kaufman, B. Krop, I. Mayer, M. Meijer, H. Mertz, S. Ohno, S. Pagani, O. Papadopoulos, E. Peccatori, F. Penault-Llorca, F. Piccart, M. J. Pierga, J. Y. Rugo, H. Shockney, L. Sledge, G. Swain, S. Thomssen, C. Tutt, A. Vorobiof, D. Xu, B. Norton, L. Winer, E. TI 3rd ESO-ESMO International Consensus Guidelines for Advanced Breast Cancer (ABC 3) SO ANNALS OF ONCOLOGY LA English DT Article ID PROGRESSION-FREE SURVIVAL; PHASE-II TRIAL; OPEN-LABEL; ESTROGEN-RECEPTOR; TRASTUZUMAB EMTANSINE; 1ST-LINE TREATMENT; ZOLEDRONIC ACID; BONE METASTASES; PERTUZUMAB P; DOUBLE-BLIND C1 [Cardoso, F.] Champalimaud Clin Ctr, European Sch Oncol, Lisbon, Portugal. [Cardoso, F.; Cardoso, M. J.] Champalimaud Clin Ctr, Breast Unit, Lisbon, Portugal. [Costa, A.; Peccatori, F.] European Sch Oncol, Milan, Italy. [Costa, A.; Peccatori, F.] European Sch Oncol, Bellinzona, Switzerland. [Senkus, E.] Med Univ Gdansk, Dept Radiotherapy & Oncol, Gdansk, Poland. [Aapro, M.] Genolier Canc Ctr, Breast Ctr, Genolier, Switzerland. [Andre, F.] Inst Gustave Roussy, Dept Med Oncol, Villejuif, France. [Barrios, C. H.] PUCRS Sch Med, Dept Med, Porto Alegre, RS, Brazil. [Bergh, J.] Karolinska Inst, Radiumhemmet, Dept Oncol, Stockholm, Sweden. [Bergh, J.] Canc Ctr Karolinska, Stockholm, Sweden. [Bergh, J.] Karolinska Univ Hosp, Stockholm, Sweden. [Bhattacharyya, G.] Fortis Hosp, Dept Med Oncol, Kolkata, India. [Biganzoli, L.] Hosp Prato, Dept Med Oncol, Prato, Italy. [Carey, L.] UNC Lineberger Comprehens Canc Ctr, Dept Hematol & Oncol, Chapel Hill, NC USA. [Corneliussen-James, D.] METAvivor Res & Support, Annapolis, MD USA. [Curigliano, G.] European Inst Oncol, Div Expt Therapeut, Milan, Italy. [Dieras, V.] Inst Curie, Dept Med Oncol, Paris, France. [El Saghir, N.] Amer Univ Beirut, Breast Ctr Excellence, NK Basile Canc Inst, Beirut, Lebanon. [Eniu, A.] Canc Inst I Chiricuta, Dept Breast Tumors, Cluj Napoca, Romania. [Fallowfield, L.] Univ Sussex, Brighton & Sussex Med Sch, Falmer, England. [Fenech, D.] Europa Donna Malta, Breast Care Support Grp, Mtarfa, Malta. [Francis, P.] Peter MacCallum Canc Ctr, Div Canc Med, Melbourne, Vic, Australia. [Gelmon, K.] BC Canc Agcy, Vancouver Canc Ctr, Vancouver, BC, Canada. [Gennari, A.] Galliera Hosp, Dept Med Oncol, Genoa, Italy. [Harbeck, N.] Brustzentrum Univ Munchen, Munich, Germany. [Hudis, C.] Mem Sloan Kettering Canc Ctr, Breast Med Serv, 1275 York Ave, New York, NY 10021 USA. [Kaufman, B.] Sheba Med Ctr, Tel Hashomer, Israel. [Krop, I.; Winer, E.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Mayer, M.] Adv Breast Canc Org, New York, NY USA. [Meijer, H.] Radvoud Univ, Dept Radiat Oncol, Med Ctr, Nijmegen, Netherlands. [Mertz, S.] Metastat Breast Canc Network US, Inversness, FL USA. [Ohno, S.] Canc Inst Hosp, Breast Oncol Ctr, Tokyo, Japan. [Pagani, O.] Oncol Inst Southern Switzerland, Bellinzona, Switzerland. [Pagani, O.] Breast Unit Southern Switzerland, Bellinzona, Switzerland. [Papadopoulos, E.] Europa Donna, Nicosia, Cyprus. [Penault-Llorca, F.] Ctr Comprehens Canc, Jean Perrin Ctr, Clermont Ferrand, France. [Piccart, M. J.] Univ Libre Bruxelles, Inst Jules Bordet, Dept Med, Brussels, Belgium. [Pierga, J. Y.] Univ Paris 05, Inst Curie, Dept Med Oncol, Paris, France. [Rugo, H.] UCSF Helen Diller Family Comprehens Canc Ctr, Dept Med, Breast Oncol Program, San Francisco, CA USA. [Shockney, L.] Johns Hopkins Breast Ctr, Dept Surg & Oncol, Baltimore, MD USA. [Sledge, G.] Indiana Univ, Med Ctr, Indianapolis, IN USA. [Swain, S.] Georgetown Univ, Lombardi Comprehens Canc Ctr, Washington, DC USA. [Thomssen, C.] Martin Luther Univ Halle Wittenberg, Dept Gynaecol, Halle, Germany. [Tutt, A.] Kings Coll London, Breakthrough Breast Canc Res Unit, London, England. [Tutt, A.] Guys & St Thomass NHS Fdn Trust, London, England. [Vorobiof, D.] Sandton Oncol Ctr, Johannesburg, South Africa. [Xu, B.] Chinese Acad Med Sci, Dept Med Oncol, Beijing, Peoples R China. [Xu, B.] Peking Union Med Coll, Beijing, Peoples R China. [Norton, L.] Mem Sloan Kettering Canc Ctr, Breast Canc Program, 1275 York Ave, New York, NY 10021 USA. RP Cardoso, F (reprint author), Champalimaud Clin Ctr, Dr Breast Unit, Ave Brasilia S-N, P-1400038 Lisbon, Portugal. EM fatimacardoso@fundacaochampalimaud.pt NR 65 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 EI 1569-8041 J9 ANN ONCOL JI Ann. Oncol. PD JAN PY 2017 VL 28 IS 1 BP 16 EP 33 DI 10.1093/annonc/mdw544 PG 18 WC Oncology SC Oncology GA EP2UU UT WOS:000397239800005 PM 28177437 ER PT J AU Dieter, SM Heining, C Agaimy, A Huebschmann, D Bonekamp, D Hutter, B Ehrenberg, KR Frohlich, M Schlesner, M Scholl, C Schlemmer, HP Wolf, S Mavratzas, A Jung, CS Groschel, S von Kalle, C Eils, R Brors, B Penzel, R Kriegsmann, M Reuss, DE Schirmacher, P Stenzinger, A Federspil, PA Weichert, W Glimm, H Frohling, S AF Dieter, S. M. Heining, C. Agaimy, A. Huebschmann, D. Bonekamp, D. Hutter, B. Ehrenberg, K. R. Froehlich, M. Schlesner, M. Scholl, C. Schlemmer, H-P Wolf, S. Mavratzas, A. Jung, C. S. Groeschel, S. von Kalle, C. Eils, R. Brors, B. Penzel, R. Kriegsmann, M. Reuss, D. E. Schirmacher, P. Stenzinger, A. Federspil, P. A. Weichert, W. Glimm, H. Froehling, S. TI Mutant KIT as imatinib-sensitive target in metastatic sinonasal carcinoma SO ANNALS OF ONCOLOGY LA English DT Article DE precision oncology; cancer genomics; head and neck cancer ID MUTATIONS; CANCER; TRACT AB Background: Sinonasal carcinomas (SNCs) comprise various rare tumor types that are characterized by marked histologic diversity and largely unknown molecular profiles, yet share an overall poor prognosis owing to an aggressive clinical course and frequent late-stage diagnosis. The lack of effective systemic therapies for locally advanced or metastatic SNC poses a major challenge to therapeutic decision making for individual patients. We here aimed to identify actionable genetic alterations in a patient with metastatic SNC whose tumor, despite all diagnostic efforts, could not be assigned to any known SNC category and was refractory to multimodal therapy. Patients and methods: We used whole-exome and transcriptome sequencing to identify a KIT exon 11 mutation (c.1733_1735del, p.D579del) as potentially druggable target in this patient and carried out cancer hotspot panel sequencing to detect secondary resistance-conferring mutations in KIT. Furthermore, as a step towards clinical exploitation of the recently described signatures of mutational processes in cancer genomes, we established and applied a novel bioinformatics algorithm that enables supervised analysis of the mutational catalogs of individual tumors. Results: Molecularly guided treatment with imatinib in analogy to the management of gastrointestinal stromal tumor (GIST) resulted in a dramatic and durable response with remission of nearly all tumor manifestations, indicating a dominant driver function of mutant KIT in this tumor. KIT dependency was further validated by a secondary KIT exon 17 mutation (c.2459_2462delATTCinsG, p.D820_S821delinsG) that was detected upon tumor progression after 10 months of imatinib treatment and provided a rationale for salvage therapy with regorafenib, which has activity against KIT exon 11/17 mutant GIST. Conclusions: These observations highlight the potential of unbiased genomic profiling for uncovering the vulnerabilities of individual malignancies, particularly in rare and unclassifiable tumors, and underscore that KIT exon 11 mutations represent tractable therapeutic targets across different histologies. C1 [Dieter, S. M.; Heining, C.; Ehrenberg, K. R.; Scholl, C.; Groeschel, S.; von Kalle, C.; Glimm, H.; Froehling, S.] Natl Ctr Tumor Dis NCT Heidelberg, Dept Translat Oncol, Heidelberg, Germany. [Dieter, S. M.; Heining, C.; Ehrenberg, K. R.; Scholl, C.; Groeschel, S.; von Kalle, C.; Glimm, H.; Froehling, S.] German Canc Res Ctr, Heidelberg, Germany. [Dieter, S. M.; Heining, C.; Hutter, B.; Froehlich, M.; Scholl, C.; Groeschel, S.; von Kalle, C.; Brors, B.; Schirmacher, P.; Glimm, H.; Froehling, S.] German Canc Consortium DKTK, Heidelberg, Germany. [Groeschel, S.; von Kalle, C.; Glimm, H.; Froehling, S.] Univ Heidelberg Hosp, Sect Personalized Oncol, Heidelberg, Germany. [Agaimy, A.] Erlangen Univ Hosp, Inst Pathol, Erlangen, Germany. [Huebschmann, D.; Schlesner, M.; Eils, R.] DKFZ, Div Theoret Bioinformat, Heidelberg, Germany. [Huebschmann, D.; Eils, R.] Heidelberg Univ, Inst Pharm & Mol Biotechnol & BioQuant, Dept Bioinformat & Funct Genom, Heidelberg, Germany. [Huebschmann, D.] Univ Heidelberg Hosp, Dept Pediat Immunol Hematol & Oncol, Heidelberg, Germany. [Bonekamp, D.; Schlemmer, H-P] DKFZ, Div Radiol, Heidelberg, Germany. [Hutter, B.; Froehlich, M.; Brors, B.] DKFZ, Div Appl Bioinformat, Heidelberg, Germany. [Hutter, B.; Froehlich, M.; Brors, B.] NCT Heidelberg, Heidelberg, Germany. [Ehrenberg, K. R.; Mavratzas, A.] NCT Heidelberg, Dept Med Oncol, Heidelberg, Germany. [Ehrenberg, K. R.; Mavratzas, A.] Univ Heidelberg Hosp, Dept Internal Med 4, Heidelberg, Germany. [Wolf, S.] DKFZ, Genom & Prote Core Facil, Heidelberg, Germany. [Jung, C. S.] Univ Heidelberg Hosp, Dept Neurosurg, Heidelberg, Germany. [von Kalle, C.; Eils, R.] DKFZ Heidelberg Ctr Personalized Oncol HIPO, Heidelberg, Germany. [Penzel, R.; Kriegsmann, M.; Schirmacher, P.; Stenzinger, A.; Weichert, W.] Univ Heidelberg Hosp, Inst Pathol, Heidelberg, Germany. [Reuss, D. E.; Weichert, W.] Univ Heidelberg Hosp, Inst Pathol, Dept Neuropathol, Heidelberg, Germany. [Stenzinger, A.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Pathol, Ctr Integrated Diagnost, Boston, MA USA. [Federspil, P. A.] Univ Heidelberg Hosp, Dept Otorhinolaryngol, Heidelberg, Germany. [Weichert, W.] Tech Univ Munich, Inst Pathol, Klinikum Rechts Isar, Munich, Germany. [Weichert, W.] DKTK, Munich, Germany. RP Frohling, S (reprint author), NCT Heidelberg, Dept Translat Oncol, Neuenheimer Feld 460, D-69120 Heidelberg, Germany. EM stefan.froehling@nct-heidelberg.de RI Eils, Roland/B-6121-2009 OI Eils, Roland/0000-0002-0034-4036 FU DKFZ-HIPO; NCT POP FX This work was supported by grant H021 from DKFZ-HIPO and NCT POP [to C.H., H.G., S.F.]. NR 21 TC 0 Z9 0 U1 2 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 EI 1569-8041 J9 ANN ONCOL JI Ann. Oncol. PD JAN PY 2017 VL 28 IS 1 BP 142 EP 148 DI 10.1093/annonc/mdw446 PG 7 WC Oncology SC Oncology GA EP2UU UT WOS:000397239800019 ER PT S AU Lin, WM Fisher, DE AF Lin, William M. Fisher, David E. BE Abbas, AK Aster, JC Feany, MB TI Signaling and Immune Regulation in Melanoma Development and Responses to Therapy SO ANNUAL REVIEW OF PATHOLOGY: MECHANISMS OF DISEASE, VOL 12 SE Annual Review of Pathology-Mechanisms of Disease LA English DT Review; Book Chapter DE melanocytes; pathogenesis; genomics; immunotherapy; targeted therapy ID CUTANEOUS MALIGNANT-MELANOMA; RAF INHIBITOR RESISTANCE; TERT PROMOTER MUTATIONS; MAPK PATHWAY INHIBITORS; BRAF-MUTANT MELANOMA; METASTATIC MELANOMA; ACQUIRED-RESISTANCE; TUMOR MICROENVIRONMENT; CONFERS RESISTANCE; CTLA-4 BLOCKADE AB Melanoma is a complex and genomically diverse malignancy, and new genes and signaling pathways involved in pathogenesis continue to be discovered. Mechanistic insights into gene and immune regulation in melanoma have led to the development of numerous successful and innovative pharmacologic agents over recent years. Multiple targeted therapies and immunotherapies have already entered the clinic, becoming new standards of care and transforming the prognosis for many patients with malignant melanoma. In this review, we provide an overview of the current understanding of signaling and immune regulation in melanoma and implications for responses to treatment, organized in the framework of hallmark characteristics in cancer. C1 [Lin, William M.; Fisher, David E.] Massachusetts Gen Hosp, Dept Dermatol, Boston, MA 02114 USA. [Fisher, David E.] Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Boston, MA 02114 USA. RP Fisher, DE (reprint author), Massachusetts Gen Hosp, Dept Dermatol, Boston, MA 02114 USA.; Fisher, DE (reprint author), Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Boston, MA 02114 USA. EM dfisher3@partners.org NR 167 TC 0 Z9 0 U1 0 U2 0 PU ANNUAL REVIEWS PI PALO ALTO PA 4139 EL CAMINO WAY, PO BOX 10139, PALO ALTO, CA 94303-0897 USA SN 1553-4006 J9 ANNU REV PATHOL-MECH JI Annu. Rev. Pathol.-Mech Dis. PY 2017 VL 12 BP 75 EP 102 DI 10.1146/annurev-pathol-052016-100208 PG 28 WC Pathology SC Pathology GA BG9PJ UT WOS:000393554200004 PM 27959628 ER PT S AU Bullman, S Meyerson, M Kostic, AD AF Bullman, Susan Meyerson, Matthew Kostic, Aleksandar D. BE Abbas, AK Aster, JC Feany, MB TI Emerging Concepts and Technologies for the Discovery of Microorganisms Involved in Human Disease SO ANNUAL REVIEW OF PATHOLOGY: MECHANISMS OF DISEASE, VOL 12 SE Annual Review of Pathology-Mechanisms of Disease LA English DT Review; Book Chapter DE pathogen discovery; next-generation sequencing; symbionts; microbiology; disease etiology; virology; microbiome ID 16S RIBOSOMAL-RNA; HENSELAE SP-NOV; INFECTIOUS-DISEASES; PATHOGEN DISCOVERY; FUSOBACTERIUM-NUCLEATUM; BACILLARY ANGIOMATOSIS; KAPOSIS-SARCOMA; CELL-CARCINOMA; ANIMAL-MODEL; HUMAN TISSUE AB Established infectious agents continue to be a major cause of human morbidity and mortality worldwide. However, the causative agent remains unknown for a wide range of diseases; many of these are suspected to be attributable to yet undiscovered microorganisms. The advent of unbiased high-throughput sequencing and bioinformatics has enabled rapid identification and molecular characterization of known and novel infectious agents in human disease. An exciting era of microbe discovery, now under way, holds great promise for the improvement of global health via the development of antimicrobial therapies, vaccination strategies, targeted public health measures, and probiotic-based preventions and therapies. Here, we review the history of pathogen discovery, discuss improvements and clinical applications for the detection of microbially associated diseases, and explore the challenges and strategies for establishing causation in human disease. C1 [Bullman, Susan; Meyerson, Matthew] Dana Farber Canc Inst, Boston, MA 02215 USA. [Bullman, Susan; Meyerson, Matthew] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. [Meyerson, Matthew] Harvard Med Sch, Boston, MA 02115 USA. [Kostic, Aleksandar D.] Joslin Diabet Ctr, Div Res, 1 Joslin Pl, Boston, MA 02215 USA. [Kostic, Aleksandar D.] Harvard Med Sch, Dept Microbiol & Immunobiol, Boston, MA 02115 USA. RP Bullman, S (reprint author), Dana Farber Canc Inst, Boston, MA 02215 USA.; Bullman, S (reprint author), Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. EM susan_bullman@dfci.harvard.edu; matthew_meyerson@dfci.harvard.edu; aleksandar.kostic@joslin.harvard.edu NR 145 TC 0 Z9 0 U1 0 U2 0 PU ANNUAL REVIEWS PI PALO ALTO PA 4139 EL CAMINO WAY, PO BOX 10139, PALO ALTO, CA 94303-0897 USA SN 1553-4006 J9 ANNU REV PATHOL-MECH JI Annu. Rev. Pathol.-Mech Dis. PY 2017 VL 12 BP 217 EP 244 DI 10.1146/annurev-pathol-012615-044305 PG 28 WC Pathology SC Pathology GA BG9PJ UT WOS:000393554200009 PM 27959634 ER PT S AU Davidson, SM Vander Heiden, MG AF Davidson, Shawn M. Vander Heiden, Matthew G. BE Insel, PA TI Critical Functions of the Lysosome in Cancer Biology SO ANNUAL REVIEW OF PHARMACOLOGY AND TOXICOLOGY, VOL 57 SE Annual Review of Pharmacology and Toxicology LA English DT Review; Book Chapter DE hallmarks of cancer; lysosome function; cancer; cancer metabolism ID ONCOGENE-INDUCED SENESCENCE; RECEPTOR TYROSINE KINASES; RAS-TRANSFORMED CELLS; GROWTH-FACTOR; HEPARAN-SULFATE; BREAST-CANCER; SELECTIVE AUTOPHAGY; ENDOTHELIAL-CELLS; INFLAMMATORY RESPONSE; ENDOPLASMIC-RETICULUM AB Lysosomes (or lytic bodies) were so named because they contain high levels of hydrolytic enzymes. Lysosome function and dysfunction have been found to play important roles in human disease, including cancer; however, the ways in which lysosomes contribute to tumorigenesis and cancer progression are still being uncovered. Beyond serving as a cellular recycling center, recent evidence suggests that the lysosome is involved in energy homeostasis, generating building blocks for cell growth, mitogenic signaling, priming tissues for angiogenesis and metastasis formation, and activating transcriptional programs. This review examines emerging knowledge of how lysosomal processes contribute to the hallmarks of cancer and highlights vulnerabilities that might be exploited for cancer therapy. C1 [Davidson, Shawn M.; Vander Heiden, Matthew G.] MIT, Koch Inst Integrat Canc Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Davidson, Shawn M.; Vander Heiden, Matthew G.] MIT, Dept Biol, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Davidson, Shawn M.] Dana Farber Canc Inst, Boston, MA 02215 USA. RP Davidson, SM (reprint author), MIT, Koch Inst Integrat Canc Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA.; Davidson, SM (reprint author), MIT, Dept Biol, 77 Massachusetts Ave, Cambridge, MA 02139 USA. EM smd10@mit.edu; mvh@mit.edu NR 205 TC 0 Z9 0 U1 1 U2 1 PU ANNUAL REVIEWS PI PALO ALTO PA 4139 EL CAMINO WAY, PO BOX 10139, PALO ALTO, CA 94303-0897 USA SN 0362-1642 BN 978-0-8243-0457-7 J9 ANNU REV PHARMACOL JI Annu. Rev. Pharmacol. Toxicol. PY 2017 VL 57 BP 481 EP 507 DI 10.1146/annurev-pharmtox-010715-103101 PG 27 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA BH0QN UT WOS:000396044800024 PM 27732799 ER PT J AU Weiner, KS Barnett, MA Lorenz, S Caspers, J Stigliani, A Amunts, K Zilles, K Fischl, B Grill-Spector, K AF Weiner, Kevin S. Barnett, Michael A. Lorenz, Simon Caspers, Julian Stigliani, Anthony Amunts, Katrin Zilles, Karl Fischl, Bruce Grill-Spector, Kalanit TI The Cytoarchitecture of Domain-specific Regions in Human High-level Visual Cortex SO CEREBRAL CORTEX LA English DT Article DE brain map; cytoarchitecture; fusiform body area (FBA); fusiform face area (FFA); parahippocampal place area (PPA); visual word form area (VWFA) ID VENTRAL TEMPORAL CORTEX; WORD FORM AREA; HUMAN EXTRASTRIATE CORTEX; POSTERIOR FUSIFORM GYRUS; HUMAN CEREBRAL-CORTEX; HUMAN OBJECT AREAS; FACE PERCEPTION; ELECTRICAL-STIMULATION; CORTICAL AREAS; DISTRIBUTED ORGANIZATION AB A fundamental hypothesis in neuroscience proposes that underlying cellular architecture (cytoarchitecture) contributes to the functionality of a brain area. However, this hypothesis has not been tested in human ventral temporal cortex (VTC) that contains domain-specific regions causally involved in perception. To fill this gap in knowledge, we used cortex-based alignment to register functional regions from living participants to cytoarchitectonic areas in ex vivo brains. This novel approach reveals 3 findings. First, there is a consistent relationship between domain-specific regions and cytoarchitectonic areas: each functional region is largely restricted to 1 cytoarchitectonic area. Second, extracting cytoarchitectonic profiles from face-and place-selective regions after back-projecting each region to 20-mu m thick histological sections indicates that cytoarchitectonic properties distinguish these regions from each other. Third, some cytoarchitectonic areas contain more than 1 domain-specific region. For example, face-, body-, and character-selective regions are located within the same cytoarchitectonic area. We summarize these findings with a parsimonious hypothesis incorporating how cellular properties may contribute to functional specialization in human VTC. Specifically, we link computational principles to correlated axes of functional and cytoarchitectonic segregation in human VTC, in which parallel processing across domains occurs along a lateral-medial axis while transformations of information within domain occur along an anterior-posterior axis. C1 [Weiner, Kevin S.; Barnett, Michael A.; Stigliani, Anthony; Grill-Spector, Kalanit] Stanford Univ, Dept Psychol, Stanford, CA 94305 USA. [Lorenz, Simon; Caspers, Julian; Amunts, Katrin; Zilles, Karl] Res Ctr Julich, Inst Neurosci & Med INM 1, D-52428 Julich, Germany. [Caspers, Julian] Univ Dusseldorf, Fac Med, Dept Diagnost & Intervent Radiol, D-40225 Dusseldorf, Germany. [Amunts, Katrin] Heinrich Heine Univ Dusseldorf, Cecile & Oskar Vogt Inst Brain Res, D-40225 Dusseldorf, Germany. [Amunts, Katrin; Zilles, Karl] Julich Aachen Res Alliance, JARA BRAIN, D-52428 Julich, Germany. [Zilles, Karl] Rhein Westfal TH Aachen, Dept Psychiat Psychotherapy & Psychosomat, D-52062 Aachen, Germany. [Fischl, Bruce] Harvard Med Sch, Martinos Ctr Biomed Imaging, Massachusetts Gen Hosp, Boston, MA 02114 USA. [Fischl, Bruce] Harvard Med Sch, Dept Radiol, Massachusetts Gen Hosp, Boston, MA 02114 USA. [Fischl, Bruce] MIT, Comp Sci & Artificial Intelligence Lab, MIT EECS HST, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Grill-Spector, Kalanit] Stanford Univ, Stanford Neurosci Inst, Stanford, CA 94305 USA. RP Weiner, KS; Grill-Spector, K (reprint author), Stanford Univ, Dept Psychol, Stanford, CA 94305 USA. EM kweiner@stanford.edu; kalanit@stanford.edu FU European Union [604102]; National Institute for Biomedical Imaging and Bioengineering [P41EB015896, R01EB006758, R21EB0 18907, R01EB019956]; National Institute on Aging [5R01AG00 8122, R01AG016495]; National Institute for Neurological Disorders and Stroke [R01NS0525851, R21NS072652, R01NS070963, R0 1NS083534, 5U01NS086625]; Shared Instrumentation Grants [1S10RR0 23401, 1S10RR019307, 1S10RR023043]; NIH Blueprint for Neuroscience Research [5U0 1-MH093765]; [1RO1EY 02231801A1]; [1R01EY02391501A1] FX Support for this research was provided by grants: 1RO1EY 02231801A1 and 1R01EY02391501A1 to K.G.S.; the European Union Seventh Framework Programme (FP7/2007-2013) under grant agreement no. 604102 (Human Brain Project) to K.A. and K.Z.; and the following grants to B.F.: the National Institute for Biomedical Imaging and Bioengineering (P41EB015896, R01EB006758, R21EB0 18907, R01EB019956), the National Institute on Aging (5R01AG00 8122, R01AG016495), the National Institute for Neurological Disorders and Stroke (R01NS0525851, R21NS072652, R01NS070963, R0 1NS083534, 5U01NS086625), and was made possible by the resources provided by Shared Instrumentation Grants 1S10RR0 23401, 1S10RR019307, and 1S10RR023043. Additional support was provided by the NIH Blueprint for Neuroscience Research (5U0 1-MH093765), part of the multi-institutional Human Connectome Project. NR 81 TC 1 Z9 1 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1047-3211 EI 1460-2199 J9 CEREB CORTEX JI Cereb. Cortex PD JAN PY 2017 VL 27 IS 1 BP 146 EP 161 DI 10.1093/cercor/bhw361 PG 16 WC Neurosciences SC Neurosciences & Neurology GA EP0GI UT WOS:000397064800013 PM 27909003 ER PT J AU Hong, S Park, KS Weissleder, R Castro, CM Lee, H AF Hong, Seonki Park, Ki Soo Weissleder, Ralph Castro, Cesar M. Lee, Hakho TI Facile silicification of plastic surface for bioassays SO CHEMICAL COMMUNICATIONS LA English DT Article ID PROTEINS; GLIOBLASTOMA; PURIFICATION; CHEMISTRY; COATINGS; SILICA; RNA; DNA AB We herein report a biomimetic technique to modify plastic substrates for bioassays. The method first places a polydopamine adhesion layer to plastic surface, and then grows conformal silica coating. As proof of principle, we coated plastic microbeads to construct a disposable filter for point-of-care nucleic acid extraction. C1 [Hong, Seonki; Park, Ki Soo; Weissleder, Ralph; Castro, Cesar M.; Lee, Hakho] Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. [Hong, Seonki; Park, Ki Soo; Weissleder, Ralph; Lee, Hakho] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Weissleder, Ralph] Harvard Med Sch, Dept Syst Biol, Boston, MA 02115 USA. [Castro, Cesar M.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. RP Castro, CM; Lee, H (reprint author), Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA.; Lee, H (reprint author), Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA.; Castro, CM (reprint author), Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. EM castro.cesar@mgh.harvard.edu; hlee@mgh.harvard.edu OI Lee, Hakho/0000-0002-0087-0909; Hong, Seonki/0000-0003-1440-5167; Castro, Cesar/0000-0002-1159-5658 FU US NIH Grants [R21-CA205322, R01-HL113156, R01-CA204019, R01-EB010011, K12CA087723-11A1]; MGH Physician Scientist Development Award; Basic Science Research Program (K.S.P.) through the National Research Foundation of Korea [2014R1A6A3A03059728] FX This work was supported in part by US NIH Grants R21-CA205322 (to H. L.), R01-HL113156 (to H. L.), R01-CA204019 (to R.W.), R01-EB010011 (to R.W.), K12CA087723-11A1 (to C.M.C.), MGH Physician Scientist Development Award (to C.M.C.) and Basic Science Research Program 2014R1A6A3A03059728 (K.S.P.) through the National Research Foundation of Korea. NR 33 TC 0 Z9 0 U1 1 U2 1 PU ROYAL SOC CHEMISTRY PI CAMBRIDGE PA THOMAS GRAHAM HOUSE, SCIENCE PARK, MILTON RD, CAMBRIDGE CB4 0WF, CAMBS, ENGLAND SN 1359-7345 EI 1364-548X J9 CHEM COMMUN JI Chem. Commun. PY 2017 VL 53 IS 13 BP 2134 EP 2137 DI 10.1039/c6cc09359k PG 4 WC Chemistry, Multidisciplinary SC Chemistry GA EM9IS UT WOS:000395625700012 PM 28134385 ER PT J AU Park, H Ha, J Koo, JY Park, J Park, SB AF Park, Hankum Ha, Jaeyoung Koo, Ja Young Park, Jongmin Park, Seung Bum TI Label-free target identification using in-gel fluorescence difference via thermal stability shift SO CHEMICAL SCIENCE LA English DT Article ID DRUG DISCOVERY; CYTOPLASMIC DYNEIN; PROTEIN; ELECTROPHORESIS; BINDING; BRYOSTATIN-1; PHARMACOLOGY; ENGAGEMENT; HORDENINE; MOLECULES AB Target engagement is a prerequisite for the therapeutic effects of bioactive small molecules, and unbiased identification of their target proteins can facilitate drug discovery and chemical biology research. Structural modifications of bioactive natural products for target identification exhibit potential limitations such as synthetic difficulties, limited supplies from natural sources, and loss of original efficacy. Herein, we developed a label-free method for proteome-wide target identification using in-gel fluorescence difference caused by thermal stability shift, namely TS-FITGE. Quantitative intra-gel image analysis of each protein spot revealed target proteins with shifted thermal stability upon drug engagement, and plotting of melting curves by inter-gel analysis confirmed the positive targets. We demonstrated the robustness and applicability of the TS-FITGE method by identifying target proteins, including membrane-anchored proteins, of complex bioactive compounds. Furthermore, we identified and functionally validated nucleophosmin as a novel target protein of hordenine, a natural product upregulator of in vitro translation. C1 [Park, Hankum; Ha, Jaeyoung; Park, Seung Bum] Seoul Natl Univ, Dept Biophys & Chem Biol, Seoul 08826, South Korea. [Koo, Ja Young; Park, Jongmin; Park, Seung Bum] Seoul Natl Univ, Dept Chem, CRI Ctr Chem Prote, Seoul 08826, South Korea. [Park, Jongmin] Harvard Med Sch, Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. RP Park, SB (reprint author), Seoul Natl Univ, Dept Biophys & Chem Biol, Seoul 08826, South Korea.; Park, SB (reprint author), Seoul Natl Univ, Dept Chem, CRI Ctr Chem Prote, Seoul 08826, South Korea. EM sbpark@snu.ac.kr OI Park, Jongmin/0000-0001-8338-9346 FU National Creative Research Initiative Grant [2014R1A3A2030423]; Bio & Medical Technology Development Program through the National Research Foundation of Korea (NRF) - Korean Government (Ministry of Science, ICT & Future Planning) [2012M3A9C4048780]; BK21 Fellowship Program FX This work was supported by the National Creative Research Initiative Grant (2014R1A3A2030423) and the Bio & Medical Technology Development Program (2012M3A9C4048780) through the National Research Foundation of Korea (NRF) funded by the Korean Government (Ministry of Science, ICT & Future Planning). H. P., J. H., J. Y. K. and J. P. are grateful for the BK21 Fellowship Program. We appreciate Prof. Sunghoon Kim at the College of Pharmacy at Seoul National University and Prof. Motonari Uesugi at the Institute for Integrated CellMaterial Sciences at Kyoto University for active discussion during the early stage of this study. We also appreciate Prof. Kong-Joo Lee at the College of Pharmacy at Ewha Womans University for mass spectrometry assistance. NR 32 TC 0 Z9 0 U1 1 U2 1 PU ROYAL SOC CHEMISTRY PI CAMBRIDGE PA THOMAS GRAHAM HOUSE, SCIENCE PARK, MILTON RD, CAMBRIDGE CB4 0WF, CAMBS, ENGLAND SN 2041-6520 EI 2041-6539 J9 CHEM SCI JI Chem. Sci. PY 2017 VL 8 IS 2 BP 1127 EP 1133 DI 10.1039/c6sc03238a PG 7 WC Chemistry, Multidisciplinary SC Chemistry GA EM6NC UT WOS:000395428300032 ER PT J AU Mehta, S Sastry, BKS Souza, R Torbicki, A Ghofrani, HA Channick, RN Delcroix, M Pulido, T Simonneau, G Wlodarczyk, J Rubin, LJ Jansa, P Hunsche, E Galie, N Perchenet, L Sitbon, O AF Mehta, Sanjay Sastry, Bhagavatula Kutumba Srinivasa Souza, Rogerio Torbicki, Adam Ghofrani, Hossein-Ardeschir Channick, Richard N. Delcroix, Marion Pulido, Tomas Simonneau, Gerald Wlodarczyk, John Rubin, Lewis J. Jansa, Pavel Hunsche, Elke Galie, Nazzareno Perchenet, Loic Sitbon, Olivier TI Macitentan Improves Health- Related Quality of Life for Patients With Pulmonary Arterial Hypertension SO CHEST LA English DT Article DE health-related quality of life; pulmonary arterial hypertension; pharmacotherapy ID REPORTED OUTCOMES; DISEASE; DIAGNOSIS; THERAPY AB BACKGROUND: Pulmonary arterial hypertension (PAH) leads to reduced health-related quality of life (HRQoL). The objectives of this analysis were to evaluate the effect of macitentan on HRQoL in patients with PAH in the Study with an Endothelin Receptor Antagonist in Pulmonary Arterial Hypertension to Improve Clinical Outcome (SERAPHIN) study. The association between baseline HRQoL and long-term outcomes was also investigated. METHODS: Patients were randomized to placebo, macitentan 3 mg, or macitentan 10 mg once daily. Patients aged 14 years or older completed the 36-Item Short Form Survey (SF-36) at baseline, at month 6 and month 12, and at the end of treatment (EOT). The absolute change from baseline to month 6 in SF-36 scores was calculated. The time to a clinically meaningful deterioration in the SF-36 physical component summary and mental component summary (PCS and MCS) scores and associations between baseline PCS/MCS scores and time to morbidity/mortality events were also assessed. RESULTS: At month 6, macitentan 10 mg significantly improved seven of eight SF-36 domains and the PCS and MCS scores vs placebo. Macitentan 10 mg significantly reduced the risk of a three-point or greater deterioration in PCS (hazard ratio [HR], 0.60; 95% CI, 0.47- 0.76; P <.0001) and MCS scores (HR, 0.76; 95% CI, 0.61- 0.95; P = .0173) until EOT vs placebo. Patients with a baseline PCS score greater than the median baseline value had a significantly reduced risk of morbidity/mortality compared with patients with a PCS score less than the median; a similar result was observed for the MCS score. CONCLUSIONS: Macitentan significantly improved HRQoL in patients with PAH compared with placebo and significantly reduced the risk of a clinically meaningful HRQoL deterioration. An association between better baseline HRQoL and improved long-term outcomes was shown. C1 [Mehta, Sanjay] Univ Western Ontario, Victoria Hosp, London Hlth Sci Ctr, 800 Commissioners Rd E, London, ON N6A 5W9, Canada. [Sastry, Bhagavatula Kutumba Srinivasa] CARE Hosp, Hyderabad, Andhra Pradesh, India. [Souza, Rogerio] Univ Sao Paulo, Sch Med, Inst Heart, Sao Paulo, Brazil. [Torbicki, Adam] Europejskie Ctr Zdrowia, Ctr Postgrad Med Educ, Otwock, Poland. [Ghofrani, Hossein-Ardeschir] Univ Giessen & Marburg Lung Ctr, Giessen, Germany. German Ctr Lung Res DZL, Giessen, Germany. Imperial Coll London, Dept Med, London, England. [Channick, Richard N.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Delcroix, Marion] Univ Hosp Gasthuisberg, Leuven, Belgium. [Pulido, Tomas] Ignacio Chavez Natl Heart Inst, Mexico City, DF, Mexico. [Simonneau, Gerald; Sitbon, Olivier] Hop Bicetre, AP HP, Serv Pneumol, Le Kremlin Bicetre, France. Univ Paris Sud, Lab Excellence Rech Medicament & Innovat Therapeu, Le Kremlin Bicetre, France. Ctr Chirurg Marie Lannelongue, INSERM, U 999, Le Plessis Robinson, France. [Wlodarczyk, John] John Wlodarczyk Consulting Serv, Newcastle, NSW, Australia. [Rubin, Lewis J.] Univ Calif San Diego, Sch Med, San Diego, CA 92103 USA. [Jansa, Pavel] Charles Univ Prague, Prague, Czech Republic. [Hunsche, Elke; Perchenet, Loic] Actel Pharmaceut Ltd, Allschwil, Switzerland. [Galie, Nazzareno] Bologna Univ Hosp, Bologna, Italy. RP Mehta, S (reprint author), Univ Western Ontario, Victoria Hosp, London Hlth Sci Ctr, 800 Commissioners Rd E, London, ON N6A 5W9, Canada. EM sanjay.mehta@lhsc.on.ca FU Actelion Pharmaceuticals Ltd. FX SERAPHIN was funded by Actelion Pharmaceuticals Ltd. NR 26 TC 0 Z9 0 U1 0 U2 0 PU AMER COLL CHEST PHYSICIANS PI GLENVIEW PA 2595 PATRIOT BLVD, GLENVIEW, IL 60026 USA SN 0012-3692 J9 CHEST JI Chest PD JAN PY 2017 VL 151 IS 1 BP 106 EP 118 DI 10.1016/j.chest.2016.08.1473 PG 13 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA EO0HE UT WOS:000396378100022 PM 27671974 ER PT J AU Khera, AV Ridker, PM AF Khera, Amit V. Ridker, Paul M. TI Demystifying HDL Cholesterol A "Human Knockout" to the Rescue? SO CLINICAL CHEMISTRY LA English DT Editorial Material ID CORONARY-HEART-DISEASE; BI C1 [Khera, Amit V.] Harvard Med Sch, Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA USA. [Khera, Amit V.] Harvard Med Sch, Massachusetts Gen Hosp, Div Cardiol, Boston, MA USA. [Ridker, Paul M.] Harvard Med Sch, Brigham & Womens Hosp, Ctr Cardiovasc Dis Prevent, Boston, MA USA. [Ridker, Paul M.] Harvard Med Sch, Brigham & Womens Hosp, Div Cardiovasc Med, Boston, MA USA. RP Ridker, PM (reprint author), Brigham & Womens Hosp, 900 Commonwealth Ave East,3rd Floor, Boston, MA 02215 USA. EM pridker@partners.org FU ACCF/Merck Cardiovascular Research Fellowship; NHLBI; NCI; Amgen; Novartis; Pfizer; Kowa; AstraZeneca FX A.V. Khera, ACCF/Merck Cardiovascular Research Fellowship; P.M Ridker, investigator initiated research support from the NHLBI, NCI, Amgen, Novartis, Pfizer, Kowa, and AstraZeneca. NR 5 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CLINICAL CHEMISTRY PI WASHINGTON PA 2101 L STREET NW, SUITE 202, WASHINGTON, DC 20037-1526 USA SN 0009-9147 EI 1530-8561 J9 CLIN CHEM JI Clin. Chem. PD JAN PY 2017 VL 63 IS 1 BP 33 EP 36 DI 10.1373/clinchem.2016.258244 PG 4 WC Medical Laboratory Technology SC Medical Laboratory Technology GA EM1AE UT WOS:000395048800008 PM 27881451 ER PT J AU Scirica, BM AF Scirica, Benjamin M. TI Use of Biomarkers in Predicting the Onset, Monitoring the Progression, and Risk Stratification for Patients with Type 2 Diabetes Mellitus SO CLINICAL CHEMISTRY LA English DT Review ID CORONARY-ARTERY-DISEASE; CHRONIC KIDNEY-DISEASE; C-REACTIVE PROTEIN; TROPONIN-T ASSAY; NATRIURETIC-PEPTIDE; HEART-FAILURE; CARDIOVASCULAR-DISEASE; GLYCATED HEMOGLOBIN; INSULIN-RESISTANCE; CARDIAC EVENTS AB BACKGROUND: As the worldwide prevalence of type 2 diabetes mellitus (T2DM) increases, it is even more important to develop cost-effective methods to predict and diagnose the onset of diabetes, monitor progression, and risk stratify patients in terms of subsequent cardiovascular and diabetes complications. CONTENT: Nonlaboratory clinical risk scores based on risk factors and anthropomorphic data can help identify patients at greatest risk of developing diabetes, but glycemic indices (hemoglobin A(1c), fasting plasma glucose, and oral glucose tolerance tests) are the cornerstones for diagnosis, and the basis for monitoring therapy. Although family history is a strong predictor of T2DM, only small populations of patients carry clearly identifiable genetic mutations. Better modalities for detection of insulin resistance would improve earlier identification of dysglycemia and guide effective therapy based on therapeutic mechanisms of action, but improved standardization of insulin assays will be required. Although clinical risk models can stratify patients for subsequent cardiovascular risk, the addition of cardiac biomarkers, in particular, high-sensitivity troponin and natriuretic peptide provide, significantly improves model performance and risk stratification. CONCLUSIONS: Much more research, prospectively planned and with clear treatment implications, is needed to define novel biomarkers that better identify the underlying pathogenic etiologies of dysglycemia. When compared with traditional risk features, biomarkers provide greater discrimination of future risk, and the integration of cardiac biomarkers should be considered part of standard risk stratification in patients with T2DM. (C) 2016 American Association for Clinical Chemistry C1 [Scirica, Benjamin M.] Harvard Med Sch, Brigham & Womens Hosp, Dept Med, TIMI Study Grp,Cardiovasc Div, Boston, MA USA. RP Scirica, BM (reprint author), Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. EM bscirica@partners.org FU TIMI Study Group; Brigham and Women's Hospital from AstraZeneca; Eisai; Poxel FX B.M. Scirica, Research grants via the TIMI Study Group and Brigham and Women's Hospital from AstraZeneca, Eisai, and Poxel. NR 67 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CLINICAL CHEMISTRY PI WASHINGTON PA 2101 L STREET NW, SUITE 202, WASHINGTON, DC 20037-1526 USA SN 0009-9147 EI 1530-8561 J9 CLIN CHEM JI Clin. Chem. PD JAN PY 2017 VL 63 IS 1 BP 186 EP 195 DI 10.1373/clinchem.2016.255539 PG 10 WC Medical Laboratory Technology SC Medical Laboratory Technology GA EM1AE UT WOS:000395048800027 PM 28062618 ER PT J AU Ibrahim, NE Januzzi, JL AF Ibrahim, Nasrien E. Januzzi, James L., Jr. TI Beyond Natriuretic Peptides for Diagnosis and Management of Heart Failure SO CLINICAL CHEMISTRY LA English DT Review ID HIGH-SENSITIVITY TROPONIN; FAMILY-MEMBER ST2; GROWTH-DIFFERENTIATION FACTOR-15; GLOMERULAR-FILTRATION-RATE; SOLUBLE ST2; CYSTATIN-C; EJECTION FRACTION; PROGNOSTIC VALUE; RISK PREDICTION; ACUTE DYSPNEA AB BACKGROUND: Heart failure (HF) is a complex syndrome with an enormous societal burden in terms of cost and morbidity and mortality. Natriuretic peptide (NP) testing is now widely used to support diagnosis, prognostication, and management of patients with HF, but NPs come with limitations, including vulnerability to the presence of obesity, atrial fibrillation, and renal dysfunction, for example. Beyond the NPs, novel biomarkers may supplement traditional clinical and laboratory testing to improve understanding of the complex disease process of HF, and possibly to personalize care for those affected through better individual phenotyping. CONTENT: In this review we discuss novel biomarkers by dividing them into categories based on major pathophysiologic pathways they represent including myocardial stretch/stress, cardiac extracellular matrix remodeling, cardiomyocyte injury/death, oxidative stress, inflammation, neurohumoral activation, and renal dysfunction. SUMMARY: Given the limitations of NPs, along with the complex physiology in HF, it is logical to consider utilization of novel biomarkers providing orthogonal biological and clinical information. Several novel HF biomarkers have shown promise but have substantial expectations to meet before being used clinically. Nonetheless, it is reasonable to expect the future lies in the application of multibiomarker panels for the improvement in management of HF and the personalization of care. (C) 2016 American Association for Clinical Chemistry C1 [Ibrahim, Nasrien E.; Januzzi, James L., Jr.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Januzzi, James L., Jr.] Harvard Clin Res Inst, Boston, MA USA. RP Januzzi, JL (reprint author), Massachusetts Gen Hosp, 32 Fruit St,Yawkey 5984, Boston, MA 02114 USA. EM jjanuzzi@partners.org FU Siemens; Prevencio; Singulex; Roche Diagnostics FX Siemens, Prevencio, Singulex, and Roche Diagnostics. NR 79 TC 0 Z9 0 U1 1 U2 1 PU AMER ASSOC CLINICAL CHEMISTRY PI WASHINGTON PA 2101 L STREET NW, SUITE 202, WASHINGTON, DC 20037-1526 USA SN 0009-9147 EI 1530-8561 J9 CLIN CHEM JI Clin. Chem. PD JAN PY 2017 VL 63 IS 1 BP 211 EP 222 DI 10.1373/clinchem.2016.259564 PG 12 WC Medical Laboratory Technology SC Medical Laboratory Technology GA EM1AE UT WOS:000395048800029 PM 28062619 ER PT J AU Arrigo, M Truong, QA Onat, D Szymonifka, J Gayat, E Tolppanen, H Sadoune, M Demmer, RT Wong, KY Launay, JM Samuel, JL Cohen-Solal, A Januzzi, JL Singh, JP Colombo, PC Mebazaa, A AF Arrigo, Mattia Truong, Quynh A. Onat, Duygu Szymonifka, Jackie Gayat, Etienne Tolppanen, Hell Sadoune, Malha Demmer, Ryan T. Wong, Ka Y. Launay, Jean Marie Samuel, Jane-Lise Cohen-Solal, Alain Januzzi, James L., Jr. Singh, Jagmeet P. Colombo, Paolo C. Mebazaa, Alexandre TI Soluble CD146 Is a Novel Marker of Systemic Congestion in Heart Failure Patients: An Experimental Mechanistic and Transcardiac Clinical Study SO CLINICAL CHEMISTRY LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; EUROPEAN-SOCIETY; VENOUS CONGESTION; IDENTIFICATION; ASSOCIATION; ACTIVATION; BIOMARKER; ENDOTHELIUM; EXPRESSION; MANAGEMENT AB BACKGROUND: Soluble CD146 (sCD146), is an endothelial marker with similar diagnostic power as natriuretic peptides in decompensated heart failure (HF). While natriuretic peptides are released by the failing heart, sCD146 may be released by veins in response to stretch induced by systemic congestion in HF. This study investigated the source, effects of vascular stress on release and prognostic properties of sCD146 in HF. METHODS: In a peripheral venous stress study, plasma concentrations of sCD146 and N-terminal probrain natriuretic-peptide (NT-proBNP) were measured in 44 HF patients at baseline and after 90 min of unilateral forearm venous congestion. In addition, sCD146 and NT-proBNP were measured in peripheral vein (PV) and coronary sinus (CS) blood samples of 137 HF patients and the transcardiac gradient was calculated. Those patients were followed for major adverse cardiovascular events (MACE) during 2 years. RESULTS: The induction of venous stress was associated with a pronounced increase in circulating concentrations of sCD146 in the congested arm (+60 mu g/L) compared to the control arm (+16 mu g/L, P = 0.025), while no difference in NT-proBNP concentrations was seen. In contrast to positive transcardiac gradient for NT-proBNP, median sCD146 concentrations were lower in CS than in PV (396 vs 434, P < 0.001), indicating a predominantly extracardiac source of sCD146. Finally, increased PV concentrations of sCD146 were associated with higher risk of MACE at 2 years. CONCLUSIONS: Soluble CD146 is released from the peripheral vasculature in response to venous stretch and may reflect systemic congestion in chronic HF patients. (C) 2016 American Association for Clinical Chemistry. C1 [Arrigo, Mattia; Gayat, Etienne; Tolppanen, Hell; Sadoune, Malha; Samuel, Jane-Lise; Cohen-Solal, Alain; Mebazaa, Alexandre] INSERM, UMR S 942, Paris, France. [Arrigo, Mattia; Gayat, Etienne; Launay, Jean Marie; Cohen-Solal, Alain; Mebazaa, Alexandre] Univ Paris Diderot, PRES Sorbonne Paris Cite, Paris, France. [Arrigo, Mattia; Gayat, Etienne; Mebazaa, Alexandre] St Louis Lariboisiere Univ Hosp, AP HP, Dept Anesthesiol & Crit Care Med, Paris, France. [Arrigo, Mattia; Cohen-Solal, Alain] St Louis Lariboisiere Univ Hosp, AP HP, Dept Cardiol, Paris, France. [Arrigo, Mattia] Univ Zurich Hosp, Dept Cardiol, Univ Heart Ctr, Zurich, Switzerland. [Truong, Quynh A.; Szymonifka, Jackie] New York Presbyterian Hosp, Dalio Inst Cardiovasc Imaging, New York, NY USA. [Truong, Quynh A.; Szymonifka, Jackie] Weill Cornell Med Coll, New York, NY USA. [Truong, Quynh A.; Szymonifka, Jackie; Januzzi, James L., Jr.; Singh, Jagmeet P.] Harvard Med Sch, Div Cardiol, Massachusetts Gen Hosp, Boston, MA USA. [Onat, Duygu; Demmer, Ryan T.; Wong, Ka Y.; Colombo, Paolo C.] Columbia Univ, Div Cardiol, Med Ctr, New York, NY USA. [Launay, Jean Marie] Lariboisiere Univ Hosp, AP HP, Dept Biochem, Paris, France. RP Mebazaa, A (reprint author), St Louis Lariboisiere Univ Hosp, 2 Rue Ambraise Pare, F-75010 Paris, France. EM alexandre.mebazaa@aphp.fr OI Arrigo, Mattia/0000-0003-4028-2869 FU European Commission [305507]; National Institute of Health (NIH) [HL092144A]; A. L. Mailman Family Foundation; MyCartis; Inserm FX The European Commission's Seventh Framework program under grant agreement number 305507 (HOMAGE), the National Institute of Health (NIH grant number HL092144A), and the A. L. Mailman Family Foundation. A financial collaboration exists between MyCartis and Inserm. M. Arrigo, Fellowship of the College de Medecine des Hopitaux de Paris; Q.A. Truong, NIH/NHLBI K23HL098370 and L30HL093896, St. Jude Medical and ACRIN; J. Szymonifka, NIH/NHLBI K23HL098370; J.L. Januzzi, Roche Diagnostics, Singulex, and Prevencio; J.P. Singh, St Jude Medical, Medtronic, BostonScientific, SorinGroup, Biotronik, BG Medicine, and Siemens. NR 28 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CLINICAL CHEMISTRY PI WASHINGTON PA 2101 L STREET NW, SUITE 202, WASHINGTON, DC 20037-1526 USA SN 0009-9147 EI 1530-8561 J9 CLIN CHEM JI Clin. Chem. PD JAN PY 2017 VL 63 IS 1 BP 386 EP 393 DI 10.1373/clinchem.2016.260471 PG 8 WC Medical Laboratory Technology SC Medical Laboratory Technology GA EM1AE UT WOS:000395048800052 PM 28062630 ER PT J AU Socinski, MA Kaye, FJ Spigel, DR Kudrik, FJ Ponce, S Ellis, PM Majem, M Lorigan, P Gandhi, L Gutierrez, ME Nepert, D Corral, J Ares, LP AF Socinski, Mark A. Kaye, Frederic J. Spigel, David R. Kudrik, Fred J. Ponce, Santiago Ellis, Peter M. Majem, Margarita Lorigan, Paul Gandhi, Leena Gutierrez, Martin E. Nepert, Dale Corral, Jesus Paz Ares, Luis TI Phase 1/2 Study of the CD56-Targeting Antibody-Drug Conjugate Lorvotuzumab Mertansine (IMGN901) in Combination With Carboplatin/Etoposide in Small-Cell Lung Cancer Patients With Extensive-Stage Disease SO CLINICAL LUNG CANCER LA English DT Article DE Clinical trial; Combination therapy; SCLC; Targeted drug delivery; Tolerability ID ADHESION MOLECULES; ETOPOSIDE; CISPLATIN; EXPRESSION; CARCINOMA; TUMORS; TRIAL; NCAM AB Lorvotuzumab mertansine (LM, IMGN901) is a CD56-targeting antibody-drug conjugate developed for tumor-selective delivery of the cytotoxic maytansinoid DM1. This phase 1/2 study evaluated the combination of LM with first-line carboplatin/etoposide chemotherapy in patients with extensive-disease small-cell lung cancer. Overall, modest improvements in patient tumor responses did not outweigh the increased safety risks of the triplet combination. Introduction: This trial assessed the safety and efficacy of LM in combination with carboplatin/etoposide therapy compared to carboplatin/etoposide treatment alone in patients with previously untreated extensive-disease small-cell lung cancer (ED-SCLC). Patients and Methods: A run-in phase 1 stage was used to determine the recommended phase 2 dose and characterize the dose-limiting toxicities of LM in combination with carboplatin/etoposide followed by LM alone in patients with CD56-positive solid tumors. In phase 2, chemotherapy-naive ED-SCLC patients were randomized 2:1 to carboplatin AUC (area under the plasma concentration vs. time curve) of 5 day 1 + etoposide 100 mg/m(2) days 1 to 3 plus LM (arm 1) or alone (arm 2). Results: In the phase 1 study (n = 33), a dose of LM at 112 mg/m(2) with carboplatin/etoposide was identified as the recommended phase 2 dose. However, because of an increased incidence of peripheral neuropathy events during early phase 2, this dose was reduced to 90 mg/m(2). In phase 2, a total of 94 and 47 evaluable patients were assigned to arms 1 and 2, respectively. No difference in median progression-free survival was observed between arms 1 and 2 (6.2 vs. 6.7 months). The most common treatment-emergent adverse event leading to discontinuation was peripheral neuropathy (29%). A total of 21 patients had a treatment-emergent adverse event leading to death (18 in arm 1 and 3 in arm 2); for 10 individuals, this was an infection (pneumonia or sepsis) deemed to be related to the study drug. Conclusion: The combination of LM plus carboplatin/etoposide did not improve efficacy over standard carboplatin/etoposide doublet therapy in ED-SCLC patients and showed increased toxicity, including a higher incidence of serious infections with fatal outcomes. (C) 2016 The Authors. Published by Elsevier Inc. C1 [Socinski, Mark A.] Univ Pittsburgh, Inst Canc, Div Hematol Oncol, Pittsburgh, PA USA. [Kaye, Frederic J.] Univ Florida, Coll Med, Hematol Oncol, Gainesville, FL USA. [Spigel, David R.] Sarah Cannon Res Inst, Lung Canc Res Program, Nashville, TN USA. [Kudrik, Fred J.] South Carolina Oncol Associates, Canc Ctr, Columbia, SC USA. [Ponce, Santiago; Corral, Jesus; Paz Ares, Luis] Hosp Univ 12 Octubre, Med Oncol Dept, Madrid, Spain. [Ponce, Santiago; Corral, Jesus; Paz Ares, Luis] Lung Canc Unit CNIO, Madrid, Spain. [Ellis, Peter M.] Juravinski Canc Ctr, Med Oncol, Hamilton, ON, Canada. [Majem, Margarita] Hosp Santa Creu & Sant Pau, Serv Oncol Med, Barcelona, Spain. [Lorigan, Paul] Univ Manchester, Christie NHS Fdn Trust, Div Mol & Clin Canc Sci, Manchester, Lancs, England. [Gandhi, Leena] Dana Farber Canc Inst, Lowe Ctr Thorac Oncol, Boston, MA 02115 USA. [Gutierrez, Martin E.] Holy Cross Hosp, Bienes Canc Ctr, Ft Lauderdale, FL USA. [Nepert, Dale] ImmunoGen Inc, Clin Dev, Waltham, MA USA. RP Socinski, MA (reprint author), Univ Pittsburgh, Div Hematol Oncol, 5150 Ctr Ave, Pittsburgh, PA 15232 USA. EM socinskima@upmc.edu OI Lorigan, Paul/0000-0002-8875-2164 FU ImmunoGen Inc FX The authors thank all the patients, their families, and investigators who participated in the trial. ImmunoGen Inc provided financial support for the conduct of the research and was involved in study design and the collection, analysis, and interpretation of data. We also thank Richard Bates for editorial assistance during the article's preparation. NR 30 TC 0 Z9 0 U1 0 U2 0 PU CIG MEDIA GROUP, LP PI DALLAS PA 3500 MAPLE AVENUE, STE 750, DALLAS, TX 75219-3931 USA SN 1525-7304 EI 1938-0690 J9 CLIN LUNG CANCER JI Clin. Lung Cancer PD JAN PY 2017 VL 18 IS 1 BP 68 EP 76 DI 10.1016/j.cllc.2016.09.002 PG 9 WC Oncology SC Oncology GA EK7AW UT WOS:000394078900009 PM 28341109 ER PT J AU Banks, WA AF Banks, William A. TI Globalization of the Scientific Literature: CPD as a Case Study Foreword SO CURRENT PHARMACEUTICAL DESIGN LA English DT Editorial Material C1 [Banks, William A.] Vet Affairs Puget Sound Hlth Care Syst, Geriatr Res Educ & Clin Ctr, Seattle, WA 98108 USA. [Banks, William A.] Univ Washington, Sch Med, Dept Med, Div Gerontol & Geriatr Med, Seattle, WA 98195 USA. RP Banks, WA (reprint author), Vet Affairs Puget Sound Hlth Care Syst, Geriatr Res Educ & Clin Ctr, Seattle, WA 98108 USA.; Banks, WA (reprint author), Univ Washington, Sch Med, Dept Med, Div Gerontol & Geriatr Med, Seattle, WA 98195 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y-2, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1381-6128 EI 1873-4286 J9 CURR PHARM DESIGN JI Curr. Pharm. Design PY 2017 VL 23 IS 1 BP 1 EP 2 DI 10.2174/138161282301170213194403 PG 2 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EL4DU UT WOS:000394572700001 PM 28292246 ER PT J AU Moheb, N Mendez, MF Kremen, SA Teng, E AF Moheb, Negar Mendez, Mario F. Kremen, Sarah A. Teng, Edmond TI Executive Dysfunction and Behavioral Symptoms Are Associated with Deficits in Instrumental Activities of Daily Living in Frontotemporal Dementia SO DEMENTIA AND GERIATRIC COGNITIVE DISORDERS LA English DT Article DE Frontotemporal lobar degeneration; Primary progressive aphasia; Semantic dementia; Progressive nonfluent aphasia; Cognition; Behavioral symptoms ID PRIMARY PROGRESSIVE APHASIA; UNIFORM DATA SET; ALZHEIMER-DISEASE; OLDER-ADULTS; COGNITIVE IMPAIRMENT; DIAGNOSTIC-CRITERIA; FUNCTIONAL STATUS; VARIANT; ASSESSMENTS; INVENTORY AB Background: Deficits in instrumental activities of daily living (ADLs) may be more prominent in behavioral variant frontotemporal dementia (bvFTD) than in nonfluent/agrammatic variant primary progressive aphasia (nfvPPA) or semantic variant primary progressive aphasia (svPPA). It is uncertain whether frontotemporal dementia (FTD) subgroups exhibit different patterns and/or predictors of functional impairment. Methods: We examined data from participants diagnosed with bvFTD (n = 607), svPPA (n = 132), and nfvPPA (n = 155) who were included in the National Alzheimer's Coordinating Center (NACC) Uniform Data Set (UDS) and assessed with the Functional Activities Questionnaire (FAQ). Stepwise multiple linear regression analyses were performed to identify associations between FAQ scores and cognitive/behavioral deficits using the NACC UDS neuropsychological testing battery and the Neuropsychiatric Inventory Questionnaire. Results: FAQ scores were higher in bvFTD than svPPA or nfvPPA. Functional deficits across FTD subtypes differed in severity, but not pattern, and were driven by executive dysfunction and behavioral symptoms. Conclusion: Executive dysfunction and behavioral symptoms underlie instrumental ADL deficits in FTD, which are most prominent in bvFTD. (C) 2017 S. Karger AG, Basel. C1 [Moheb, Negar; Mendez, Mario F.; Kremen, Sarah A.; Teng, Edmond] Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurol, Los Angeles, CA 90095 USA. [Mendez, Mario F.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Psychiat & Behav Sci, Los Angeles, CA 90095 USA. [Mendez, Mario F.; Teng, Edmond] Vet Affairs Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. RP Teng, E (reprint author), West Los Angeles VA Healthcare Ctr, Neurobehav Serv 116AF, 11301 Wilshire Blvd, Los Angeles, CA 90073 USA. EM eteng@mednet.ucla.edu FU Alzheimer's Disease Research Centers of California; Sidell-Kagan Foundation; NIA/NIH grant [U01 AG016976]; NIA [P30 AG019610, P30 AG013846, P50 AG008702, P50 AG025688, P50 AG047266, P30 AG010133, P50 AG005146, P50 AG005134, P50 AG016574, P50 AG005138, P30 AG008051, P30 AG013854, P30 AG008017, P30 AG010161, P50 AG047366, P30 AG010129, P50 AG016573]; [P50 AG016570]; [P50 AG005131]; [P50 AG023501]; [P30 AG035982]; [P30 AG028383]; [P30 AG010124]; [P50 AG005133]; [P50 AG005142]; [P30 AG012300]; [P50 AG005136]; [P50 AG033514]; [P50 AG005681]; [P50 AG047270] FX This research was supported by the Alzheimer's Disease Research Centers of California and the Sidell-Kagan Foundation. The NACC database is funded by NIA/NIH grant U01 AG016976. NACC data were contributed by the NIA-funded Alzheimer Disease Centers: P30 AG019610 (PI Eric Reiman, MD), P30 AG013846 (PI Neil Kowall, MD), P50 AG008702 (PI Scott Small, MD), P50 AG025688 (PI Allan Levey, MD, PhD), P50 AG047266 (PI Todd Golde, MD, PhD), P30 AG010133 (PI Andrew Saykin, PsyD), P50 AG005146 (PI Marilyn Albert, PhD), P50 AG005134 (PI Bradley Hyman, MD, PhD), P50 AG016574 (PI Ronald Petersen, MD, PhD), P50 AG005138 (PI Mary Sano, PhD), P30 AG008051 (PI Steven Ferris, PhD), P30 AG013854 (PI M. Marsel Mesulam, MD), P30 AG008017 (PI Jeffrey Kaye, MD), P30 AG010161 (PI David Bennett, MD), P50 AG047366 (PI Victor Henderson, MD, MS), P30 AG010129 (PI Charles DeCarli, MD), P50 AG016573 (PI Frank LaFerla, PhD), P50 AG016570 (PI Marie-Francoise Chesselet, MD, PhD), P50 AG005131 (PI Douglas Galasko, MD), P50 AG023501 (PI Bruce Miller, MD), P30 AG035982 (PI Russell Swerdlow, MD), P30 AG028383 (PI Linda Van Eldik, PhD), P30 AG010124 (PI John Trojanowski, MD, PhD), P50 AG005133 (PI Oscar Lopez, MD), P50 AG005142 (PI Helena Chui, MD), P30 AG012300 (PI Roger Rosenberg, MD), P50 AG005136 (PI Thomas Montine, MD, PhD), P50 AG033514 (PI Sanjay Asthana, MD, FRCP), P50 AG005681 (PI John Morris, MD), and P50 AG047270 (PI Stephen Strittmatter, MD, PhD). NR 48 TC 0 Z9 0 U1 0 U2 0 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 1420-8008 EI 1421-9824 J9 DEMENT GERIATR COGN JI Dement. Geriatr. Cogn. Disord. PY 2017 VL 43 IS 1-2 BP 89 EP 99 DI 10.1159/000455119 PG 11 WC Geriatrics & Gerontology; Clinical Neurology; Psychiatry SC Geriatrics & Gerontology; Neurosciences & Neurology; Psychiatry GA EM9XL UT WOS:000395664800009 PM 28103593 ER PT J AU Kocarnik, BM Moore, KP Smith, NL Boyko, EJ AF Kocarnik, Beverly M. Moore, Kathryn P. Smith, Nicholas L. Boyko, Edward J. TI Weight change after initiation of oral hypoglycemic monotherapy for diabetes predicts 5-year mortality: An observational study SO DIABETES RESEARCH AND CLINICAL PRACTICE LA English DT Article DE Weight change; Oral hypoglycemic medication; Mortality; Epidemiology; Prospective research ID ALL-CAUSE MORTALITY; BODY-MASS INDEX; OBESITY PARADOX; US ADULTS; MELLITUS; INDIVIDUALS; ASSOCIATION; COHORT; RISK AB Purpose: To investigate whether weight change in the first year after initiating an oral hypoglycemic agent (OHA) for type 2 diabetes treatment is associated with mortality in a national cohort. Procedures: We prospectively followed Veterans Health Administration patients with type 2 diabetes initiating treatment with an OHA and not receiving any other diabetes pharmacotherapy for at least one year. Information on OHAs, weight, co-morbidities, other medications, demographics, and laboratory measurements was obtained from electronic medical records. Logistic regression was used to estimate 5-year mortality odds by weight change during the first year after OHA treatment initiation. Findings: Patients (mean age 65 years, 97% male, mean BMI 32.3 kg/m2) initiating OHA monotherapy between 2003 and 2008 totaled 145,198 (metformin n = 89,111, glipizide n = 27,100, glyburide n = 25,226, rosiglitazone n = 3,761). Most patients (65%) maintained a stable weight (change <= 5% from baseline) during the first year after OHA initiation. Those losing >5% of baseline weight had a significantly higher odds of death over the subsequent 5-years ranging from 1.64 to 2.13 depending on OHA type. In the metformin group, weight gain >5% of baseline was also associated with higher odds of 5-year mortality. The same results were obtained after conducting three sensitivity analyses that excluded patients for the following reasons: weight loss in the one year prior to OHA initiation, weight change >100 lbs, or weight change >50 lbs. Conclusions: Weight loss was associated with higher odds of 5-year mortality among patients initiating an OHA, as was weight gain for metformin only. Published by Elsevier Ireland Ltd. C1 [Kocarnik, Beverly M.; Boyko, Edward J.] Gen Med & Hosp & Specialty Med Serv, Vet Affairs Puget Sound Hlth Care Syst, Seattle, WA USA. [Kocarnik, Beverly M.] Univ Washington, Dept Med, Div Endocrinol Metab & Nutr, Seattle, WA USA. [Kocarnik, Beverly M.; Moore, Kathryn P.; Smith, Nicholas L.; Boyko, Edward J.] Vet Affairs Puget Sound Hlth Care Syst, Seattle Epidemiol Res & Informat Ctr, Seattle, WA USA. [Smith, Nicholas L.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Smith, Nicholas L.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA USA. [Boyko, Edward J.] Univ Washington, Dept Med, Div Gen Internal Med, Seattle, WA USA. RP Boyko, EJ (reprint author), VA Puget Sound Hlth Care Syst S 123 PCC, 1660 South Columbian Way, Seattle, WA 98108 USA. EM eboyko@uw.edu FU Seattle Epidemiologic Research and Information Center (ERIC) of VA Puget Sound in Seattle; VA Advanced Fellowship in Geriatrics; NIH [2T32HL007028-36A1] FX This work was supported by the Seattle Epidemiologic Research and Information Center (ERIC) of VA Puget Sound in Seattle, and by facilities and services provided by the Diabetes Research Center (NIH DK-17047) at the University of Washington. VA Puget Sound Health Care System provided support for Drs. Boyko and Smith's involvement in this research. Dr. Kocarnik was supported by a VA Advanced Fellowship in Geriatrics and NIH Training Grant 2T32HL007028-36A1. The funding sources had no role in the conduct of the research or the preparation of the article. NR 27 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0168-8227 EI 1872-8227 J9 DIABETES RES CLIN PR JI Diabetes Res. Clin. Pract. PD JAN PY 2017 VL 123 BP 181 EP 191 DI 10.1016/j.diabres.2016.11.025 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EK5CO UT WOS:000393944700021 PM 28056429 ER PT J AU Khairi, S Sagvand, BT Pulaski-Liebert, KJ Tritos, NA Klibanski, A Nachtigall, LB AF Khairi, Shafaq Sagvand, Babak Torabi Pulaski-Liebert, Karen J. Tritos, Nicholas A. Klibanski, Anne Nachtigall, Lisa B. TI CLINICAL OUTCOMES AND SELF-REPORTED SYMPTOMS IN PATIENTS WITH ACROMEGALY: AN 8-YEAR FOLLOW-UP OF A LANREOTIDE STUDY SO ENDOCRINE PRACTICE LA English DT Article ID QUALITY-OF-LIFE; LONG-TERM REMISSION; AUTOGEL 120 MG; ILLNESS PERCEPTIONS; PRIMARY THERAPY; OCTREOTIDE LAR; FORMULATION; TRIAL; DEPOT AB Objective: The aim of this study was to evaluate the proportion of patients with acromegaly who remained on long-term lanreotide depot after completion of an open-label multicenter phase III clinical trial (SALSA: A Multi Center Open Label Study to Assess the Ability of Subjects With Acromegaly or Their Partners to Administer Somatuline Autogel), compare baseline and long-term follow-up symptoms scores, and correlate scores with individual longitudinal clinical outcomes. Methods: Records of all subjects previously enrolled at the Massachusetts General Hospital site of SALSA were reviewed. Those who remained on lanreotide were interviewed and asked to complete a questionnaire that they had filled out in SALSA in 2007 regarding their current symptomatology and injection side effects, as well as to complete the Acromegaly Quality of Life Questionnaire. Furthermore, clinical, biochemical, and radiographic data related to acromegaly and its comorbidities were tracked throughout follow-up. Results: Six out of 7 patients chose to remain on lanreotide, and 5 of them continued lanreotide depot through last follow-up, for up to 8 years or in 1 case until death. In all cases, lanreotide remained well tolerated, and insulinlike growth factor-1 levels and pituitary imaging remained well controlled on stable doses. While comorbidities persisted or developed, the self-reported symptom score after up to 8 years of therapy showed a significant decrease in frequency or resolution in symptoms that were reported at baseline. Conclusion: This study shows a significant decrease in frequency or resolution in self-reported symptoms in well-controlled patients receiving long-term lanreotide therapy. C1 [Nachtigall, Lisa B.] Massachusetts Gen Hosp, Neuroendocrine Unit, Zero Emerson Pl,Suite 112, Boston, MA 02114 USA. Harvard Med Sch, Boston, MA USA. RP Nachtigall, LB (reprint author), Massachusetts Gen Hosp, Neuroendocrine Unit, Zero Emerson Pl,Suite 112, Boston, MA 02114 USA. EM lnachtigall@mgh.harvard.edu FU Ipsen FX This study was supported by an investigator-initiated grant from Ipsen. NR 21 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CLINICAL ENDOCRINOLOGISTS PI JACKSONVILLE PA 245 RIVERSIDE AVENUE, STE 200, JACKSONVILLE, FL 32202 USA SN 1530-891X EI 1934-2403 J9 ENDOCR PRACT JI Endocr. Pract. PD JAN PY 2017 VL 23 IS 1 BP 56 EP 65 DI 10.4158/EP161439.OR PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EP2XO UT WOS:000397247100009 PM 27682353 ER PT J AU Becker, KL Arts, P Jaeger, M Plantinga, TS Gilissen, C van Laarhoven, A van Ingen, J Veltman, JA Joosten, LAB Hoischen, A Netea, MG Iseman, MD Chan, ED van de Veerdonk, FL AF Becker, Katharina L. Arts, Peer Jaeger, Martin Plantinga, Theodorus S. Gilissen, Christian van Laarhoven, Arjan van Ingen, Jakko Veltman, Joris A. Joosten, Leo A. B. Hoischen, Alexander Netea, Mihai G. Iseman, Michael D. Chan, Edward D. van de Veerdonk, Frank L. TI MST1R mutation as a genetic cause of Lady Windermere syndrome SO EUROPEAN RESPIRATORY JOURNAL LA English DT Letter ID MYCOBACTERIAL LUNG-DISEASE; NONTUBERCULOUS MYCOBACTERIA; INTERFERON-GAMMA; AVIUM COMPLEX; RECEPTOR; BODY C1 [Becker, Katharina L.; Jaeger, Martin; Plantinga, Theodorus S.; van Laarhoven, Arjan; Joosten, Leo A. B.; Netea, Mihai G.; van de Veerdonk, Frank L.] Radboud Univ Nijmegen, Med Ctr, Radboud Ctr Infect Dis, Dept Internal Med, Nijmegen, Netherlands. [Arts, Peer; Gilissen, Christian; Veltman, Joris A.; Hoischen, Alexander] Radboud Univ Nijmegen, Med Ctr, Donders Ctr Neurosci, Dept Human Genet, Nijmegen, Netherlands. [van Ingen, Jakko] Radboud Univ Nijmegen, Med Ctr, Radboud Ctr Infect Dis, Dept Microbiol, Nijmegen, Netherlands. [Veltman, Joris A.] Maastricht Univ, Med Ctr, GROW Sch Oncol & Dev Biol, Dept Clin Genet, Maastricht, Netherlands. [Iseman, Michael D.; Chan, Edward D.] Natl Jewish Hlth, Dept Med & Acad Affairs, Denver, CO USA. [Chan, Edward D.] Denver Vet Affairs Med Ctr, Dept Med, Denver, CO USA. [Chan, Edward D.] Univ Colorado, Div Pulm Sci & Crit Care Med, Anschutz Med Campus, Denver, CO USA. RP van de Veerdonk, FL (reprint author), Radboud Univ Nijmegen, Med Ctr, Dept Internal Med, Geert Grooteplein Zuid 8, NL-6525 GA Nijmegen, Netherlands. EM frank.vandeveerdonk@radboudumc.nl FU Netherlands Organisation for Scientific Research (NWO); European Research Council (ERC) [281964]; NWO; ERC [310372]; Euopean Research Area-Net for Research Programmes on Rare Diseases "EURO-CMC" FX A. Hoischen, C. Gilissen and F. van de Veerdonk are supported by Veni grants of the Netherlands Organisation for Scientific Research (NWO). J.A. Veltman was supported by a European Research Council (ERC) starting grant (281964). M.G. Netea is supported by Vici grants from the NWO and by an ERC consolidator grant (310372). F. van de Veerdonk is supported by the Euopean Research Area-Net for Research Programmes on Rare Diseases "EURO-CMC". Funding information for this article has been deposited with Open Funder registry. NR 14 TC 0 Z9 0 U1 0 U2 0 PU EUROPEAN RESPIRATORY SOC JOURNALS LTD PI SHEFFIELD PA 442 GLOSSOP RD, SHEFFIELD S10 2PX, ENGLAND SN 0903-1936 EI 1399-3003 J9 EUR RESPIR J JI Eur. Resp. J. PD JAN PY 2017 VL 49 IS 1 AR 1601478 DI 10.1183/13993003.01478-2016 PG 4 WC Respiratory System SC Respiratory System GA EP5MU UT WOS:000397423500029 ER PT J AU Luks, AM Swenson, ER Bartsch, P AF Luks, Andrew M. Swenson, Erik R. Baertsch, Peter TI Acute high-altitude sickness SO EUROPEAN RESPIRATORY REVIEW LA English DT Article ID ACUTE MOUNTAIN-SICKNESS; HYPOXIC PULMONARY VASOCONSTRICTION; TESTING IDENTIFIES SUBJECTS; EXHALED NITRIC-OXIDE; CEREBRAL EDEMA; NORMOBARIC HYPOXIA; ALVEOLAR HYPOXIA; INFLAMMATORY PROCESSES; EXERCISE PERFORMANCE; PROSPECTIVE COHORT AB At any point 1-5 days following ascent to altitudes. 2500 m, individuals are at risk of developing one of three forms of acute altitude illness: acute mountain sickness, a syndrome of nonspecific symptoms including headache, lassitude, dizziness and nausea; high-altitude cerebral oedema, a potentially fatal illness characterised by ataxia, decreased consciousness and characteristic changes on magnetic resonance imaging; and high-altitude pulmonary oedema, a noncardiogenic form of pulmonary oedema resulting from excessive hypoxic pulmonary vasoconstriction which can be fatal if not recognised and treated promptly. This review provides detailed information about each of these important clinical entities. After reviewing the clinical features, epidemiology and current understanding of the pathophysiology of each disorder, we describe the current pharmacological and nonpharmacological approaches to the prevention and treatment of these diseases. C1 [Luks, Andrew M.; Swenson, Erik R.] Univ Washington, Dept Med, Div Pulm & Crit Care Med, Seattle, WA USA. [Swenson, Erik R.] Vet Affairs Puget Sound Hlth Care Syst, Med Serv, Seattle, WA USA. [Baertsch, Peter] Univ Clin Heidelberg, Dept Internal Med, Heidelberg, Germany. RP Luks, AM (reprint author), Harborview Med Ctr, Div Pulm & Crit Care Med, 325 Ninth Ave,Box 359762, Seattle, WA 98104 USA. EM aluks@u.washington.edu NR 139 TC 0 Z9 0 U1 1 U2 1 PU EUROPEAN RESPIRATORY SOC JOURNALS LTD PI SHEFFIELD PA 442 GLOSSOP RD, SHEFFIELD S10 2PX, ENGLAND SN 0905-9180 EI 1600-0617 J9 EUR RESPIR REV JI Eur. Respir. Rev. PD JAN 1 PY 2017 VL 26 IS 143 AR UNSP 160096 DI 10.1183/16000617.0096-2016 PG 14 WC Respiratory System SC Respiratory System GA EO9WH UT WOS:000397038300018 ER PT J AU Tyler, JM Teerlink, JR AF Tyler, Jeffrey M. Teerlink, John R. TI The safety of sacubitril-valsartan for the treatment of chronic heart failure SO EXPERT OPINION ON DRUG SAFETY LA English DT Review DE Cardiomyopathy; drug combination; drug safety; heart failure; LCZ696; pharmacology; sacubitril-valsartan ID NEPRILYSIN INHIBITOR LCZ696; NEUTRAL ENDOPEPTIDASE INHIBITOR; CONVERTING ENZYME-INHIBITOR; RANDOMIZED CONTROLLED-TRIAL; BETA-AMYLOID PEPTIDE; NATRIURETIC-PEPTIDE; ALZHEIMER-DISEASE; CEREBROSPINAL-FLUID; EJECTION FRACTION; PARADIGM-HF AB Introduction: Sacubitril-valsartan is a combination drug that contains the neprilysin inhibitor sacubitril and angiotensin II receptor blocker valsartan. In 2015, the US Food and Drug Administration approved sacubitril-valsartan for treatment of heart failure patients with reduced ejection fraction and New York Heart Association class II-IV symptoms following a large, Phase III clinical trial (PARADIGM-HF) that demonstrated a 20% reduction in the combined primary end-point of death from cardiovascular cause or hospitalization for heart failure compared to enalapril. Areas covered: This review discusses the clinical efficacy and safety of angiotensin receptor neprilysin inhibitor sacubitril-valsartan in heart failure with reduced ejection fraction. Expert opinion: Based on the PARADIGM-HF trial, sacubitril-valsartan offers compelling reductions in meaningful clinical endpoints, independent of age or severity of disease. The rate of adverse events was comparable between the enalapril and sacubitril-valsartan groups, although the absolute rates are likely underestimated due to the entry criteria and run-in period. Future trials and post-market surveillance are critical to better understand the risk of angioedema in high risk populations, particularly African-Americans, as well as long-term theoretical risks including the potential for increased cerebral amyloid plaque deposition with possible development of neurocognitive disease. Current trials are underway to evaluate potential benefit in patients with heart failure with preserved ejection fraction. C1 [Tyler, Jeffrey M.; Teerlink, John R.] Univ Calif San Francisco, Sch Med, San Francisco, CA USA. [Teerlink, John R.] San Francisco VA Med Ctr, Cardiol Sect, San Francisco, CA USA. RP Teerlink, JR (reprint author), San Francisco VA Med Ctr Cardiol, 111C4150 Clement St, San Francisco, CA 94121 USA. EM john.teerlink@ucsf.edu NR 48 TC 0 Z9 0 U1 0 U2 0 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND SN 1474-0338 EI 1744-764X J9 EXPERT OPIN DRUG SAF JI Expert Opin. Drug Saf. PY 2017 VL 16 IS 2 BP 257 EP 263 DI 10.1080/14740338.2017.1279144 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EL4WB UT WOS:000394620500014 PM 28060547 ER PT J AU Robertson, DJ Lee, JK Boland, CR Dominitz, JA Giardiello, FM Johnson, DA Kaltenbach, T Lieberman, D Levin, TR Rex, DK AF Robertson, Douglas J. Lee, Jeffrey K. Boland, C. Richard Dominitz, Jason A. Giardiello, Francis M. Johnson, David A. Kaltenbach, Tonya Lieberman, David Levin, Theodore R. Rex, Douglas K. TI Recommendations on fecal immunochemical testing to screen for colorectal neoplasia: a consensus statement by the US Multi-Society Task Force on colorectal cancer SO GASTROINTESTINAL ENDOSCOPY LA English DT Article ID OCCULT-BLOOD-TEST; RANDOMIZED CONTROLLED-TRIAL; LOW-DOSE ASPIRIN; AVERAGE-RISK POPULATION; SAMPLE RETURN TIME; ADENOMA DETECTION; ASYMPTOMATIC ADULTS; COLONOSCOPY SURVEILLANCE; AMBIENT-TEMPERATURE; SEASONAL-VARIATIONS AB The use of the fecal occult blood test (FOBT) for colorectal cancer (CRC) screening is supported by randomized trials demonstrating effectiveness in cancer prevention and widely recommended by guidelines for this purpose. The fecal immunochemical test (FIT), as a direct measure of human hemoglobin in stool has a number of advantages relative to conventional FOBT and is increasingly used relative to that test. This review summarizes current evidence for FIT in colorectal neoplasia detection and the comparative effectiveness of FIT relative to other commonly used CRC screening modalities. Based on evidence, guidance statements on FIT application were developed and quality metrics for program implementation proposed. C1 [Robertson, Douglas J.] VA Med Ctr, 215 N Main St, White River Jct, VT 05009 USA. [Robertson, Douglas J.] Geisel Sch Med Dartmouth, Hanover, NH USA. [Lee, Jeffrey K.] Univ Calif San Francisco, Med Ctr, San Francisco, CA USA. [Boland, C. Richard] Baylor Univ, Med Ctr, Dallas, TX USA. [Dominitz, Jason A.] Univ Washington, Sch Med, VA Puget Sound Hlth Care Syst, Seattle, WA USA. [Giardiello, Francis M.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Johnson, David A.] Eastern VA Med Sch, Norfolk, VA USA. [Kaltenbach, Tonya] Univ Calif San Francisco, San Francisco Vet Affairs Med Ctr, San Francisco, CA 94143 USA. [Lieberman, David] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Levin, Theodore R.] Kaiser Permanente Med Ctr, Walnut Creek, CA USA. [Rex, Douglas K.] Indiana Univ Sch Med, Indianapolis, IN 46202 USA. RP Robertson, DJ (reprint author), VA Med Ctr, Gastroenterol 111E, 215 N Main St, White River Jct, VT 05009 USA. EM douglas.robertson@va.gov FU Olympus; Endochoice FX These authors disclose the following: David A. Johnson is a clinical investigator for Exact Sciences and Epigenomics. David Lieberman served on scientific advisory Board for Exact Sciences. Douglas K. Rex received consulting fees from Olympus and research support from Endochoice. Douglas J. Robertson is on the scientific advisory board for Medtronic. Tonya Kaltenbach served as Consultant for Olympus America. The remaining authors disclose no conflicts. NR 118 TC 1 Z9 1 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0016-5107 EI 1097-6779 J9 GASTROINTEST ENDOSC JI Gastrointest. Endosc. PD JAN PY 2017 VL 85 IS 1 BP 2 EP + DI 10.1016/j.gie.2016.09.025 PG 23 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EO1YQ UT WOS:000396494200002 PM 27769516 ER PT J AU Guo, XY Yang, ZP Zhao, LN Leung, FL Luo, H Kang, XY Li, X Jia, H Yang, SY Tao, Q Pan, YL Guo, XG AF Guo, Xiaoyang Yang, Zhiping Zhao, Lina Leung, Felix Luo, Hui Kang, Xiaoyu Li, Xin Jia, Hui Yang, Shengye Tao, Qin Pan, Yanglin Guo, Xuegang TI Enhanced instructions improve the quality of bowel preparation for colonoscopy: a meta-analysis of randomized controlled trials SO GASTROINTESTINAL ENDOSCOPY LA English DT Review ID COLORECTAL-CANCER; POLYETHYLENE-GLYCOL; IMPACT; VALIDATION; EDUCATION; TELEPHONE; SOCIETY; SCALE; RISK AB Background and Aims: The success of a colonoscopy is highly dependent on the quality of bowel preparation (BP). Many patients have poor BP due to non-compliance with regular instructions. Reports concerning the effects of enhanced instructions on BP quality are inconsistent. The aim of this meta-analysis was to compare BP quality between patients receiving enhanced instructions in addition to regular instructions and those who received regular instructions only. Methods: MEDLINE, EMBASE, Web of Science, and the Cochrane Library were searched to identify relevant studies published for August 2015. The quality of BP (adequate/inadequate), adenoma detection rate, polyp detection rate, willingness to repeat preparation, and adverse events were estimated by using odds ratios (OR) and 95% confidence intervals (CI) with random effects models. Results: Eight randomized controlled trials (n = 3795) were included. Patients who received enhanced instructions showed significantly better BP quality than those receiving only regular instructions (OR, 2.35; 95% CI, 1.65-3.35; P < .001). Subgroup analysis showed that the beneficial effects of enhanced instructions on BP quality were consistent among patients receiving different purgative types, administration methods, or diet restriction (all P < .05). Patients in the enhanced instructions group showed more willingness to repeat the preparation (OR, 1.91; 95% CI, 1.20-3.04; P = .006). Conclusions: Enhanced instructions significantly improved the quality of BP and willingness to repeat the preparation in patients undergoing colonoscopy. Factors related to patient instructions appear to be as important as the preparation method itself in improving BP quality. C1 [Guo, Xiaoyang; Yang, Zhiping; Luo, Hui; Kang, Xiaoyu; Jia, Hui; Yang, Shengye; Tao, Qin; Pan, Yanglin; Guo, Xuegang] Fourth Mil Med Univ, Xijing Hosp Digest Dis, 127 Changle West Rd, Xian 710032, Shaanxi, Peoples R China. [Zhao, Lina] Fourth Mil Med Univ, Xijing Hosp, Dept Radiotherapy, Xian, Shaanxi, Peoples R China. [Leung, Felix] Vet Affairs Greater Los Angeles Healthcare Syst, Dept Med, Div Gastroenterol, Sepulveda Ambulatory Care Ctr, 16111 Plummer St, North Hills, CA USA. [Leung, Felix] Univ Calif Los Angeles, David Geffen Sch Med, 10833 Le Conte Ave, Los Angeles, CA 90095 USA. [Li, Xin] Fourth Mil Med Univ, Dept Nursing, Xian, Shaanxi, Peoples R China. RP Pan, YL; Guo, XG (reprint author), Fourth Mil Med Univ, Xijing Hosp Digest Dis, 127 Changle West Rd, Xian 710032, Shaanxi, Peoples R China. FU National Natural Science Foundation of China [81172288, 81570482] FX This work was supported in part by the National Natural Science Foundation of China (81172288 and 81570482). NR 28 TC 2 Z9 2 U1 1 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0016-5107 EI 1097-6779 J9 GASTROINTEST ENDOSC JI Gastrointest. Endosc. PD JAN PY 2017 VL 85 IS 1 BP 90 EP + DI 10.1016/j.gie.2016.05.012 PG 14 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EO1YQ UT WOS:000396494200010 PM 27189659 ER PT J AU Cadoni, S Falt, P Gallittu, P Liggi, M Smajstrla, V Leung, FW AF Cadoni, Sergio Falt, Premysl Gallittu, Paolo Liggi, Mauro Smajstrla, Vit Leung, Felix W. TI Impact of carbon dioxide insufflation and water exchange on postcolonoscopy outcomes in patients receiving on-demand sedation: a randomized controlled trial SO GASTROINTESTINAL ENDOSCOPY LA English DT Article ID UNSEDATED COLONOSCOPY; AIR INSUFFLATION; CO2 INSUFFLATION; DOUBLE-BLIND; PAIN; IMMERSION; INSERTION; TIME; COMPLICATIONS; METAANALYSIS AB Background and Aims: Water exchange (WE) is the least painful insertion method during colonoscopy. Its impact on postcolonoscopy discomfort has not been well-described. Carbon dioxide (CO2) insufflation consistently reduced postcolonoscopy discomfort. We compared postcolonoscopy outcomes of various combinations of insertion and withdrawal techniques (insertion-withdrawal modality): WE-CO2, WE-air insufflation (WE-AI), andCO(2)-CO2. Methods: A total of 240 patients undergoing on-demand sedation diagnostic colonoscopy were randomized to WE-CO2 (n = 79), WE-AI (n = 80), CO2-CO2 (n = 81), with postprocedural data collected up to 24 hours. The primary outcome was postcolonoscopy bloating. Other postcolonoscopy outcomes included pain scores, flatus and incontinence episodes, toilet use, interference with normal activities, patient satisfaction, and patient willingness to repeat the procedure. Results: Demographic and procedural data were comparable. Compared with WE-AI, WE-CO2 and CO2-CO2 resulted in significantly less bloating (all P < .0005) and lower pain scores (P values ranged from .008 to < .0005) up to 3 hours and fewer flatus episodes up to 6 hours (P values ranged from .003 to < .0005). WE-CO2 resulted in less interference with same-day activities compared with WE-AI (P = .043). The differences in postprocedural outcomes were significant, but the magnitude was small. Patient satisfaction and willingness to repeat the procedure were high and comparable among groups. WE was the least painful insertion technique (P < .0005). Conclusions: The combination WE-CO2 appears to be the optimal choice to decrease pain during the examination and to reduce bloating and other undesired procedural outcomes afterward. If a CO2 insufflator is already available, it seems advisable to adopt the combination WE-CO2. In the absence of a CO2 insufflator, the cost effectiveness of the addition of withdrawal CO2 to WE in diagnostic and nondiagnostic settings needs to be critically assessed. (Clinical trial registration number: NCT02409979.) C1 [Cadoni, Sergio; Gallittu, Paolo; Liggi, Mauro] St Barbara Hosp, Digest Endoscopy Unit, Via S Leonardo 1, I-09016 Iglesias, CI, Italy. [Falt, Premysl; Smajstrla, Vit] Vitkovice Hosp, Ctr Digest Dis, Ostrava, Czech Republic. [Leung, Felix W.] Vet Affairs Greater Los Angeles Healthcare Syst, Sepulveda Ambulatory Care Ctr, North Hills, CA USA. [Leung, Felix W.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. RP Cadoni, S (reprint author), St Barbara Hosp, Digest Endoscopy Unit, Via S Leonardo 1, I-09016 Iglesias, CI, Italy. EM cadonisergio@gmail.com NR 33 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0016-5107 EI 1097-6779 J9 GASTROINTEST ENDOSC JI Gastrointest. Endosc. PD JAN PY 2017 VL 85 IS 1 BP 210 EP + DI 10.1016/j.gie.2016.05.021 PG 10 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EO1YQ UT WOS:000396494200028 PM 27207825 ER PT J AU Sun, Q Loughran, P Shapiro, R Shrivastava, IH Antoine, DJ Li, T Yan, ZZ Fan, J Billiar, TR Scott, MJ AF Sun, Qian Loughran, Patricia Shapiro, Richard Shrivastava, Indira H. Antoine, Daniel J. Li, Tunliang Yan, Zhengzheng Fan, Jie Billiar, Timothy R. Scott, Melanie J. TI Redox-Dependent Regulation of Hepatocyte Absent in Melanoma 2 Inflammasome Activation in Sterile Liver Injury in Mice SO HEPATOLOGY LA English DT Article ID GROUP BOX 1; ACETAMINOPHEN-INDUCED HEPATOTOXICITY; HEMORRHAGIC-SHOCK; CELL-DEATH; AIM2 INFLAMMASOME; DNA; HMGB1; AUTOPHAGY; RELEASE; PROTEIN AB Sterile liver inflammation, such as liver ischemia-reperfusion, hemorrhagic shock after trauma, and drug-induced liver injury, is initiated and regulated by endogenous mediators including DNA and reactive oxygen species. Here, we identify a mechanism for redox-mediated regulation of absent in melanoma 2 (AIM2) inflammasome activation in hepatocytes after redox stress in mice, which occurs through interaction with cytosolic high mobility group box 1 (HMGB1). We show that in liver during hemorrhagic shock in mice and in hepatocytes after hypoxia with reoxygenation, cytosolic HMGB1 associates with AIM2 and is required for activation of caspase-1 in response to cytosolic DNA. Activation of caspase-1 through AIM2 leads to subsequent hepatoprotective responses such as autophagy. HMGB1 binds to AIM2 at a non-DNAbinding site on the hematopoietic interferon-inducible nuclear antigen domain of AIM2 to facilitate inflammasome and caspase-1 activation in hepatocytes. Furthermore, binding of HMGB1 to AIM2 is stronger with fully reduced all-thiol HMGB1 than with partially oxidized disulfide-HMGB1, and binding strength corresponds to caspase-1 activation. These data suggest that HMGB1 redox status regulates AIM2 inflammasome activation. Conclusion: These findings suggest a novel and important mechanism for regulation of AIM2 inflammasome activation in hepatocytes during redox stress and may suggest broader implications for how this and other inflammasomes are activated and how their activation is regulated during cell stress, as well as the mechanisms of inflammasome regulation in nonimmune cell types. C1 [Sun, Qian; Loughran, Patricia; Li, Tunliang; Yan, Zhengzheng; Fan, Jie; Billiar, Timothy R.; Scott, Melanie J.] Univ Pittsburgh, Dept Surg, Pittsburgh, PA USA. [Loughran, Patricia] Univ Pittsburgh, Ctr Biol Imaging, Pittsburgh, PA USA. [Shrivastava, Indira H.] Univ Pittsburgh, Computat & Syst Biol, Pittsburgh, PA USA. [Antoine, Daniel J.] Univ Liverpool, MRC Ctr Drug Safety Sci, Dept Mol & Clin Pharmacol, Liverpool, Merseyside, England. [Li, Tunliang] Xiangya Hosp Cent South Univ 3, Dept Anesthesiol, Xiangtan, Peoples R China. [Fan, Jie] Vet Affairs Pittsburgh Healthcare Syst, Surg Res, Pittsburgh, PA USA. RP Scott, MJ (reprint author), Dept Surg Labs MUH, 3459 Fifth Ave, Pittsburgh, PA 3459 USA. EM scottm@upmc.edu FU National Institutes of Health [R01GM102146, R01HL079669] FX Supported by the National Institutes of Health (R01GM102146, to M.J.S., and R01HL079669, to J.F.). NR 43 TC 0 Z9 0 U1 2 U2 2 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD JAN PY 2017 VL 65 IS 1 BP 253 EP 268 DI 10.1002/hep.28893 PG 16 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EP3RE UT WOS:000397298600023 PM 27774630 ER PT J AU Ronan, MV Theisen-Toupal, J AF Ronan, Matthew V. Theisen-Toupal, Jesse TI Opioid Use Disorder in the Hospitalized Patient SO HOSPITAL MEDICINE CLINICS LA English DT Article DE Opioid use disorder; Heroin; Controlled prescription drugs; Opioid withdrawal; Opioid maintenance therapy; Medication; assisted treatment; Harm-reduction strategies ID INJECTING DRUG-USERS; MEDICAL COMPLICATIONS; ADDICTION; NALOXONE; ABUSE; PAIN AB Opioid misuse and opioid use disorder are common in hospitalized patients. They often manifest with the development of opioid withdrawal. It is important that hospitalists properly evaluate for and adequately manage opioid withdrawal in these patients. In addition, hospitalizations serve as important opportunities to engage individuals into the treatment of their addiction. Hospitalists should take advantage of these opportunities to provide linkage-of-care with addiction specialists, provide harm-reduction education, and increase the distribution of naloxone. C1 [Ronan, Matthew V.] Harvard Med Sch, VA Boston Healthcare Syst, Dept Med, 25 Shattuck St, Boston, MA 02115 USA. [Ronan, Matthew V.] VA Med Ctr, Dept Med, 1400 VFW Pkwy, West Roxbury, MA 02132 USA. [Theisen-Toupal, Jesse] VA Med Ctr, Dept Med, 50 Irving St,Northwest,Med Serv 111, Washington, DC 20422 USA. [Theisen-Toupal, Jesse] George Washington Univ, Dept Med, Sch Med & Hlth Sci, Ross Hall 2300 Eye St,Northwest, Washington, DC 20037 USA. [Theisen-Toupal, Jesse] Uniformed Serv Univ Hlth Sci, Dept Med, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. RP Ronan, MV (reprint author), VA Med Ctr, 1400 VFW Pkwy, West Roxbury, MA 02132 USA. EM matthew.ronan@va.gov NR 31 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 2211-5943 J9 HOSP MED CLIN JI Hosp. Med. Clin. PD JAN PY 2017 VL 6 IS 1 BP 79 EP + DI 10.1016/j.ehmc.2016.07.007 PG 17 WC Medicine, General & Internal SC General & Internal Medicine GA EP2BJ UT WOS:000397187700008 ER PT J AU Carter, JA Curry, W AF Carter, Jocelyn A. Curry, William TI Intracerebral Hemorrhage Pathophysiology and Management for Generalists SO HOSPITAL MEDICINE CLINICS LA English DT Article DE Intracerebral hemorrhage; Intraventricular hemorrhage; Cerebral hemorrhage; Hemorrhagic stroke; Management; Pathophysiology ID ASSOCIATION/AMERICAN STROKE ASSOCIATION; HEALTH-CARE PROFESSIONALS; BLOOD-PRESSURE REDUCTION; DECOMPRESSIVE HEMICRANIECTOMY; CEREBRAL-HEMORRHAGE; ICH SCORE; RECURRENT STROKE; ISCHEMIC-STROKE; BRAIN EDEMA; TRIAL AB Intracerebral hemorrhage (ICH) is associated with 30% to 55% mortality at six months and permanent disability in 75% to 80% of survivors. Recent studies have shown that most patients presenting with ICH have small bleeds (<30 mL) with possible survivability with the application of evidence- based care. This finding triggered the revision of the American Heart Association and American Stroke Association guideline to capture clinically informative research published on management, imaging, diagnostics, use of critical care, as well as medical and surgical therapies for ICH. This article is for the generalist and describes ICH pathophysiology, epidemiology, management, imaging, diagnostics, and medical and surgical interventions. C1 [Carter, Jocelyn A.] Massachusetts Gen Hosp, Dept Med, 55 Fruit St,Bulfinch 015, Boston, MA 02114 USA. [Curry, William] Massachusetts Gen Hosp, Dept Neurosurg, 55 Fruit St,Gray 502, Boston, MA 02114 USA. RP Carter, JA (reprint author), Massachusetts Gen Hosp, Dept Med, 55 Fruit St,Bulfinch 015, Boston, MA 02114 USA. EM jcarter0@partners.org NR 68 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 2211-5943 J9 HOSP MED CLIN JI Hosp. Med. Clin. PD JAN PY 2017 VL 6 IS 1 BP 95 EP + DI 10.1016/j.ehmc.2016.08.002 PG 19 WC Medicine, General & Internal SC General & Internal Medicine GA EP2BJ UT WOS:000397187700009 ER PT J AU Gjesteby, L Xi, Y Kalra, MK Yang, QS Wang, G AF Gjesteby, Lars Xi, Yan Kalra, Mannudeep K. Yang, Qingsong Wang, Ge TI Hybrid Imaging System for Simultaneous Spiral MR and X-ray (MRX) Scans SO IEEE ACCESS LA English DT Article DE X-ray radiography; CT; MRI; spiral scanning; joint image reconstruction. ID INTERIOR TOMOGRAPHY; ENERGY-STORAGE; SUPERCAPACITOR; CT AB The needs and the feasibility of simultaneous computed tomography (CT) and magnetic resonance imaging (MRI) were recently reported. In this paper, a spiral magnetic resonance X-ray CT (MRX) imaging system is proposed for head and extremities imaging, which serves as a simple, cost-effective solution on the path to a full-scale CT-MRI fusion. While MRI and X-ray radiography were integrated before, we propose novel designs to acquire simultaneous CT and MR views for synchronized radiographic imaging or joint tomographic reconstruction. Our preliminary permanent magnet configurations achieve a magnetic field strength between 0.1 and 0.2 T while keeping weight low enough for portability. We have also shown that a field strength up to 0.35 T is achievable with permanent magnets that maintain a compact profile, though increased weight would hinder ease of transportation. Simulation results of a joint tomographic reconstruction scheme show the advantage of simultaneously acquired images. The proposed MRX system performs double helical scans in CT and MRI mechanisms, and has multiple niche applications, such as medical imaging on disaster sites, in battle fields, and for under-developed regions. C1 [Gjesteby, Lars; Xi, Yan; Yang, Qingsong; Wang, Ge] Rensselaer Polytech Inst, Dept Biomed Engn, Biomed Imaging Ctr, Troy, NY 12180 USA. [Kalra, Mannudeep K.] Massachusetts Gen Hosp, Dept Imaging, Boston, MA 02114 USA. RP Wang, G (reprint author), Rensselaer Polytech Inst, Dept Biomed Engn, Biomed Imaging Ctr, Troy, NY 12180 USA. EM ge-wang@ieee.org NR 33 TC 0 Z9 0 U1 0 U2 0 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 2169-3536 J9 IEEE ACCESS JI IEEE Access PY 2017 VL 5 BP 1050 EP 1061 DI 10.1109/ACCESS.2016.2637660 PG 12 WC Computer Science, Information Systems; Engineering, Electrical & Electronic; Telecommunications SC Computer Science; Engineering; Telecommunications GA EP1HV UT WOS:000397136900032 ER PT S AU Lanzillotta, M Della-Torre, E Stone, JH AF Lanzillotta, Marco Della-Torre, Emanuel Stone, John H. BE Okazaki, K TI Roles of Plasmablasts and B Cells in IgG4-Related Disease: Implications for Therapy and Early Treatment Outcomes SO IGG4-RELATED DISEASE SE Current Topics in Microbiology and Immunology LA English DT Review; Book Chapter ID CIRCULATING PLASMABLASTS; RITUXIMAB; DIFFERENTIATION; LYMPHOCYTE AB High serum IgG4 concentrations are a striking feature of many patients with IgG4-related disease (IgG4-RD). Blood levels of IgG4 often reach ten, twenty, and even thirty or more times higher than the upper limit of normal. Under the proper clinical circumstances, the finding of an elevated serum IgG4 concentration serves as a useful biomarker for the diagnosis of this condition. This serum IgG4 elevation quickly called attention to the possibility of therapies targeting cells of the B lymphocyte lineage. In addition, a greater understanding of the cellular mechanisms that underpin IgG4-RD has identified peripheral blood plasmablasts as a promising biomarker for this disease. The roles of plasmablasts and B cells in IgG4-RD are discussed in this chapter. C1 [Lanzillotta, Marco; Della-Torre, Emanuel] Univ Vita Salute San Raffaele, IRCCS San Raffaele Sci Inst, Unit Med & Clin Immunol, Milan, Italy. [Stone, John H.] Harvard Med Sch, Massachusetts Gen Hosp, Clin Rheumatol, Boston, MA 02115 USA. RP Stone, JH (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Clin Rheumatol, Boston, MA 02115 USA. EM jhstone@mgh.harvard.edu NR 18 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER INT PUBLISHING AG PI CHAM PA GEWERBESTRASSE 11, CHAM, CH-6330, SWITZERLAND SN 0070-217X BN 978-3-319-52542-6; 978-3-319-52541-9 J9 CURR TOP MICROBIOL JI Curr.Top.Microbiol.Immunol. PY 2017 VL 401 BP 85 EP 92 DI 10.1007/82_2016_58 D2 10.1007/978-3-319-52542-6 PG 8 WC Gastroenterology & Hepatology; Immunology; Pathology SC Gastroenterology & Hepatology; Immunology; Pathology GA BH0ZY UT WOS:000397389400008 PM 28091934 ER PT J AU Rodrigo, GJ Price, D Anzueto, A Singh, D Altman, P Bader, G Patalano, F Fogel, R Kostikas, K AF Rodrigo, Gustavo J. Price, David Anzueto, Antonio Singh, Dave Altman, Pablo Bader, Giovanni Patalano, Francesco Fogel, Robert Kostikas, Konstantinos TI LABA/LAMA combinations versus LAMA monotherapy or LABA/ICS in COPD: a systematic review and meta-analysis SO INTERNATIONAL JOURNAL OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE LA English DT Article DE LABA/LAMA combinations; COPD; LAMA; LABA/ICS; meta-analysis ID OBSTRUCTIVE PULMONARY-DISEASE; FIXED-DOSE COMBINATION; UMECLIDINIUM/VILANTEROL 62.5/25 MCG; RANDOMIZED CONTROLLED-TRIALS; PARALLEL-GROUP; DOUBLE-BLIND; FLUTICASONE PROPIONATE/SALMETEROL; SALMETEROL-FLUTICASONE; NETWORK METAANALYSIS; COMPARATIVE EFFICACY AB Background: Randomized controlled trials (RCTs) indicate that long-acting bronchodilator combinations, such as beta 2-agonist (LABA)/muscarinic antagonist (LAMA), have favorable efficacy compared with commonly used COPD treatments. The objective of this analysis was to compare the efficacy and safety of LABA/LAMA with LAMA or LABA/inhaled corticosteroid (ICS) in adults with stable moderate-to-very-severe COPD. Methods: This systematic review and meta-analysis (PubMed/MEDLINE, Embase, Cochrane Library and clinical trial/manufacturer databases) included RCTs comparing. 12 weeks' LABA/ LAMA treatment with LAMA and/or LABA/ICS (approved doses only). Eligible studies were independently selected by two authors using predefined data fields; the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed. Results: Eighteen studies (23 trials) were eligible (N= 20,185). LABA/LAMA significantly improved trough forced expiratory volume in 1 second (FEV1) from baseline to week 12 versus both LAMA and LABA/ICS (0.07 L and 0.08 L, P. 0.0001), with patients more likely to achieve clinically important improvements in FEV1 of. 100 mL (risk ratio[RR]: 1.33, 95% confidence interval[CI]:[1.20, 1.46] and RR: 1.44, 95% CI:[1.33, 1.56], respectively, the number needed to treat being eight and six, respectively). LABA/LAMA improved transitional dyspnea index and St George's Respiratory Questionnaire scores at week 12 versus LAMA (both P. 0.0001), but not versus LABA/ICS, and reduced rescue medication use versus both (P. 0.0001 and P= 0.001, respectively). LABA/LAMA significantly reduced moderate/severe exacerbation rate compared with LABA/ICS (RR 0.82, 95% CI:[0.75, 0.91]). Adverse event (AE) incidence was no different for LABA/LAMA versus LAMA treatment, but it was lower versus LABA/ICS (RR 0.94, 95% CI: [0.89, 0.99]), including a lower pneumonia risk (RR 0.59, 95% CI:[0.43, 0.81]). LABA/LAMA presented a lower risk for withdrawals due to lack of efficacy versus LAMA (RR: 0.66, 95% CI: [0.51, 0.87]) and due to AEs versus LABA/ICS (RR: 0.83, 95% CI:[0.69, 0.99]). Conclusion: The greater efficacy and comparable safety profiles observed with LABA/LAMA combinations versus LAMA or LABA/ICS support their potential role as first-line treatment options in COPD. These findings are of direct relevance to clinical practice because we included all currently available LABA/LAMAs and comparators, only at doses approved for clinical use. C1 [Rodrigo, Gustavo J.] Hosp Cent Fuerzas Armadas, Dept Emergencia, Ave 8 Octubre 3020, Montevideo 11300, Uruguay. [Price, David] Univ Aberdeen, Acad Primary Care, Div Appl Hlth Sci, Aberdeen, Scotland. [Price, David] Observat & Pragmat Res Inst, Singapore, Singapore. [Anzueto, Antonio] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Anzueto, Antonio] South Texas Vet Hlth Care Syst, San Antonio, TX USA. [Singh, Dave] Univ Manchester, Natl Inst Hlth Res Resp & Allergy Clin Res Facil, Univ Hosp South Manchester NHSNHS Fdn Trust, Med Evaluat Unit, Manchester, Lancs, England. [Altman, Pablo; Fogel, Robert] Novartis Pharmaceut, E Hanover, NJ USA. [Bader, Giovanni; Patalano, Francesco; Kostikas, Konstantinos] Novartis Pharma AG, Basel, Switzerland. RP Rodrigo, GJ (reprint author), Hosp Cent Fuerzas Armadas, Dept Emergencia, Ave 8 Octubre 3020, Montevideo 11300, Uruguay. EM gustavo.javier.rodrigo@gmail.com OI Price, David/0000-0002-9728-9992 FU Novartis; Novartis Pharma AG (Basel, Switzerland) FX The meta-analysis work was performed by Guruprasad Rao KS and Sharanbasappa Durg of Molecular Connections (P) Ltd, Bangalore, India, under the guidance of the manuscript authors and Novartis Pharma AG (Basel, Switzerland). Medical writing assistance was provided by Colette O'Sullivan, PhD, of Scriva Medical Communications Ltd, a professional medical writer funded by Novartis. Development of the manuscript was supported by Novartis Pharma AG (Basel, Switzerland). The authors received no compensation related to the development of the manuscript. NR 51 TC 0 Z9 0 U1 0 U2 0 PU DOVE MEDICAL PRESS LTD PI ALBANY PA PO BOX 300-008, ALBANY, AUCKLAND 0752, NEW ZEALAND SN 1178-2005 J9 INT J CHRONIC OBSTR JI Int. J. Chronic Obstr. Pulm. Dis. PY 2017 VL 12 BP 907 EP 922 DI 10.2147/COPD.S130482 PG 16 WC Respiratory System SC Respiratory System GA EP5MR UT WOS:000397423200018 PM 28360514 ER PT J AU Ebrahimi, A Jung, MH Dreyfuss, JM Pan, H Sgroi, D Bonner-Weir, S Weir, GC AF Ebrahimi, Aref Jung, Min-Ho Dreyfuss, Jonathan M. Pan, Hui Sgroi, Dennis Bonner-Weir, Susan Weir, Gordon C. TI Evidence of stress in beta cells obtained with laser capture microdissection from pancreases of brain dead donors SO ISLETS LA English DT Article DE Beta cell stress; islets; islet transplantation; laser capture microdissection; pancreatic beta cells ID CLINICAL ISLET TRANSPLANTATION; UNFOLDED PROTEIN RESPONSE; INSULIN-SECRETION; ENDOPLASMIC-RETICULUM; TISSUE FACTOR; EXPRESSION; ACTIVATION; INHIBITOR; RELEVANCE; GENES AB Isolated islets used for transplantation are known to be stressed, which can result from the circumstances of death, in particular brain death, the preservation of the pancreas with its warm and cold ischemia, from the trauma of the isolation process, and the complex events that occur during tissue culture. The current study focused upon the events that occur before the islet isolation procedure. Pancreases were obtained from brain dead donors (n = 7) with mean age 50 (11) and normal pancreatic tissue obtained at surgery done for pancreatic neoplasms (n = 7), mean age 69 (9). Frozen sections were subjected to laser capture microdissection (LCM) to obtain beta-cell rich islet tissue, from which extracted RNA was analyzed with microarrays. Gene expression of the 2 groups was evaluated with differential expression analysis for genes and pathways. Marked changes were found in pathways concerned with endoplasmic reticulum stress with its unfolded protein response (UPR), apoptotic pathways and components of inflammation. In addition, there were changes in genes important for islet cell identity. These findings advance our understanding of why islets are stressed before transplantation, which may lead to strategies to reduce this stress and lead to better clinical outcomes. C1 [Ebrahimi, Aref; Jung, Min-Ho; Bonner-Weir, Susan; Weir, Gordon C.] Harvard Med Sch, Joslin Diabet Ctr, Boston, MA USA. [Dreyfuss, Jonathan M.; Pan, Hui] Joslin Diabet Ctr, Div Res, Bioinformat Core, One Joslin Pl, Boston, MA 02215 USA. [Dreyfuss, Jonathan M.; Pan, Hui] Boston Univ, Dept Biomed Engn, Boston, MA 02215 USA. [Sgroi, Dennis] Harvard Med Sch, Dept Mol Pathol, Massachusetts Gen Hosp, Boston, MA USA. RP Weir, GC (reprint author), Joslin Diabet Ctr, Div Res, One Joslin Pl, Boston, MA 02215 USA. EM Gordon.Weir@joslin.harvard.edu FU NIH [R01 DK093909]; NCRR ICR [U4Z 16606, U42 RR0023244-01, P30 DK036836]; Diabetes Research and Wellness Foundation FX This study was supported by grants from the NIH (R01 DK093909 [SBW], NCRR ICR U4Z 16606 (GCW), NCRR ICR U42 RR0023244-01(GCW), P30 DK036836 Joslin Diabetes Research Center (DRC), the Diabetes Research and Wellness Foundation and an important group of private donors. No conflicts of interest relevant to this article are reported. NR 40 TC 0 Z9 0 U1 0 U2 0 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 1938-2014 EI 1938-2022 J9 ISLETS JI Islets PY 2017 VL 9 IS 2 BP 19 EP 29 DI 10.1080/19382014.2017.1283083 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EO3FG UT WOS:000396579700002 PM 28252345 ER PT J AU Waltz, P Zuckerbraun, BS AF Waltz, Paul Zuckerbraun, Brian S. TI Inferior Vena Cava Filters in Trauma Patients-For Whom the Benefit Tolls? SO JAMA SURGERY LA English DT Editorial Material C1 [Zuckerbraun, Brian S.] Univ Pittsburgh, Div Trauma & Gen Surg, 200 Lothrop St,Ste F1200, Pittsburgh, PA 15213 USA. Vet Affairs Pittsburgh Healthcare Syst, Pittsburgh, PA USA. RP Zuckerbraun, BS (reprint author), Univ Pittsburgh, Div Trauma & Gen Surg, 200 Lothrop St,Ste F1200, Pittsburgh, PA 15213 USA.; Zuckerbraun, BS (reprint author), Presbyterian Univ Hosp, Vet Affairs Pittsburgh Healthcare Syst, 200 Lothrop St,Ste F1200, Pittsburgh, PA 15213 USA. EM zuckerbraunbs@upmc.edu NR 2 TC 0 Z9 0 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6254 EI 2168-6262 J9 JAMA SURG JI JAMA Surg. PD JAN PY 2017 VL 152 IS 1 BP 81 EP 81 DI 10.1001/jamasurg.2016.3121 PG 1 WC Surgery SC Surgery GA EL6GM UT WOS:000394718400018 PM 27681537 ER PT J AU Morgan, AE Wozniak, CJ Gulati, S Ge, L Grossi, EA Weinsaft, JW Ratcliffe, MB AF Morgan, Ashley E. Wozniak, Curtis J. Gulati, Sarthak Ge, Liang Grossi, Eugene A. Weinsaft, Jonathan W. Ratcliffe, Mark B. TI Association of Uneven MitraClip Application and Leaflet Stress in a Finite Element Model SO JAMA SURGERY LA English DT Letter ID REPAIR C1 [Morgan, Ashley E.] UCSF East Bay Surg Residency, San Francisco, CA USA. [Wozniak, Curtis J.] Univ Calif San Francisco, Dept Surg, Div Cardiac Surg, San Francisco, CA 94143 USA. [Wozniak, Curtis J.; Ge, Liang; Ratcliffe, Mark B.] San Francisco VA Med Ctr, 4150 Clement St, San Francisco, CA 94121 USA. [Gulati, Sarthak] Univ Calif Los Angeles, Dept Cardiol, Los Angeles, CA USA. [Ge, Liang] Univ Calif San Francisco, Dept Surg & Bioengn, San Francisco, CA USA. [Grossi, Eugene A.] NYU, Sch Med, Dept Cardiothorac Surg, New York, NY USA. [Weinsaft, Jonathan W.] Weill Cornell Coll Med, Dept Med Cardiol, New York, NY USA. [Weinsaft, Jonathan W.] Weill Cornell Coll Med, Dept Radiol, New York, NY USA. [Ratcliffe, Mark B.] Univ Calif San Francisco, Dept Surg & Bioengn, San Francisco, CA USA. RP Ratcliffe, MB (reprint author), San Francisco VA Med Ctr, 4150 Clement St, San Francisco, CA 94121 USA. EM Mark.Ratcliffe@va.gov FU National Institutes of Health [R01 HL128278-01] FX An National Institutes of Health grant (No. R01 HL128278-01) provided salary support for Dr Morgan, who designed the study in conjunction with Dr Ratcliffe and Dr Wozniak; the grant provided further salary support to Dr Weinsaft, who reviewed the manuscript. NR 6 TC 0 Z9 0 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6254 EI 2168-6262 J9 JAMA SURG JI JAMA Surg. PD JAN PY 2017 VL 152 IS 1 BP 111 EP 114 DI 10.1001/jamasurg.2016.3360 PG 5 WC Surgery SC Surgery GA EL6GM UT WOS:000394718400028 PM 27706490 ER PT J AU Ibrahim, SA Blum, M Lee, GC Mooar, P Medvedeva, E Collier, A Richardson, D AF Ibrahim, Said A. Blum, Marissa Lee, Gwo-Chin Mooar, Pekka Medvedeva, Elina Collier, Aliya Richardson, Diane TI Effect of a Decision Aid on Access to Total Knee Replacement for Black Patients With Osteoarthritis of the Knee A Randomized Clinical Trial SO JAMA SURGERY LA English DT Article ID CORONARY-REVASCULARIZATION PROCEDURES; TOTAL HIP-ARTHROPLASTY; 1ST NATIONAL-HEALTH; OF-VETERANS-AFFAIRS; AFRICAN-AMERICAN; JOINT REPLACEMENT; UNITED-STATES; RACIAL-DIFFERENCES; RHEUMATOID-ARTHRITIS; ETHNIC-DIFFERENCES AB IMPORTANCE. Black patients with advanced osteoarthritis (OA) of the knee are significantly less likely than white patients to undergo surgery. No strategies have been proved to improve access to surgery for black patients with end-stage OA of the knee. OBJECTIVE To assess whether a decision aid improves access to total knee replacement (TKR)surgery for black patients with OA of the knee. DESIGN, SETTING, AND PARTICIPANTS. In a randomized clinical trial, 336 eligible participants who self-identified as black and 50 years or older with chronic and frequent knee pain, a Western Ontario McMaster Universities Osteoarthritis Index score of at least 39, and radiographic evidence of OA of the knee were recruited from December 1, 2010, to May 31, 2014, at 3 medical centers. Exclusion criteria were history of major joint replacement, terminal illness, inflammatory arthritis, prosthetic leg, cognitive impairment, lack of a telephone, or contraindications to elective replacement surgery. Data were analyzed on a per-protocol and intention-to-treat (ITT) basis. EXPOSURE. Access to a decision aid for OA of the knee, a 40-minute video that describes the risks and benefits of TKR surgery. MAIN OUTCOMES AND MEASURES. Receipt of TKR surgery within 12 months and/or a recommendation for TKR surgery from an orthopedic surgeon within 6 months after the intervention. RESULTS. Among 336 patients (101 men [30.1%]; 235 women [69.9%]; mean [SD] age, 59.1 [7.2] years) randomized to the intervention or control group, 13 of 168 controls (7.7%) and 25 of 168 intervention patients (14.9%) underwent TKR within 12 months (P =.04). These changes represent a 70% increase in the TKR rate, which increased by 86%(11 of 154 [7.1%] vs 23 of 150 [15.3%]; P =.02) in the per-protocol sample. Twenty-six controls (15.5%) and 34 intervention patients (20.2%) in the ITT analysis received a recommendation for surgery within 6 months (P =.25). The difference in the surgery recommendation rate between the controls (24 of 154 [15.6%]) and the intervention group (31 of 150 [20.7%]) in the per-protocol analysis also was not statistically significant (P =.25). Adjustment for study site yielded similar results: for receipt of TKR at 12 months, adjusted ORs were 2.10 (95% CI, 1.04-4.27) for the ITT analysis and 2.39 (95% CI, 1.12-5.10) for the per-protocol analysis; for recommendation of TKR at 6 months, 1.39 (95% CI, 0.79- 2.44) and 1.41 (95% CI, 0.78-2.55). CONCLUSIONS AND RELEVANCE. A decision aid increased rates of TKR among black patients. However, rates of recommendation for surgery did not differ significantly. A patient-centered counseling and educational intervention may help to address racial variations in the use of TKR for the management of end-stage OA of the knee. C1 [Ibrahim, Said A.; Collier, Aliya] Univ Penn, Dept Med, Div Gen Internal Med, Perelman Sch Med, Philadelphia, PA 19104 USA. [Ibrahim, Said A.; Medvedeva, Elina; Collier, Aliya; Richardson, Diane] Philadelphia Vet Affairs Med Ctr, Ctr Hlth Equity Res & Promot, Philadelphia, PA USA. [Blum, Marissa] Temple Univ, Sch Med, Dept Med, Philadelphia, PA 19122 USA. [Lee, Gwo-Chin] Univ Penn, Dept Orthoped Surg, Perelman Sch Med, Philadelphia, PA 19104 USA. [Mooar, Pekka] Temple Univ, Sch Med, Dept Orthoped Surg & Sports Med, Philadelphia, PA 19122 USA. RP Ibrahim, SA (reprint author), Univ Penn, Perelman Sch Med, 3900 Woodland Ave, Philadelphia, PA 19104 USA. EM said.ibrahim2@va.gov FU National Institute of Arthritis and Musculoskeletal Skin Diseases [1R01AR059615-0]; National Institutes of Health; National Institute of Arthritis and Musculoskeletal and Skin Diseases [K24AR055259] FX This study was supported by grant 1R01AR059615-0 from the National Institute of Arthritis and Musculoskeletal Skin Diseases, National Institutes of Health. Dr Ibrahim reports receiving Mid-Career Development Award K24AR055259 from the National Institute of Arthritis and Musculoskeletal and Skin Diseases. NR 54 TC 0 Z9 0 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6254 EI 2168-6262 J9 JAMA SURG JI JAMA Surg. PD JAN PY 2017 VL 152 IS 1 AR e164225 DI 10.1001/jamasurg.2016.4225 PG 8 WC Surgery SC Surgery GA EL6GM UT WOS:000394718400034 ER PT J AU Rosenberg, AR Bona, K Ketterl, T Wharton, CM Wolfe, J Baker, KS AF Rosenberg, Abby R. Bona, Kira Ketterl, Tyler Wharton, Claire M. Wolfe, Joanne Baker, K. Scott TI Intimacy, Substance Use, and Communication Needs During Cancer Therapy: A Report From the "Resilience in Adolescents and Young Adults" Study SO JOURNAL OF ADOLESCENT HEALTH LA English DT Article DE Risky health behaviors; Substance use; Sexual behaviors; Mixed-methods research; Quality of life ID CHILDHOOD-CANCER; HEALTH BEHAVIORS; ROMANTIC RELATIONSHIPS; SUBSEQUENT NEOPLASMS; SURVIVORS; OUTCOMES; IMPACT; PREVALENCE; PREVENTION; ONCOLOGY AB Purpose: The prevalence of intimacy and substance use among adolescents and young adults during cancer therapy has not been well described. Methods: The "Resilience in Adolescents and Young Adults with Cancer" study was a prospective, multicenter, mixed-methods cohort study. English-speaking patients 14-25 years old with newly diagnosed cancer were invited to complete a comprehensive survey at the time of enrollment (T1) and 3-6 months later (T2). Intimate relationships and health behaviors were assessed with questions adapted from the Guidelines for Adolescent Preventative Services assessment. Descriptive statistics characterized the prevalence of sexual and substance-related behaviors at each time point. Results: Of 42 eligible and enrolled participants, 35 (83%) and 25 (59%) completed T1 and T2 surveys, respectively. Their mean age was 17.6 years (standard deviation 2.3), 57% were male, and the most common diagnoses were sarcoma and acute leukemia. Over a third of participants reported dating at each time point; 26% were sexually active at T1, and 32% at T2. Of those endorsing sexual activity, fewer than half reported consistent birth control or condom use and 4 reported their first sexual intercourse during our observation. In addition, 46% (T1) and 44% (T2) reported alcohol use and 23% (T1) and 26% (T2) reported illicit drug use. Despite these activities, fewer than 10% endorsed a worry or need to discuss these behaviors with oncology providers. Conclusions: Intimacy and substance use among adolescents and young adults are common during cancer therapy. Clinical and research implications include the identification of optimal communication and patient-centered supports. (C) 2016 Society for Adolescent Health and Medicine. All rights reserved. C1 [Rosenberg, Abby R.; Ketterl, Tyler; Wharton, Claire M.; Baker, K. Scott] Seattle Childrens Hosp, Canc & Blood Disorders Ctr, 4800 Sand Point Way NE,M-S MB-8-501, Seattle, WA 98145 USA. [Rosenberg, Abby R.; Ketterl, Tyler; Wharton, Claire M.; Baker, K. Scott] Fred Hutchinson Canc Res Ctr, Div Clin Res, Seattle, WA 98104 USA. [Rosenberg, Abby R.] Seattle Childrens Res Inst, Treuman Katz Ctr Pediat Bioeth, Seattle, WA USA. [Rosenberg, Abby R.; Ketterl, Tyler; Baker, K. Scott] Univ Washington, Sch Med, Dept Pediat, Seattle, WA 98195 USA. [Bona, Kira; Wolfe, Joanne] Boston Childrens Hosp, Dept Med, Boston, MA USA. [Bona, Kira] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Bona, Kira; Wolfe, Joanne] Harvard Med Sch, Dept Pediat Hematol Oncol, Boston, MA USA. [Wolfe, Joanne] Dana Farber Canc Inst, Dept Psychosocial Oncol & Palliat Care, Boston, MA 02115 USA. RP Rosenberg, AR (reprint author), Seattle Childrens Hosp, Canc & Blood Disorders Ctr, 4800 Sand Point Way NE,M-S MB-8-501, Seattle, WA 98145 USA. EM abby.rosenberg@seattlechildrens.org FU St. Baldrick's Fellow Award; Young Investigator Award from CureSearch for Children's Cancer; Clinical Research Scholar Award from Seattle Children's Hospital's Center for Clinical and Translational Research; National Center for Advancing Translational Sciences of the National Institutes of Health [KL2TR000421] FX This research was funded by a St. Baldrick's Fellow Award, a Young Investigator Award from CureSearch for Children's Cancer, a Clinical Research Scholar Award from Seattle Children's Hospital's Center for Clinical and Translational Research, and the National Center for Advancing Translational Sciences of the National Institutes of Health (KL2TR000421). NR 40 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 1054-139X EI 1879-1972 J9 J ADOLESCENT HEALTH JI J. Adolesc. Health PD JAN PY 2017 VL 60 IS 1 BP 93 EP 99 DI 10.1016/j.jadohealth.2016.08.017 PG 7 WC Psychology, Developmental; Public, Environmental & Occupational Health; Pediatrics SC Psychology; Public, Environmental & Occupational Health; Pediatrics GA EO1BX UT WOS:000396433700014 PM 27769762 ER PT J AU Sweerus, K Lachowicz-Scroggins, M Gordon, E LaFemina, M Huang, XZ Parikh, M Kanegai, C Fahy, JV Frank, JA AF Sweerus, Kelly Lachowicz-Scroggins, Marrah Gordon, Erin LaFemina, Michael Huang, Xiaozhu Parikh, Mihir Kanegai, Cindy Fahy, John V. Frank, James A. TI Claudin-18 deficiency is associated with airway epithelial barrier dysfunction and asthma SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE Asthma; epithelium; epithelial barrier function; tight junction; antigen sensitization; airway hyperresponsiveness ID INTRAEPITHELIAL MAST-CELLS; HUMAN TRACHEAL EPITHELIUM; TIGHT JUNCTION; ATOPIC-DERMATITIS; EXPRESSION; MICE; GENE; INTERLEUKIN-13; INFLAMMATION; EXPOSURE AB Background: Epithelial barrier dysfunction and increased permeability may contribute to antigen sensitization and disease progression in asthma. Claudin-18.1 is the only known lung-specific tight junction protein, but its contribution to airway barrier function or asthma is unclear. Objectives: We sought to test the hypotheses that claudin-18 is a determinant of airway epithelial barrier function that is downregulated by IL-13 and that claudin-18 deficiency results in increased aeroantigen sensitization and airway hyperresponsiveness. Methods: Claudin-18.1 mRNA levels were measured in airway epithelial brushings from healthy controls and patients with asthma. In patients with asthma, claudin-18 levels were compared with a three-gene-mean marker of T(H)2 inflammation. Airway epithelial permeability changes due to claudin-18 deficiency were measured in 16HBE cells and claudin-18 null mice. The effect of IL-13 on claudin expression was determined in primary human airway epithelial cells and in mice. Airway hyperresponsiveness and serum IgE levels were compared in claudin-18 null and wild-type mice following aspergillus sensitization. Results: Epithelial brushings from patients with asthma (n = 67) had significantly lower claudin-18 mRNA levels than did those from healthy controls (n = 42). Claudin-18 levels were lowest among T(H)2-high patients with asthma. Loss of claudin-18 was sufficient to impair epithelial barrier function in 16HBE cells and in mouse airways. IL-13 decreased claudin-18 expression in primary human cells and in mice. Claudin-18 null mice had significantly higher serum IgE levels and increased airway responsiveness following intranasal aspergillus sensitization. Conclusions: These data support the hypothesis that claudin-18 is an essential contributor to the airway epithelial barrier to aeroantigens. Furthermore, T(H)2 inflammation suppresses claudin-18 expression, potentially promoting sensitization and airway hyperresponsiveness. C1 [Sweerus, Kelly; Lachowicz-Scroggins, Marrah; Gordon, Erin; LaFemina, Michael; Huang, Xiaozhu; Parikh, Mihir; Kanegai, Cindy; Fahy, John V.; Frank, James A.] Univ Calif San Francisco, Div Pulm Crit Care Sleep & Allergy Med, San Francisco, CA 94143 USA. [Sweerus, Kelly; LaFemina, Michael; Parikh, Mihir; Frank, James A.] San Francisco VA Med Ctr, San Francisco, CA USA. [Sweerus, Kelly; LaFemina, Michael; Parikh, Mihir; Frank, James A.] Northern Calif Inst Res & Educ, San Francisco, CA USA. [Lachowicz-Scroggins, Marrah; Huang, Xiaozhu; Fahy, John V.] Univ Calif San Francisco, Sandler Asthma Basic Res Ctr, San Francisco, CA 94143 USA. RP Frank, JA (reprint author), Univ Calif San Francisco, San Francisco VA Med Ctr, 4150 Clement St,Box 111D, San Francisco, CA 94121 USA. EM James.frank@ucsf.edu OI Lachowicz-Scroggins, Marrah/0000-0002-3173-5662 FU National Institutes of Health/National Heart, Lung, and Blood Institute [R21HL111707] FX This study was funded by the National Institutes of Health/National Heart, Lung, and Blood Institute (grant no. R21HL111707 to J.A.F.). NR 42 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 EI 1097-6825 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD JAN PY 2017 VL 139 IS 1 BP 72 EP + DI 10.1016/j.jaci.2016.02.035 PG 11 WC Allergy; Immunology SC Allergy; Immunology GA EK5WM UT WOS:000393996800009 PM 27215490 ER PT J AU Vickery, BP Berglund, JP Burk, CM Fine, JP Kim, EH Kim, JI Keet, CA Kulis, M Orgel, KG Guo, RS Steele, PH Virkud, YV Ye, P Wright, BL Wood, RA Burks, AW AF Vickery, Brian P. Berglund, Jelena P. Burk, Caitlin M. Fine, Jason P. Kim, Edwin H. Kim, Jung In Keet, Corinne A. Kulis, Michael Orgel, Kelly G. Guo, Rishu Steele, Pamela H. Virkud, Yamini V. Ye, Ping Wright, Benjamin L. Wood, Robert A. Burks, A. Wesley TI Early oral immunotherapy in peanut-allergic preschool children is safe and highly effective SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE Oral immunotherapy; desensitization; sustained unresponsiveness; early intervention; peanut allergy; randomized clinical trial ID NATURAL-HISTORY; FOOD ALLERGY; EGG ALLERGY; RANDOMIZED-TRIAL; DOUBLE-BLIND; IGE LEVELS; HIGH-RISK; INFANTS; DESENSITIZATION; PREDICTORS AB Background: Oral immunotherapy (OIT) is an effective experimental food allergy treatment that is limited by treatment withdrawal and the frequent reversibility of desensitization if interrupted. Newly diagnosed preschool children may have clinical and immunological characteristics more amenable to treatment. Objective: We sought to test the safety, effectiveness, and feasibility of early OIT (E-OIT) in the treatment of peanut allergy. Methods: We enrolled 40 children aged 9 to 36 months with suspected or known peanut allergy. Qualifying subjects reacted to peanut during an entry food challenge and were block randomized 1: 1 to receive E-OIT at goal maintenance doses of 300 or 3000 mg/d in a double-blinded fashion. The primary end point, sustained unresponsiveness at 4 weeks after stopping early intervention oral immunotherapy (4-SU), was assessed by double blinded, placebo-controlled food challenge either upon achieving 4 prespecified criteria, or after 3 maintenance years. Peanut-specific immune responses were serially analyzed. Outcomes were compared with 154 matched standard-care controls. Results: Of 40 consented subjects, 3 (7.5%) did not qualify. Overall, 29 of 37 (78%) in the intent-to-treat analysis achieved 4-SU (300-mg arm, 17 of 20 [85%]; 3000 mg, 12 of 17 [71%], P =.43) over a median of 29 months. Per-protocol, the overall proportion achieving 4-SU was 29 of 32 (91%). Peanut-specific IgE levels significantly declined in E-OIT-treated children, who were 19 times more likely to successfully consume dietary peanut than matched standard-care controls, in whom peanut-specific IgE levels significantly increased (relative risk, 19.42; 95% CI, 8.7-43.7; P < .001). Allergic side effects during E-OIT were common but all were mild to moderate. Conclusions: At both doses tested, E-OIT had an acceptable safety profile and was highly successful in rapidly suppressing allergic immune responses and achieving safe dietary reintroduction. C1 [Berglund, Jelena P.] Duke Univ, Sch Med, Durham, NC USA. [Keet, Corinne A.; Wood, Robert A.] Johns Hopkins Sch Med, Baltimore, MD USA. [Virkud, Yamini V.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Wright, Benjamin L.] Mayo Clin, Scottsdale, AZ USA. RP Burks, AW (reprint author), Univ North Carolina Chapel Hill, 4032 Bondurant Hall,CB 7000, Chapel Hill, NC 27599 USA. EM wesley.burks@unc.edu FU National Center for Advancing Translational Sciences, National Institutes of Health (NIH) [UL1TR001111, UL1TR001117]; National Institutes of Allergy and Infectious Disease [5K23AI099083, 1K23AI103187, 1R21HD: 073557]; Thrasher Research Fund [NR-0101]; Departments of Pediatrics at Duke; Departments of Pediatrics at UNC FX Supported by the National Center for Advancing Translational Sciences, National Institutes of Health (NIH), through Grant Awards (nos. UL1TR001111 and UL1TR001117); the National Institutes of Allergy and Infectious Disease (through grant no. 5K23AI099083 to B.P.V. and grant nos. 1K23AI103187 and 1R21HD: 073557 to C.K.); the Thrasher Research Fund (award no. NR-0101 to B.P.V.); and departmental funds from the Departments of Pediatrics at Duke and UNC. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. NR 44 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 EI 1097-6825 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD JAN PY 2017 VL 139 IS 1 BP 173 EP + DI 10.1016/j.jaci.2016.05.027 PG 17 WC Allergy; Immunology SC Allergy; Immunology GA EK5WM UT WOS:000393996800019 PM 27522159 ER PT J AU Lindemer, ER Greve, DN Fischl, B Augustinack, JC Salat, DH AF Lindemer, Emily R. Greve, Douglas N. Fischl, Bruce Augustinack, Jean C. Salat, David H. CA Alzheimers Dis Neuroimaging TI Differential Regional Distribution of Juxtacortical White Matter Signal Abnormalities in Aging and Alzheimer's Disease SO JOURNAL OF ALZHEIMERS DISEASE LA English DT Article DE Aging; Alzheimer's disease; cerebrovascular; hyperintensities; magnetic resonance imaging; mild cognitive impairment; white matter ID MILD COGNITIVE IMPAIRMENT; SMALL VESSEL DISEASE; CEREBROVASCULAR RISK-FACTORS; HUMAN CEREBRAL-CORTEX; VASCULAR DEMENTIA; LEWY BODIES; BLOOD-FLOW; HYPERINTENSITIES; LESIONS; BRAIN AB Background: White matter signal abnormalities (WMSA) (also known as 'hyperintensities') on MRI are commonly seen in normal aging and increases have been noted in Alzheimer's disease (AD), but whether there is a spatial specificity to these increases is unknown. Objective: To discern whether or not there is a spatial pattern of WMSA in the brains of individuals with AD that differs from those who exhibit cognitively healthy aging. Method: Structural MRI data from the Alzheimer's Disease Neuroimaging Initiative public database were used to quantify WMSA in 35 regions of interest (ROIs). Regional measures were compared between cognitively healthy older controls (OC; n = 107) and individuals with a clinical diagnosis of AD (n = 127). Regional WMSA volume was also assessed in individuals with mild cognitive impairment (MCI; n = 74) who were 6, 12, and 24 months away from AD conversion. Results: WMSA volume was significantly greater in AD compared to OC in 24 out of 35 ROIs after controlling for age, and nine were significantly higher after normalizing for total WMSA. Regions with greater WMSA volume in AD included rostral frontal, inferior temporal, and inferior parietal WM. In MCI, frontal and temporal regions demonstrated significantly greater WMSA volume with decreasing time-to-AD-conversion. Discussion: Individuals with AD have greater regional volume of WMSA compared to OC regardless of age or total WMSA volume. Accumulation of regional WMSAis linked to time to AD conversion in individuals with MCI. These findings indicate WMSA is an important pathological component of AD development. C1 [Lindemer, Emily R.; Fischl, Bruce] Harvard MIT Div Hlth Sci & Technol, Cambridge, MA USA. [Lindemer, Emily R.; Greve, Douglas N.; Fischl, Bruce; Augustinack, Jean C.; Salat, David H.] Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Lindemer, Emily R.; Greve, Douglas N.; Fischl, Bruce; Augustinack, Jean C.; Salat, David H.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Radiol, Boston, MA USA. [Fischl, Bruce] MIT, CSAIL, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Salat, David H.] VA Boston Healthcare Syst, Neuroimaging Res Vet NeRVe Ctr, Boston, MA USA. RP Lindemer, ER (reprint author), Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Bldg 149 13th St,CNY 2301, Charlestown, MA 02129 USA. EM lindemer@mit.edu FU NIH Neuroimaging Training Program Grant from the National Institute of Biomedical Imaging and Bioengineering (NIBIB) [T32 EB001680]; NIH Blueprint for Neuroscience Research [T90DA022759/R90DA023427, 5U01-MH093765]; National Institute for Nursing Research [R01NR010827]; National Institute for Biomedical Imaging and Bioengineering [P41EB015896, R01EB006758, R21EB018907, R01EB019956]; National Institute on Aging [5R01AG008122, R01AG016495]; National Institute of Diabetes and Digestive and Kidney Diseases [1-R21-DK-108277-01]; National Institute for Neurological Disorders and Stroke [R01NS0525851, R21NS072652, R01NS070963, R01NS083534, 5U01NS086625]; Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant) [U01 AG024904]; DOD ADNI (Department of Defense) [W81XWH-12-2-0012]; National Institute on Aging; National Institute of Biomedical Imaging and Bioengineering; AbbVie; Alzheimer's Association; Alzheimer's Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol-Myers SquibbCompany; CereSpir, Inc.; Cogstate; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd; Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Lumosity; Lundbeck; Merck Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; Transition Therapeutics; Canadian Institutes of Health Research; [1S10RR023401]; [1S10RR019307]; [1S10RR023043] FX Support for this work was provided by the NIH Neuroimaging Training Program Grant #T32 EB001680 from the National Institute of Biomedical Imaging and Bioengineering (NIBIB), a training grant from the NIH Blueprint for Neuroscience Research (T90DA022759/R90DA023427), and National Institute for Nursing Research R01NR010827. Additional support was provided in part by the National Institute for Biomedical Imaging and Bioengineering (P41EB015896, R01EB006758, R21EB018907, R01EB019956), the National Institute on Aging (5R01AG008122, R01AG016495), the National Institute of Diabetes and Digestive and Kidney Diseases (1-R21-DK-108277-01), the National Institute for Neurological Disorders and Stroke (R01NS0525851, R21NS072652, R01NS070963, R01NS083534, 5U01NS086625), and was made possible by the resources provided by Shared Instrumentation Grants 1S10RR023401, 1S10RR019307, and 1S10RR023043. Additional support was provided by the NIH Blueprint for Neuroscience Research (5U01-MH093765), part of the multi-institutional Human Connectome Project.; Data collection and sharing for this project was funded by the Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: AbbVie, Alzheimer's Association; Alzheimer's Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol-Myers SquibbCompany; CereSpir, Inc.; Cogstate; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Lumosity; Lundbeck; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (http://www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer's Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California. NR 59 TC 0 Z9 0 U1 0 U2 0 PU IOS PRESS PI AMSTERDAM PA NIEUWE HEMWEG 6B, 1013 BG AMSTERDAM, NETHERLANDS SN 1387-2877 EI 1875-8908 J9 J ALZHEIMERS DIS JI J. Alzheimers Dis. PY 2017 VL 57 IS 1 BP 293 EP 303 DI 10.3233/JAD-161057 PG 11 WC Neurosciences SC Neurosciences & Neurology GA EN8SQ UT WOS:000396270500025 PM 28222518 ER PT J AU Zhu, CW Cosentino, S Ornstein, KA Gu, Y Andrews, H Stern, Y AF Zhu, Carolyn W. Cosentino, Stephanie Ornstein, Katherine A. Gu, Yian Andrews, Howard Stern, Yaakov TI Interactive Effects of Dementia Severity and Comorbidities on Medicare Expenditures SO JOURNAL OF ALZHEIMERS DISEASE LA English DT Article DE Health expenditure; Medicare; economics; comorbidities; longitudinal analysis ID MULTIPLE CHRONIC CONDITIONS; ALZHEIMERS-DISEASE; HEALTH-CARE; RETROSPECTIVE COHORT; ADMINISTRATIVE DATA; COSTS; PREVALENCE; MULTIMORBIDITY; CLAIMS; EPIDEMIOLOGY AB Background: Few studies have examined how dementia and comorbidities may interact to affect healthcare expenditures. Objective: To examine whether effects of dementia severity on Medicare expenditures differed for individuals with different levels of comorbidities. Methods: Data are drawn from the Washington Heights-Inwood Columbia Aging Project (WHICAP). Comprehensive clinical assessments of dementia severity were systematically carried out at similar to 18 month intervals. Dementia severity was measured by Clinical Dementia Rating (CDR). Comorbidities were measured by a modified Elixhauser comorbidities index. Generalized linear models examined effects of dementia severity, comorbidities, and their interactions on Medicare expenditures (1999-2010). Results: At baseline, 1,280 subjects were dementia free (CDR = 0, 66.4%), 490 had very mild dementia (CDR = 0.5, 25.4%), 108 had mild dementia (CDR = 1, 5.6%), and 49 had moderate/severe dementia (CDR = 2/3, 2.5%). Average annual Medicare expenditures for individuals with moderate/severe dementia were more than twice as high as those who were dementia free (CDR = 0: $9,108, CDR= 0.5/1: $11,664, CDR= 2: $19,604, p < 0.01). Expenditures were approximately 10 times higher among those with >= 3 comorbidities than among those with no comorbidities ($2,612 for those with no comorbidities, to $6,109 for those with 1, $10,656 for those with 2, and $30,244 for those with >= 3 comorbidities, p < 0.001). Dementia severity was associated with higher expenditures, but comorbidities were the most important predictor of expenditures. We did not find strong interaction effects between number of comorbidities and dementia severity. Conclusions: Increasing dementia severity and higher comorbidities are associated with higher Medicare expenditures. Care of individuals with dementia should focus on management of comorbidities. C1 [Zhu, Carolyn W.; Ornstein, Katherine A.] Icahn Sch Med Mt Sinai, Dept Geriatr & Palliat Med, New York, NY 10029 USA. [Zhu, Carolyn W.] James J Peters VA Med Ctr, 130 West Kingsbridge Rd, Bronx, NY 10468 USA. [Cosentino, Stephanie; Gu, Yian; Stern, Yaakov] Columbia Univ, Taub Inst Res Alzheimers Dis & Aging Brain, Med Ctr, Cognit Neurosci Div,Dept Neurol, New York, NY USA. [Andrews, Howard] Columbia Univ, Mailman Sch Publ Hlth, Dept Biostat, New York, NY USA. RP Zhu, CW (reprint author), James J Peters VA Med Ctr, 130 West Kingsbridge Rd, Bronx, NY 10468 USA. EM carolyn.zhu@mssm.edu FU National Institute on Aging [AG07370, AG037212]; Department of Veterans Affairs, Veterans Health Administration FX This research was supported by grants from the National Institute on Aging (AG07370, AG037212). Dr. Zhu is also supported by the Department of Veterans Affairs, Veterans Health Administration. The views expressed in this article are those of the authors and do not necessarily represent the views of the Department of Veterans Affairs. NR 50 TC 0 Z9 0 U1 0 U2 0 PU IOS PRESS PI AMSTERDAM PA NIEUWE HEMWEG 6B, 1013 BG AMSTERDAM, NETHERLANDS SN 1387-2877 EI 1875-8908 J9 J ALZHEIMERS DIS JI J. Alzheimers Dis. PY 2017 VL 57 IS 1 BP 305 EP 315 DI 10.3233/JAD-161077 PG 11 WC Neurosciences SC Neurosciences & Neurology GA EN8SQ UT WOS:000396270500026 PM 28222520 ER PT J AU Yarchoan, M James, BD Shah, RC Arvanitakis, Z Wilson, RS Schneider, J Bennett, DA Arnold, SE AF Yarchoan, Mark James, Bryan D. Shah, Raj C. Arvanitakis, Zoe Wilson, Robert S. Schneider, Julie Bennett, David A. Arnold, Steven E. TI Association of Cancer History with Alzheimer's Disease Dementia and Neuropathology SO JOURNAL OF ALZHEIMERS DISEASE LA English DT Article DE Alzheimer's disease; amyloid-beta; cancer; cohort study; dementia; malignancy; neurofibrillary tangles; PHFtau ID PROLYL ISOMERASE PIN1; COGNITIVE FUNCTION; APOLIPOPROTEIN-E; TRANSPORT DEFICITS; BREAST-CANCER; AGING PROJECT; RISK-FACTORS; RUSH MEMORY; CHEMOTHERAPY; IMPAIRMENT AB Background: Cancer and Alzheimer's disease (AD) are common diseases of aging and share many risk factors. Surprisingly, however, epidemiologic data from several recent independent cohort studies suggest that there may be an inverse association between these diseases. Objective: To determine the relationship between history of cancer and odds of dementia proximate to death and neuropathological indices of AD. Methods: Using data from two separate clinical-pathologic cohort studies of aging and AD, the Religious Orders Study (ROS) and the Rush Memory and Aging Project (MAP), we compared odds of AD dementia proximate to death among participants with and without a history of cancer. We then examined the relation of history of cancer with measures of AD pathology at autopsy, i.e., paired helical filament tau (PHFtau) neurofibrillary tangles and amyloid-beta load. Results: Participants reporting a history of cancer had significantly lower odds of AD (OR 0.70 [0.55-0.89], p = 0.0040) proximate to death as compared to participants reporting no prior history of cancer. The results remained significant after adjusting for multiple risk factors including age, sex, race, education, and presence of an APOE epsilon 4 allele. At autopsy, participants with a history of cancer had significantly fewer PHFtau tangles (p < 0.001) than participants without a history of cancer, but similar levels of amyloid-beta. Conclusions: Cancer survivors have reduced odds of developing AD and a lower burden of neurofibrillary tangle deposition. C1 [Yarchoan, Mark] Sidney Kimmel Comprehens Canc Ctr Johns Hopkins, Baltimore, MD USA. [James, Bryan D.; Shah, Raj C.; Arvanitakis, Zoe; Wilson, Robert S.; Schneider, Julie; Bennett, David A.] Rush Univ, Med Ctr, Rush Alzheimers Dis Ctr, Chicago, IL 60612 USA. [Arnold, Steven E.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. RP Arnold, SE (reprint author), Massachusetts Gen Hosp, Harvard Med Sch, Dept Neurol, 114 16th St, Charlestown, MA 02129 USA. EM searnold@mgh.harvard.edu FU National Institute on Aging [P30AG10161, R01AG17917, R01AG15819, R01AG039478] FX This work was supported by grants from the National Institute on Aging (P30AG10161, R01AG17917, R01AG15819, R01AG039478). We are deeply indebted to all the volunteers in the Rush Religious Order Study and the Memory and Aging Project, and the staff engaged in subject assessment, autopsy, and brain banking at Rush University Medical Center. NR 42 TC 0 Z9 0 U1 0 U2 0 PU IOS PRESS PI AMSTERDAM PA NIEUWE HEMWEG 6B, 1013 BG AMSTERDAM, NETHERLANDS SN 1387-2877 EI 1875-8908 J9 J ALZHEIMERS DIS JI J. Alzheimers Dis. PY 2017 VL 56 IS 2 BP 699 EP 706 DI 10.3233/JAD-160977 PG 8 WC Neurosciences SC Neurosciences & Neurology GA EM1KT UT WOS:000395077200023 PM 28035936 ER PT J AU Ismail, Z Agueera-Ortiz, L Brodaty, H Cieslak, A Cummings, J Fischer, CE Gauthier, S Geda, YE Herrmann, N Kanji, J Lanctot, KL Miller, DS Mortby, ME Onyike, CU Rosenberg, PB Smith, EE Smith, GS Sultzer, DL Lyketsos, C AF Ismail, Zahinoor Agueera-Ortiz, Luis Brodaty, Henry Cieslak, Alicja Cummings, Jeffrey Fischer, Corinne E. Gauthier, Serge Geda, Yonas E. Herrmann, Nathan Kanji, Jamila Lanctot, Krista L. Miller, David S. Mortby, Moyra E. Onyike, Chiadi U. Rosenberg, Paul B. Smith, Eric E. Smith, Gwenn S. Sultzer, David L. Lyketsos, Constantine CA NPS-PIA ISTAART TI The Mild Behavioral Impairment Checklist (MBI-C): A Rating Scale for Neuropsychiatric Symptoms in Pre- Dementia Populations SO JOURNAL OF ALZHEIMERS DISEASE LA English DT Article DE Behavioral and psychological symptoms of dementia; dementia; mild behavioral impairment; mild cognitive impairment; neuropsychiatric symptoms; preclinical dementia; prodromal dementia ID ALZHEIMERS-DISEASE; COGNITIVE IMPAIRMENT; CACHE COUNTY; PROSPECTIVE COHORT; INCIDENT DEMENTIA; RISK-FACTORS; INVENTORY; PROGRESSION; PREDICTORS; PSYCHOSIS AB Background: Mild behavioral impairment (MBI) is a construct that describes the emergence at = 50 years of age of sustained and impactful neuropsychiatric symptoms (NPS), as a precursor to cognitive decline and dementia. MBI describes NPS of any severity, which are not captured by traditional psychiatric nosology, persist for at least 6 months, and occur in advance of or in concert with mild cognitive impairment. While the detection and description of MBI has been operationalized in the International Society to Advance Alzheimer's Research and Treatment -Alzheimer's Association (ISTAART-AA) research diagnostic criteria, there is no instrument that accurately reflects MBI as described. Objective: To develop an instrument based on ISTAART-AA MBI criteria. Methods: Eighteen subject matter experts participated in development using a modified Delphi process. An iterative process ensured items reflected the five MBI domains of 1) decreased motivation; 2) emotional dysregulation; 3) impulse dyscontrol; 4) social inappropriateness; and 5) abnormal perception or thought content. Instrument language was developed a priori to pertain to non-demented functionally independent older adults. Results: We present the Mild Behavioral Impairment Checklist (MBI-C), a 34-item instrument, which can easily be completed by a patient, close informant, or clinician. Conclusion: The MBI-C provides the first measure specifically developed to assess the MBI construct as explicitly described in the criteria. Its utility lies in MBI case detection, and monitoring the emergence of MBI symptoms and domains over time. Studies are required to determine the prognostic value of MBI for dementia development, and for predicting different dementia subtypes. C1 [Ismail, Zahinoor] Cumming Sch Med, Dept Psychiat, Calgary, AB, Canada. [Ismail, Zahinoor] Cumming Sch Med, Mathison Ctr Mental Hlth Res & Educ, Calgary, AB, Canada. [Ismail, Zahinoor; Cieslak, Alicja; Kanji, Jamila; Smith, Eric E.] Univ Calgary, Hotchkiss Brain Inst, Dept Clin Neurosci, Calgary, AB, Canada. [Ismail, Zahinoor; Cieslak, Alicja; Kanji, Jamila; Smith, Eric E.] Univ Calgary, Hotchkiss Brain Inst, Ron & Rene Ward Ctr Healthy Brain Aging Res, Calgary, AB, Canada. [Agueera-Ortiz, Luis] Univ 12 Octubre, Ctr Invest Biomed & Red Salud Mental CIBERSAM, Dept Psychiat, Madrid, Spain. [Agueera-Ortiz, Luis] Univ 12 Octubre, Res Inst i 12, Madrid, Spain. [Brodaty, Henry] Univ New South Wales, Ctr Healthy Brain Ageing, Sydney, NSW, Australia. [Brodaty, Henry] Univ New South Wales, Dementia Collaborat Res Ctr, Sydney, NSW, Australia. [Cummings, Jeffrey] Cleveland Clin, Lou Ruvo Ctr Brain Hlth, Las Vegas, NV USA. [Fischer, Corinne E.] Univ Toronto, St Michaels Hosp, Fac Med,Keenan Res Ctr Biomed Res, Li Ka Shing Knowledge Inst,Dept Psychiat, Toronto, ON, Canada. [Gauthier, Serge] McGill Ctr Studies Aging, Douglas Mental Hlth Res Inst, Montreal, PQ, Canada. [Geda, Yonas E.] Mayo Clin, Dept Psychiat & Neurol, Scottsdale, AZ USA. [Herrmann, Nathan] Univ Toronto, Sunnybrook Hlth Sci Ctr, Div Geriatr Psychiat, Toronto, ON, Canada. [Lanctot, Krista L.] Univ Toronto, Fac Med, Neuropsychopharmacol Res Program Sunnybrook Res I, Toronto, ON, Canada. [Lanctot, Krista L.] Univ Toronto, Fac Med, Dept Psychiat & Pharmacol Toxicol, Toronto, ON, Canada. [Miller, David S.] Bracket Global, Wayne, PA USA. [Mortby, Moyra E.] Australian Natl Univ, Ctr Res Ageing Hlth & Wellbeing, Res Sch Populat Hlth, NHMRC Natl Inst Dementia Res, Canberra, ACT, Australia. [Onyike, Chiadi U.; Rosenberg, Paul B.] Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Div Geriatr Psychiat & Neuropsychiat, Baltimore, MD USA. [Smith, Gwenn S.] Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD USA. [Smith, Gwenn S.] Johns Hopkins Univ, Sch Med, Russell H Morgan Dept Radiol & Radiol Sci, Baltimore, MD USA. [Sultzer, David L.] Univ Calif Los Angeles, Geffen Sch Med, Dept Psychiat & Biobehav Sci, Los Angeles, CA USA. [Sultzer, David L.] VA Greater Angeles Healthcare Syst, Brain Behav & Aging Res Ctr, Los Angeles, CA USA. [Lyketsos, Constantine] Johns Hopkins Bayview & Johns Hopkins Med, Memory & Alzheimers Treatment Ctr, Baltimore, MD USA. [Lyketsos, Constantine] Johns Hopkins Bayview & Johns Hopkins Med, Alzheimers Dis Res Ctr, Dept Psychiat & Behav Sci, Baltimore, MD USA. RP Ismail, Z (reprint author), TRW Bldg 1st Floor,3280 Hosp Dr NW, Calgary, AB T2N 4Z6, Canada. EM zahinoor@gmail.com FU Hotchkiss Brain Institute via the Alzheimer Society of Calgary; Katthy Taylor Chair in Vascular Dementia; CIHR; Department of Veterans Affairs; National Institute of Health [AG038893, AG041633]; National Institute of General Medical Sciences [P20GM109025]; Keep Memory Alive; Australian National Health and Medical Research Council (NHMRC); Australian Research Council (ARC) Dementia Research Development Fellowship [1102028]; Weston Brain Institute; NIH [P50AG005146] FX ZI is supported by the Hotchkiss Brain Institute via the Alzheimer Society of Calgary. EES is supported by the Katthy Taylor Chair in Vascular Dementia and CIHR. DS is supported in part by the Department of Veterans Affairs. GS is supported by National Institute of Health: AG038893 and AG041633. JC acknowledges funding from the National Institute of General Medical Sciences (Grant: P20GM109025) and support from Keep Memory Alive. MEM is supported by the Australian National Health and Medical Research Council (NHMRC) and Australian Research Council (ARC) Dementia Research Development Fellowship #1102028. SG is supported by CIHR and the Weston Brain Institute. KGL is supported in part by NIH grant P50AG005146 for the Johns Hopkins ADRC. NR 45 TC 0 Z9 0 U1 0 U2 0 PU IOS PRESS PI AMSTERDAM PA NIEUWE HEMWEG 6B, 1013 BG AMSTERDAM, NETHERLANDS SN 1387-2877 EI 1875-8908 J9 J ALZHEIMERS DIS JI J. Alzheimers Dis. PY 2017 VL 56 IS 3 BP 929 EP 938 DI 10.3233/JAD-160979 PG 10 WC Neurosciences SC Neurosciences & Neurology GA EM1LK UT WOS:000395078900008 PM 28059789 ER PT J AU Joyce, KE Biggs, ML Djousse, L Ix, JH Kizer, JR Siscovick, DS Shores, MM Matsumoto, AM Mukamal, KJ AF Joyce, Katherine E. Biggs, Mary L. Djousse, Luc Ix, Joachim H. Kizer, Jorge R. Siscovick, David S. Shores, Molly M. Matsumoto, Alvin M. Mukamal, Kenneth J. TI Testosterone, Dihydrotestosterone, Sex Hormone-Binding Globulin, and Incident Diabetes Among Older Men: The Cardiovascular Health Study SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID MIDDLE-AGED MEN; INSULIN SENSITIVITY; BODY-COMPOSITION; SKELETAL-MUSCLE; ELDERLY-MEN; RISK; ANDROGENS; WOMEN; STRENGTH; GLUCOSE AB Context: Although sex hormone-binding globulin (SHBG) and testosterone (T) have been inversely associated with risk of diabetes, few studies have examined dihydrotestosterone (DHT), a more potent androgen than T, in older adults, whose glycemic pathophysiology differs from younger adults. Objective: To determine the associations of SHBG, T, and DHT with insulin resistance and incident diabetes in older adult men. Design: In a prospective cohort study, we evaluated baseline levels of SHBG, T, and DHT using liquid chromatography-tandem mass spectrometry among 852 men free of diabetes and cardiovascular disease in the Cardiovascular Health Study in 1994. Main Outcome: Insulin resistance estimated by Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) and insulin sensitivity estimated by the Gutt index in 1996, and incident diabetes (n = 112) ascertained over a mean follow-up of 9.8 years. Results: In linear regression models adjusted for demographics, alcohol consumption, current smoking, body mass index, and other androgens, SHBG [HOMA-IR 0.30 units lower per doubling; 95% confidence interval (CI), 0.08 to 0.52; P = 0.01] and total DHT (HOMA-IR 0.18 units lower per doubling; 95% CI, 0.06 to 0.30; P = 0.01), but not free T (P = 0.33), were inversely associated with insulin resistance. In corresponding Cox proportional hazards models, total DHT was again inversely associated with risk of diabetes (adjusted hazard ratio per doubling, 0.69; 95% CI, 0.52 to 0.92; P = 0.01), but SHBG (hazard ratio, 1.09; 95% CI, 0.74 to 1.59; P = 0.66) and free T (hazard ratio, 1.15; 95% CI, 0.92 to 1.43; P = 0.23) were not. Conclusions: Among older men, higher levels of DHT were inversely associated with insulin resistance and risk of diabetes over the ensuing 10 years, whereas levels of T were not. Future studies are still needed to clarify the role of SHBG in risk of diabetes in this population. C1 [Joyce, Katherine E.; Mukamal, Kenneth J.] Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02215 USA. [Biggs, Mary L.] Univ Washington, Dept Biostat, Seattle, WA 98115 USA. [Shores, Molly M.] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98115 USA. [Matsumoto, Alvin M.] Univ Washington, Dept Med, Seattle, WA 98115 USA. [Djousse, Luc] Brigham & Womens Hosp, Div Aging, 75 Francis St, Boston, MA 02115 USA. [Djousse, Luc] Harvard Med Sch, Boston, MA 02115 USA. [Ix, Joachim H.] Univ Calif San Diego, Div Nephrol Hypertens, San Diego, CA 92093 USA. [Ix, Joachim H.] Vet Affairs San Diego Healthcare Syst, San Diego, CA 92093 USA. [Kizer, Jorge R.] Albert Einstein Coll Med, Dept Med, Bronx, NY 10461 USA. [Kizer, Jorge R.] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10461 USA. [Siscovick, David S.] New York Acad Med, New York, NY 10029 USA. [Matsumoto, Alvin M.] Educ & Clin Ctr, Geriatr Res, Seattle, WA 98108 USA. [Shores, Molly M.; Matsumoto, Alvin M.] VA Puget Sound Hlth Care Syst, Seattle, WA 98108 USA. RP Mukamal, KJ (reprint author), Beth Israel Deaconess Med Ctr, 1309 Beacon St,2nd Floor, Brookline, MA 02446 USA. EM kmukamal@bidmc.harvard.edu RI Djousse, Luc/F-5033-2017 OI Djousse, Luc/0000-0002-9902-3047 FU National Heart, Lung, and Blood Institute [HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, U01HL080295, R01HL094555, R01HL091952]; National Institute on Aging [R01AG023629]; Veterans Affairs Research Service; Veterans Affairs Epidemiology Research and Information Center; Veterans Affairs Geriatric Research, Education and Clinical Center FX This research was supported by contracts HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, and grants U01HL080295, R01HL094555, and R01HL091952 from the National Heart, Lung, and Blood Institute, with additional contribution from the National Institute of Neurologic Disorders and Stroke. Additional support was provided by R01AG023629 from the National Institute on Aging, the Veterans Affairs Research Service, the Veterans Affairs Epidemiology Research and Information Center, and the Veterans Affairs Geriatric Research, Education and Clinical Center. A full list of principal CHS investigators and institutions can be found at www.chs-nhlbi.org. NR 29 TC 0 Z9 0 U1 0 U2 0 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD JAN PY 2017 VL 102 IS 1 BP 33 EP 39 DI 10.1210/jc.2016-2623 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EP0IV UT WOS:000397071900006 PM 27732332 ER PT J AU Bachmann, KN Schorr, M Bruno, AG Bredella, MA Lawson, EA Gill, CM Singhal, V Meenaghan, E Gerweck, AV Slattery, M Eddy, KT Ebrahimi, S Koman, SL Greenblatt, JM Keane, RJ Weigel, T Misra, M Bouxsein, ML Klibanski, A Miller, KK AF Bachmann, Katherine N. Schorr, Melanie Bruno, Alexander G. Bredella, Miriam A. Lawson, Elizabeth A. Gill, Corey M. Singhal, Vibha Meenaghan, Erinne Gerweck, Anu V. Slattery, Meghan Eddy, Kamryn T. Ebrahimi, Seda Koman, Stuart L. Greenblatt, James M. Keane, Robert J. Weigel, Thomas Misra, Madhusmita Bouxsein, Mary L. Klibanski, Anne Miller, Karen K. TI Vertebral Volumetric Bone Density and Strength Are Impaired in Women With Low-Weight and Atypical Anorexia Nervosa SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID QUANTITATIVE COMPUTED-TOMOGRAPHY; MINERAL DENSITY; FRACTURE RISK; CORTICAL BONE; MEN; TESTOSTERONE; FAT; INCREASES; ANDROGENS; ESTROGEN AB Context: Areal bone mineral density (BMD) is lower, particularly at the spine, in low-weight women with anorexia nervosa (AN). However, little is known about vertebral integral volumetric BMD (Int. vBMD) or vertebral strength across the AN weight spectrum, including "atypical" AN [body mass index (BMI) >= 18.5 kg/m(2)]. Objective: To investigate Int. vBMD and vertebral strength, and their determinants, across the AN weight spectrum Design: Cross-sectional observational study Setting: Clinical research center Participants: 153 women (age 18 to 45): 64 with low-weight AN (BMI,18.5 kg/m(2); 58% amenorrheic), 44 with atypical AN (18.5 <= BMI<23 kg/m(2); 30% amenorrheic), 45 eumenorrheic controls (19.2 <= BMI, 25 kg/m(2)). Measures: Int. vBMD and cross-sectional area (CSA) by quantitative computed tomography of L4; estimated vertebral strength (derived from Int. vBMD and CSA) Results: Int. vBMD and estimated vertebral strength were lowest in low-weight AN, intermediate in atypical AN, and highest in controls. CSA did not differ between groups; thus, vertebral strength (calculated using Int. vBMD and CSA) was driven by Int. vBMD. In AN, Int. vBMD and vertebral strengthwere associated positively with current BMI and nadir lifetime BMI (independent of current BMI). Int. vBMD and vertebral strength were lower in AN with current amenorrhea and longer lifetime amenorrhea duration. Among amenorrheic AN, Int. vBMD and vertebral strength were associated positively with testosterone. Conclusions: Int. vBMD and estimated vertebral strength (driven by Int. vBMD) are impaired across the AN weight spectrum and are associated with low BMI and endocrine dysfunction, both current and previous. Women with atypical AN experience diminished vertebral strength, partially due to prior low-weight and/or amenorrhea. Lack of current low-weight or amenorrhea in atypicalANdoes not preclude compromise of vertebral strength. C1 [Bachmann, Katherine N.; Schorr, Melanie; Lawson, Elizabeth A.; Singhal, Vibha; Meenaghan, Erinne; Gerweck, Anu V.; Slattery, Meghan; Klibanski, Anne; Miller, Karen K.] Massachusetts Gen Hosp, Neuroendocrine Unit, Bulfinch 457b,55 Fruit St, Boston, MA 02114 USA. [Bredella, Miriam A.; Gill, Corey M.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Eddy, Kamryn T.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Singhal, Vibha; Misra, Madhusmita] Massachusetts Gen Hosp, Pediat Endocrine Unit, Boston, MA 02114 USA. [Singhal, Vibha; Misra, Madhusmita] Harvard Med Sch, Boston, MA 02114 USA. [Bruno, Alexander G.; Bouxsein, Mary L.] MIT, Harvard Massachusetts Inst Technol Hlth Sci & Tec, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Ebrahimi, Seda] Cambridge Eating Disorders Ctr, Cambridge, MA 02138 USA. [Koman, Stuart L.; Greenblatt, James M.; Keane, Robert J.] Walden Behav Care, Waltham, MA 02453 USA. [Weigel, Thomas] McLean Hosp, Klarman Ctr, Belmont, MA 02478 USA. [Weigel, Thomas] Harvard Med Sch, Belmont, MA 02478 USA. [Bruno, Alexander G.; Bouxsein, Mary L.] Beth Israel Deaconess Med Ctr, Ctr Adv Orthoped Studies, Boston, MA 02215 USA. [Bruno, Alexander G.; Bouxsein, Mary L.] Harvard Med Sch, Boston, MA 02215 USA. RP Miller, KK (reprint author), Massachusetts Gen Hosp, Neuroendocrine Unit, Bulfinch 457b,55 Fruit St, Boston, MA 02114 USA. EM kkmiller@mgh.harvard.edu FU National Institutes of Health [T32 DK 007028, K24 HL092902, RO1 HL 077674, R01 MH083657, R01 DK052625, RO3-DK59297, M01-RR01066-27S1, M01-RR01066, UL1 RR025758, 8UL1 TR000170, 1UL1TR001102, K23 RR-23090, R01 AR053986, F31AG041629, K24 HD071843] FX This work was supported by the following National Institutes of Health grants: T32 DK 007028, K24 HL092902, RO1 HL 077674, R01 MH083657, R01 DK052625, RO3-DK59297, M01-RR01066-27S1, M01-RR01066, UL1 RR025758, 8UL1 TR000170, 1UL1TR001102, K23 RR-23090, R01 AR053986, F31AG041629, and K24 HD071843. NR 31 TC 0 Z9 0 U1 0 U2 0 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD JAN PY 2017 VL 102 IS 1 BP 57 EP 68 DI 10.1210/jc.2016-2099 PG 12 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EP0IV UT WOS:000397071900009 PM 27732336 ER PT J AU Buchanan, DT Landis, CA Hohensee, C Guthrie, KA Otte, JL Paudel, M Anderson, GL Caan, B Freeman, EW Joffe, H LaCroix, AZ Newton, KM Reed, SD Ensrud, KE AF Buchanan, Diana Taibi Landis, Carol A. Hohensee, Chancellor Guthrie, Katherine A. Otte, Julie L. Paudel, Misti Anderson, Garnet L. Caan, Bette Freeman, Ellen W. Joffe, Hadine LaCroix, Andrea Z. Newton, Katherine M. Reed, Susan D. Ensrud, Kristine E. TI Effects of Yoga and Aerobic Exercise on Actigraphic Sleep Parameters in Menopausal Women with Hot Flashes SO JOURNAL OF CLINICAL SLEEP MEDICINE LA English DT Article DE actigraphy; exercise; insomnia symptoms; menopause; variability; vasomotor symptoms; yoga ID MODERATE-INTENSITY EXERCISE; RANDOMIZED CONTROLLED-TRIAL; POSTMENOPAUSAL WOMEN; QUALITY INDEX; SYMPTOMS; TRANSITION; SEVERITY; INSOMNIA; INTERVENTION; VARIABILITY AB Study Objectives: To determine effects of yoga and aerobic exercise compared with usual activity on objective assessments of sleep in midlife women. Methods: Secondary analyses of a randomized controlled trial in the Menopause Strategies: Finding Lasting Answers for Symptoms and Health (MsFLASH) network conducted among 186 late transition and postmenopausal women aged 40-62 y with hot flashes. Women were randomized to 12 w of yoga, supervised aerobic exercise, or usual activity. The mean and coefficient of variation (CV) of change in actigraph sleep measures from each intervention group were compared to the usual activity group using linear regression models. Results: Baseline values of the primary sleep measures for the entire sample were mean total sleep time (TST) = 407.5 +/- 56.7 min; mean wake after sleep onset (WASO) = 54.6 +/- 21.8 min; mean CV for WASO = 37.7 +/- 18.7 and mean CV for number of long awakenings > 5 min = 81.5 +/- 46.9. Changes in the actigraphic sleep outcomes from baseline to weeks 11-12 were small, and none differed between groups. In an exploratory analysis, women with baseline Pittsburgh Sleep Quality Index higher than 8 had significantly reduced TST-CV following yoga compared with usual activity. Conclusions: This study adds to the currently scant literature on objective sleep outcomes from yoga and aerobic exercise interventions for this population. Although small effects on self-reported sleep quality were previously reported, the interventions had no statistically significant effects on actigraph measures, except for potentially improved sleep stability with yoga in women with poor self-reported sleep quality. C1 [Buchanan, Diana Taibi; Landis, Carol A.] Univ Washington, Sch Nursing, Biobehav Nursing & Hlth Syst, Seattle, WA 98195 USA. [Hohensee, Chancellor; Guthrie, Katherine A.; Anderson, Garnet L.] Fred Hutchinson Canc Res Ctr, MsFLASH Data Coordinating Ctr, 1124 Columbia St, Seattle, WA 98104 USA. [Otte, Julie L.] Indiana Univ, Sch Nursing, Sci Nursing Care, Indianapolis, IN 46204 USA. [Paudel, Misti] Univ Chicago, Hlth Care Dept, Natl Opin Res Ctr, Bethesda, MD USA. [Caan, Bette] Kaiser Permanente Med Program Northern Calif, Div Res, Oakland, CA USA. [Freeman, Ellen W.] Univ Penn, Dept Obstet Gynecol, Philadelphia, PA USA. [Freeman, Ellen W.] Univ Penn, Dept Psychiat, Philadelphia, PA USA. [Joffe, Hadine] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. [Joffe, Hadine] Dana Farber Canc Inst, Boston, MA 02115 USA. [LaCroix, Andrea Z.] Univ Calif San Diego, Sch Med, Div Epidemiol, San Diego, CA 92103 USA. [Newton, Katherine M.] Grp Hlth Res Inst, Seattle, WA USA. [Reed, Susan D.] Univ Washington, Dept Obstet Gynecol, Sch Med, Seattle, WA USA. [Reed, Susan D.] Univ Washington, Sch Med, Dept Epidemiol, Seattle, WA USA. [Ensrud, Kristine E.] Univ Minnesota, Dept Med, Div Epidemiol & Community Hlth, Box 736 UMHC, Minneapolis, MN 55455 USA. [Ensrud, Kristine E.] VA Hlth Care Syst, Dept Med, Minneapolis, MN USA. RP Buchanan, DT (reprint author), Univ Washington, Biobehav Nursing & Hlth Syst, Box 357266, Seattle, WA 98195 USA. EM dmtaibi@uw.edu FU National Institutes of Health; National Institute on Aging [U01AG032656, U01AG032659, U01AG032669, U01AG032682, U01AG032699, U01AG032700]; Indiana Clinical and Translational Sciences Institute; National Institutes of Health, National Center for Research Resources [UL1RR02571]; Clinical and Translational Sciences Award; National Institutes of Health (NIH); Forest Laboratories Inc.; Merck; Cephalon/Teva; Bayer Pharmaceutical [WO2014089019A1]; NIH FX This was not an industry supported study. This study was funded by the National Institutes of Health as a cooperative agreement issued by the National Institute on Aging, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Center for Complementary and Alternative Medicine, Office of Research on Women's Health, and grants U01AG032656, U01AG032659, U01AG032669, U01AG032682, U01AG032699, and U01AG032700 from the National Institute on Aging. At Indiana University, the project was partly funded by the Indiana Clinical and Translational Sciences Institute, grant UL1RR02571 from the National Institutes of Health, National Center for Research Resources, and Clinical and Translational Sciences Award. Diana Taibi Buchanan, Carol A. Landis, Katherine A. Guthrie, Julie L. Otte, Garnet L. Anderson, and Andrea Z. LaCroix received funding from the National Institutes of Health (NIH) during the conduction of the study. Ellen W. Freeman has received research support from Forest Laboratories Inc. Hadine Joffe has received grant support from Merck and Cephalon/Teva and is a consultant for Noven, Merck, and Mitsubishi Tanabe, and has done consulting for Sunovion. Andrea Z. LaCroix has consulted for Pfizer and Sermonix. Susan D. Reed has received research support from Bayer Pharmaceutical, holds a patent relating to methods and compositions for treating vasomotor symptoms (WO2014089019A1), and has received royalties from UpToDate and Scientific American Medicine. Katherine M. Newton received research support from NIH during the conduction of the study; she serves on the board of the North American Menopause Society. Kristine E. Ensrud received grants from NIH during the conduction of the study and is a consultant to a Data Monitoring Committee for Merck, Sharp, and Dohme. The other authors have indicated no financial conflicts of interest. NR 33 TC 0 Z9 0 U1 1 U2 1 PU AMER ACAD SLEEP MEDICINE PI DARIEN PA 2510 N FRONTAGE RD, DARIEN, IL 60561 USA SN 1550-9389 EI 1550-9397 J9 J CLIN SLEEP MED JI J. Clin. Sleep Med. PY 2017 VL 13 IS 1 BP 11 EP 18 AR PII jc-00520-15 DI 10.5664/jcsm.6376 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA EL2RV UT WOS:000394468000004 PM 27707450 ER PT J AU Khanna, S Button, JE Lombardo, MJ Vulic, M Henn, MR Cook, DN Pomerantz, RJ Hohmann, EL AF Khanna, Sahil Button, Julie E. Lombardo, Mary-Jane Vulic, Marin Henn, Matthew R. Cook, David N. Pomerantz, Roger J. Hohmann, Elizabeth L. TI Critical Microbiological View of SER-109 Reply SO JOURNAL OF INFECTIOUS DISEASES LA English DT Letter ID SP NOV.; FUSOBACTERIUM-PRAUSNITZII; CLOSTRIDIUM-HATHEWAYI; HUMAN FECES; COMB. NOV; GEN. NOV.; BACTERIUM; PROPOSAL; PHYLOGENY C1 [Khanna, Sahil] Mayo Clin, Rochester, MN USA. [Button, Julie E.; Lombardo, Mary-Jane; Vulic, Marin; Henn, Matthew R.; Cook, David N.; Pomerantz, Roger J.] Seres Therapeut, 200 Sidney St, Cambridge, MA 02139 USA. [Hohmann, Elizabeth L.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Lombardo, MJ (reprint author), Seres Therapeut, 200 Sidney St, Cambridge, MA 02139 USA. NR 15 TC 0 Z9 0 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 JAN 1 PY 2017 VL 215 IS 1 BP 162 EP 164 DI 10.1093/infdis/jiw490 PG 3 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA EP2HH UT WOS:000397203500026 PM 28077592 ER PT J AU Palladino, B Montgomery, AE Sommers, M Fargo, JD AF Palladino, B. Montgomery, A. E. Sommers, M. Fargo, J. D. TI Risk of Suicide Among Veterans with Traumatic Brain Injury Experiencing Homelessness SO JOURNAL OF MILITARY AND VETERANS HEALTH LA English DT Article C1 [Palladino, B.; Sommers, M.] Univ Penn, Sch Nursing, Ctr Hlth Equ Res, Philadelphia, PA 19104 USA. [Montgomery, A. E.] US Dept Vet Affairs, Natl Ctr Homelessness Vet, Philadelphia, PA 19144 USA. [Fargo, J. D.] Utah State Univ, Dept Psychol, Logan, UT 84322 USA. RP Montgomery, AE (reprint author), US Dept Vet Affairs, Natl Ctr Homelessness Vet, Philadelphia, PA 19144 USA. EM ann.montgomery2@va.gov FU U.S. Department of Veterans Affairs, National Center on Homelessness Among Veterans FX This study was funded by the U.S. Department of Veterans Affairs, National Center on Homelessness Among Veterans. NR 10 TC 0 Z9 0 U1 0 U2 0 PU AUSTRALASIAN MILITARY MEDICINE ASSOC PI HOBART PA AMMA SECRETARIAT, 113 HARRINGTON ST, HOBART, TAS 7000, AUSTRALIA SN 1835-1271 EI 1839-2733 J9 J MIL VETERANS HEALT JI J. Mil. Veterans Health PD JAN PY 2017 VL 25 IS 1 BP 34 EP 38 PG 5 WC Medicine, General & Internal SC General & Internal Medicine GA EO0YV UT WOS:000396425500007 ER PT J AU Brennan, E Woods, DW Franklin, ME Keuthen, N Piacentini, J Flessner, CA AF Brennan, Elle Woods, Douglas W. Franklin, Martin E. Keuthen, Nancy Piacentini, John Flessner, Christopher A. TI The role body-esteem plays in impairment associated with hair-pulling and skin picking in adolescents SO JOURNAL OF OBSESSIVE-COMPULSIVE AND RELATED DISORDERS LA English DT Article DE Hair-pulling disorder; Skin picking; Body-esteem; Psychosocial impairment; Adolescence ID CHILDRENS DEPRESSION INVENTORY; FUNCTIONAL IMPAIRMENT; SELF-ESTEEM; EXPLORING DIFFERENCES; SYMPTOM SEVERITY; ANXIETY SCALE; TRICHOTILLOMANIA; IMPACT; BEHAVIORS; SAMPLE AB Trichotillomania (hair pulling disorder, HPD) and pathological skin picking (PSP) are associated with significant rates of psychosocial impairment and distress. Little research has addressed the physical consequences and associated impairment in youth (e.g., poor body-esteem). The present study explores the relationship between body-esteem, skin picking (SP), and pulling-related impairment in a sample of adolescents with primary HPD. Ninety four adolescents who pull their hair, 40 of whom also pick their skin, were recruited via internet-sampling as part of the Child and Adolescent Trichotillomania Impact Study (CA-TIP). All youth and a parent completed anonymous questionnaires online assessing psychiatric symptoms, repetitive behaviors, and psychosocial impairment, among other variables. Appearance-based body-esteem was not found to be predictive of more severe psychosocial impairment in these youth. However, SP, in combination with HPD, contributed to worse appearance-based body-esteem above and beyond symptoms of HPD alone. The current study suggests that psychosocial functioning in youth with HPD is less impacted by body-esteem or pulling than other factors (e.g., depression and anxiety), and that SP contributes to lowered body-esteem. These findings suggest the importance of addressing body-esteem in case conceptualization for youth with both HPD and SP. Further research is required to confirm these suggestions. C1 [Brennan, Elle; Flessner, Christopher A.] Kent State Univ, Dept Psychol Sci, Kent, OH 44242 USA. [Woods, Douglas W.] Marquette Univ, Dept Psychol, Milwaukee, WI 53233 USA. [Franklin, Martin E.] Univ Penn, Dept Psychiat, Philadelphia, PA 19104 USA. [Keuthen, Nancy] Massachusetts Gen Hosp, Trichotillomania Clin & Res Unit, Boston, MA 02114 USA. [Piacentini, John] Univ Calif Los Angeles, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90024 USA. RP Brennan, E (reprint author), Kent State Univ, Dept Psychol Sci, Kent, OH 44242 USA. EM ebrenna2@kent.edu NR 47 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 2211-3649 J9 J OBSESS-COMPULS REL JI J. Obsessive-Compuls. Relat. Disord. PD JAN PY 2017 VL 12 BP 46 EP 51 DI 10.1016/j.jocrd.2016.12.003 PG 6 WC Psychiatry SC Psychiatry GA EM5MZ UT WOS:000395357000008 ER PT J AU Worden, BL Bowe, WM Tolin, DF AF Worden, Blaise L. Bowe, William M. Tolin, David F. TI An open trial of cognitive behavioral therapy with contingency management for hoarding disorder SO JOURNAL OF OBSESSIVE-COMPULSIVE AND RELATED DISORDERS LA English DT Article DE Contingency management; Hoarding disorder; Clutter; Saving Inventory-Revised; Cognitive-behavioral treatment; Group treatment ID OBSESSIVE-COMPULSIVE DISORDER; COCAINE-DEPENDENT OUTPATIENTS; MARIJUANA DEPENDENCE; COST-EFFECTIVENESS; INTRINSIC MOTIVATION; COPING SKILLS; PREDICTORS; INTERVIEW; DISSEMINATION; INCENTIVES AB Cognitive behavioral therapy (CBT) for hoarding disorder (HD) has resulted in statistically significant improvements in hoarding symptoms, but gains have been modest and most participants continue to have clinically significant symptoms at post treatment. Contingency management, an empirically-supported intervention for substance use, may be effective in overcoming barriers to effective treatment of HD, such as fluctuating motivation and insight. The objective of the current open trial was to examine the potential effectiveness of contingency management for HD in the context of a cognitive-behavioral group therapy. Twenty-two patients completing 16-week CBT groups for HD were administered monthly contingency payments based on independent evaluator-rated reductions in overall in-home clutter. Mixed effects models suggested significant reductions in hoarding symptoms as measured by the Saving Inventory-Revised (SI-R; Frost, Steketee, & Grisham, 2004) and the Clutter Image Rating Scale (CIR; Frost, Steketee, Tolin, & Renaud, 2008), with SI-R reductions resulting in a large effect size (Cohen's d =2.59) that surpassed those obtained previously in trials of CBT for HD. Mean total earning per patient was $139, and ranged from $0 to $270. These preliminary results suggest that contingency management shows promise as a cost-efficient adjunctive intervention to boost gains in CBT for HD. C1 [Worden, Blaise L.; Bowe, William M.; Tolin, David F.] Hartford Hosp, Inst Living, Hartford, CT 06115 USA. [Tolin, David F.] Yale Univ, Sch Med, Dept Psychiat, New Haven, CT 06520 USA. [Bowe, William M.] VA Boston Healthcare Syst, 150 South Huntington Ave, Boston, MA 02130 USA. RP Worden, BL (reprint author), Ctr CBT, Anxiety Disorders Ctr, Inst Living, 200 Retreat Ave, Hartford, CT 06106 USA. EM blaise.worden@hhchealth.org FU Hartford Hospital [WORD004040HI] FX This study was funded by a grant from Hartford Hospital (WORD004040HI) to Dr. Worden. The authors thank Nancy Petry, Ph.D., for her consultation on this project, and Ralitza Gueorgiva, Ph. D., for assistance with statistical analysis. NR 74 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 2211-3649 J9 J OBSESS-COMPULS REL JI J. Obsessive-Compuls. Relat. Disord. PD JAN PY 2017 VL 12 BP 78 EP 86 DI 10.1016/j.jocrd.2016.12.005 PG 9 WC Psychiatry SC Psychiatry GA EM5MZ UT WOS:000395357000013 ER PT J AU Clement, JM Sweeney, CJ AF Clement, Jessica M. Sweeney, Christopher J. TI Evolving Treatment of Oligometastatic Hormone-Sensitive Prostate Cancer SO JOURNAL OF ONCOLOGY PRACTICE LA English DT Review ID ANDROGEN-DEPRIVATION THERAPY; LYMPH-NODE DISSECTION; RADICAL PROSTATECTOMY; LOCAL TREATMENT; MULTIINSTITUTIONAL ANALYSIS; FREE SURVIVAL; RECURRENCE; MEN; TOMOGRAPHY; TRIAL AB Oligometastatic disease was postulated by Hellman and Weichselbaum in 1995 to be a disease state that may reflect a time point in the malignant process that may be amenable to local therapies to allow for patients to achieve a durable response or possible cure despite having advanced disease. Aggressive metastasis-directed therapy has been used inmalignancies such as renal cell carcinoma, non-small-cell lung cancer, and colorectal cancer with some evidence of long-term benefit in selected patients. Recently, it has been proposed that some men with oligometastatic hormone-sensitive prostate cancer may also benefit from metastasis-directed therapy. As with most malignancies, optimal therapy for prostate cancer relies on multimodal therapy, best highlighted by the survival benefit seen in high-volume metastatic prostate cancer with the addition of docetaxel to androgen-deprivation therapy. This is becoming increasingly evident for oligometastatic prostate cancer, with emerging data sets suggesting a possible benefit of local ablative therapies for metastatic lesions combined with androgen-deprivation therapy. However, the bulk of the data is retrospective and thus subject to bias. Ongoing clinical trials are evaluating combination therapy to help elucidate the role of each therapy separately and together to determine optimal interventions for this population. This clinical review discusses the retrospective data evaluating local therapies such as radiation and surgery in men with lymph node-positive disease, as well as limited bone metastases, and outlines ongoing, prospective clinical trials designed to further investigate the role of multimodality therapy in the outcomes of men with oligometastatic hormone-sensitive prostate cancer. C1 UConn Hlth, Carole & Ray Neag Comprehens Canc Ctr, Farmington, CT USA. Harvard Med Sch, Dana Farber Canc Inst, Boston, MA USA. RP Clement, JM (reprint author), Univ Connecticut, UConn Hlth, Sch Med, 263 Farmington Ave, Farmington, CT 06030 USA. EM clement@uchc.edu NR 27 TC 2 Z9 2 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 1554-7477 EI 1935-469X J9 J ONCOL PRACT JI J. Oncol. Pract. PD JAN 1 PY 2017 VL 13 IS 1 BP 9 EP + DI 10.1200/JOP.2016.018523 PG 11 WC Health Care Sciences & Services SC Health Care Sciences & Services GA EO0FN UT WOS:000396373800015 PM 28045610 ER PT J AU Berry, LL Dalwadi, SM Jacobson, JO AF Berry, Leonard L. Dalwadi, Shraddha Mahesh Jacobson, Joseph O. TI Supporting the Supporters: What Family Caregivers Need to Care for a Loved One With Cancer SO JOURNAL OF ONCOLOGY PRACTICE LA English DT Review ID QUALITY-OF-LIFE; INFORMAL CAREGIVERS; PALLIATIVE CARE; HEALTH; INTERVENTIONS; METAANALYSIS; EMERGENCY; OUTCOMES; BURDEN; DYSREGULATION AB Patients with cancer who live at home often require help with activities of daily living, basic medical care (eg, injections), social needs, and patient advocacy. Most of that support comes from intimate caregivers, typically members of the patient's family. These family caregivers themselves require support so that they can be effective and maintain their own well-being while caring for the patient with cancer. Research shows that support for caregivers contributes to achieving these goals. We propose a four-part framework for supporting family caregivers: (1) assess caregivers' needs using formal measures, just as the cancer patient's own needs are assessed, (2) educate caregivers for their caregiving roles, most notably, with training in the low-level medical support that cancer patients require at home, (3) empower caregivers to become full-fledged members of the patient's cancer team, all working toward common goals, and(4) assist caregivers proactively in their duties, so that they retain a sense of control and self-efficacy rather than having to react to imminent medical crises without sufficient resources at their disposal. Funding support for family caregivers requires refocusing on the overall well-being of the patient-caregiver dyad rather than just on the patient. It will necessitate a paradigm shift in reimbursement that recognizes the need for holistic cancer care. C1 Texas A&M Univ, College Stn, TX USA. Inst Healthcare Improvement, Cambridge, MA USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Med Sch, Boston, MA USA. RP Berry, LL (reprint author), Texas A&M Univ, Mays Business Sch, College Stn, TX 77843 USA. EM LBerry@mays.tamu.edu FU What Family Caregivers Need to Care for a Loved One With Cancer FX What Family Caregivers Need to Care for a Loved One With Cancer NR 58 TC 0 Z9 0 U1 1 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 1554-7477 EI 1935-469X J9 J ONCOL PRACT JI J. Oncol. Pract. PD JAN 1 PY 2017 VL 13 IS 1 BP 35 EP + DI 10.1200/JOP.2016.017913 PG 8 WC Health Care Sciences & Services SC Health Care Sciences & Services GA EO0FN UT WOS:000396373800021 PM 27997304 ER PT J AU Belstrom, D Holmstrup, P Fiehn, NE Kirkby, N Kokaras, A Paster, BJ Bardow, A AF Belstrom, Daniel Holmstrup, Palle Fiehn, Nils-Erik Kirkby, Nikolai Kokaras, Alexis Paster, Bruce J. Bardow, Allan TI Salivary microbiota in individuals with different levels of caries experience SO JOURNAL OF ORAL MICROBIOLOGY LA English DT Article DE Caries susceptibility; microbiology; HOMINGS; oral diagnosis; clinical studies/trials ID DENTAL-CARIES; BACTERIAL PROFILES; ORAL-HEALTH; LESIONS; COHORT; AGE AB This study compared salivary bacterial profiles in two groups having a 10-fold difference in levels of caries experience, as it was hypothesized that the composition of the salivary microbiota might associate with the levels of caries experience. Bacterial profiles in stimulated saliva samples from 85 individuals with low levels of caries experience (healthy group) and 79 individuals with high levels of caries experience (caries group) were analyzed by means of the Human Oral Microbiome Identification Next Generation Sequencing ( HOMINGS) technique. Subsequently, saliva samples from caries-free individuals in the healthy group (n = 57) and the caries group (n = 31) were compared. A significantly higher a-diversity (p < 0.0001) and a twofold higher relative abundance of Neisseria, Haemophilus, and Fusobacterium were recorded in saliva samples from the healthy group compared with the caries group. Differences observed were more pronounced when limiting the analyses to caries-free individuals in each group. Data from this cross-sectional analysis suggest that low levels of caries experience might associate with a characteristic salivary bacterial composition different from that in individuals with high caries experience. Consequently, longitudinal studies are required to determine if the composition of the salivary microbiota might be a predictive factor of caries risk at the individual level. C1 [Belstrom, Daniel; Holmstrup, Palle] Univ Copenhagen, Fac Hlth & Med Sci, Dept Odontol, Sect Periodontol Microbiol & Community Dent, Copenhagen, Denmark. [Fiehn, Nils-Erik] Univ Copenhagen, Fac Hlth & Med Sci, Dept Immunol & Microbiol, Copenhagen, Denmark. [Kirkby, Nikolai] Copenhagen Univ Hosp, Dept Med Microbiol, Copenhagen, Denmark. [Kokaras, Alexis; Paster, Bruce J.] Forsyth Inst, Dept Microbiol, Cambridge, MA USA. [Paster, Bruce J.] Harvard Sch Dent Med, Dept Oral Med Infect & Immun, Boston, MA USA. [Bardow, Allan] Univ Copenhagen, Fac Hlth Sci, Dept Odontol, Sect Oral Med, Copenhagen, Denmark. RP Belstrom, D (reprint author), Univ Copenhagen, Fac Hlth & Med Sci, Dept Odontol, Sect Periodontol Microbiol & Community Dent, Copenhagen, Denmark. EM dbel@sund.ku.dk FU Danish Dental Association; Danish Foundation of Mutual Efforts in Dental Care; Simon Spies Foundation; Trygfonden FX The authors wish to thank professor Morten Gronbaek, National Institute of Public Health, University of Southern Denmark for access to the DANHES database. This study was supported by external financial support from the Danish Dental Association, the Danish Foundation of Mutual Efforts in Dental Care, Trygfonden, and the Simon Spies Foundation. NR 24 TC 0 Z9 0 U1 0 U2 0 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND SN 2000-2297 J9 J ORAL MICROBIOL JI J. Oral Microbiology PY 2017 VL 9 AR 1270614 DI 10.1080/20002297.2016.1270614 PG 8 WC Microbiology SC Microbiology GA EO5VB UT WOS:000396759900001 PM 28326153 ER PT J AU Hagan, TL Fishbein, JN Nipp, RD Jacobs, JM Traeger, L Irwin, KE Pirl, WF Greer, JA Park, ER Jackson, VA Temel, JS AF Hagan, Teresa L. Fishbein, Joel N. Nipp, Ryan D. Jacobs, Jamie M. Traeger, Lara Irwin, Kelly E. Pirl, William F. Greer, Joseph A. Park, Elyse R. Jackson, Vicki A. Temel, Jennifer S. TI Coping in Patients With Incurable Lung and Gastrointestinal Cancers: A Validation Study of the Brief COPE SO JOURNAL OF PAIN AND SYMPTOM MANAGEMENT LA English DT Article DE Psychometrics; coping skills; coping behaviors; palliative care; palliative medicine; neoplasm/cancer ID QUALITY-OF-LIFE; BREAST-CANCER; DEPRESSIVE SYMPTOMS; FAMILY CAREGIVERS; 1ST YEAR; PREDICTORS; STRATEGIES; MORTALITY; WOMEN; CARE AB Context. Patients with incurable cancer engage in several coping styles to manage the impact of cancer and its treatment. The Brief COPE is a widely used measure intended to capture multiple and distinct types of coping. The Brief COPE has not been validated among patients with incurable cancer. Objectives. We sought to validate seven subscales of the Brief COPE in a large sample of patients newly diagnosed with incurable lung and noncolorectal gastrointestinal cancers ( N = 350). Methods. Participants completed the Brief COPE and measures assessing quality of life (QOL) (Functional Assessment of Cancer TherapydGeneral) and psychological distress (Hospital Anxiety and Depression Scale) within eight weeks of diagnosis of incurable cancer. We evaluated the psychometric properties of the Brief COPE using a confirmatory factor analysis and tests of correlation with the QOL and distress scales. Results. The Brief COPE factors were consistent with the original subscales, although the Behavioral Disengagement Scale had low internal consistency. Factors showed anticipated relationships with QOL and distress measures, except emotional support coping, which was correlated with increased depression and anxiety. We also conducted an exploratory high-order factor analysis to determine if subscales' score variances grouped together. The high-order factor analysis resulted in two factors, with active, emotional support, positive reframing, and acceptance loading onto one factor and denial and self-blame loading onto the second. Conclusion. The selected subscales of the Brief COPE are appropriate measures of coping among individuals newly diagnosed with incurable lung and gastrointestinal cancers. (C) 2016 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved. C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Harvard Med Sch, Boston, MA USA. RP Hagan, TL (reprint author), Massachusetts Gen Hosp, Canc Outcomes Res Program, 55 Fruit St,Yawkey Bldg,Suite 10B, Boston, MA 02114 USA. EM tlh42@pitt.edu OI Hagan, Teresa/0000-0001-7403-7314 FU National Institute of Nursing Research [R01 NR012735]; National Cancer Institute [K24 CA181253] FX Funding was provided by the National Institute of Nursing Research (R01 NR012735) and the National Cancer Institute (K24 CA181253) for data collection and analysis. The authors declare no conflicts of interest. NR 38 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 0885-3924 EI 1873-6513 J9 J PAIN SYMPTOM MANAG JI J. Pain Symptom Manage. PD JAN PY 2017 VL 53 IS 1 BP 131 EP 138 DI 10.1016/j.jpainsymman.2016.06.005 PG 8 WC Health Care Sciences & Services; Medicine, General & Internal; Clinical Neurology SC Health Care Sciences & Services; General & Internal Medicine; Neurosciences & Neurology GA EO2BW UT WOS:000396502600017 PM 27725249 ER PT J AU Wilkins, LM Kaye, EK Wang, HY Rogus, J Doucette-Stamm, L Kornman, K Garcia, RI AF Wilkins, Leon M. Kaye, Elizabeth K. Wang, Hwa-Ying Rogus, John Doucette-Stamm, Lynn Kornman, Kenneth Garcia, Raul I. TI Influence of Obesity on Periodontitis Progression Is Conditional on Interleukin-1 Inflammatory Genetic Variation SO JOURNAL OF PERIODONTOLOGY LA English DT Article DE Cytokines; diagnosis; genetics; obesity; periodontitis ID C-REACTIVE PROTEIN; CREVICULAR FLUID BIOMARKERS; TYPE-2 DIABETES-MELLITUS; TO-HEIGHT RATIO; DISEASE PROGRESSION; RISK-FACTORS; CARDIOVASCULAR-DISEASE; SYSTEMIC INFLAMMATION; ABDOMINAL OBESITY; THERAPY OUTCOMES AB Background: This study evaluates whether specific patterns of interleukin (IL)-1 gene variants, known to affect periodontitis severity, influence the previously reported association between obesity and subsequent periodontitis progression in a longitudinal database. The study population included 292 men (aged 29 to 64 years at entry) from the Veterans Affairs Dental Longitudinal Study from whom DNA and dental and anthropometric endpoints were collected during multiple examinations (approximately every 3 years for up to 27 years). Methods: Key variables assessed included: 1) periodontitis; 2) body mass index; 3) waist circumference to height (WHTR) ratio for central adiposity; 4) age; 5) smoking; 6) glucose tolerance; and 7) two previously reported versions of IL-1 genetic patterns associated with periodontitis severity and progression. Disease progression was determined using predefined criteria that used a combination of change in classification of disease severity based on alveolar bone loss and tooth loss during follow-up. Extended Cox regression analyses were used to estimate hazards of experiencing periodontal disease progression with or without adjustments for appropriate covariates. Results: In hazard ratio analyses, men with WHTR >50% at baseline and positive for either IL-1 genotype version were at significantly higher risk (two-fold) for disease progression (P for interaction = 0.04). Participants positive for IL-1 genotype version 2 exhibited earlier progression (fewer years from baseline to first incidence of progression) than those who were negative (P = 0.02, adjusted for age and smoking). Conclusion: In this longitudinally monitored male population, observed effect of baseline central adiposity on future periodontitis progression is conditional on proinflammatory IL-1 genetic variations. C1 [Wilkins, Leon M.; Wang, Hwa-Ying; Rogus, John; Doucette-Stamm, Lynn; Kornman, Kenneth] Interleukin Genet, Waltham, MA USA. [Kaye, Elizabeth K.; Garcia, Raul I.] Boston Univ, Dept Hlth Policy & Hlth Serv Res, Henry M Goldman Sch Dent Med, Boston, MA 02215 USA. [Kaye, Elizabeth K.; Garcia, Raul I.] VA Boston Healthcare Syst, Boston, MA USA. RP Doucette-Stamm, L (reprint author), Interleukin Genet Inc, 135 Beaver St, Waltham, MA 02452 USA. EM ldoucette@ilgenetics.com FU National Institute of Dental and Craniofacial Research, Bethesda, Maryland [R01 DE019833]; Massachusetts Veterans Epidemiology Research and Information Center, Boston, Massachusetts; US Department of Veterans Affairs Cooperative Studies Program, Washington, DC FX This work was supported by National Institute of Dental and Craniofacial Research, Bethesda, Maryland (R01 DE019833) and Massachusetts Veterans Epidemiology Research and Information Center, Boston, Massachusetts, which is supported by the US Department of Veterans Affairs Cooperative Studies Program, Washington, DC (Drs. Krall Kaye and Garcia). The authors thank Jennifer Ihle and Sam Simmers, laboratory technologists, Interleukin Genetics Inc., for laboratory processing of DNA samples, and Rene Oda, Director of Technology, Interleukin Genetics Inc., for assistance in genotyping data QC. Drs. Wilkins, Doucette-Stamm, Wang, and Rogus are employees of or consultants to Interleukin Genetics, Inc., Waltham, Massachusetts. Dr. Kornman is an employee and officer of Interleukin Genetics, Inc., which has patents on genetic factors related to multiple complex diseases including periodontitis. Drs. Garcia and Krall Kaye report no corporate funding for this research and no conflicts of interest. NR 50 TC 0 Z9 0 U1 0 U2 0 PU AMER ACAD PERIODONTOLOGY PI CHICAGO PA 737 NORTH MICHIGAN AVENUE, SUITE 800, CHICAGO, IL 60611-2690 USA SN 0022-3492 EI 1943-3670 J9 J PERIODONTOL JI J. Periodont. PD JAN PY 2017 VL 88 IS 1 BP 59 EP 68 DI 10.1902/jop.2016.160408 PG 10 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA EL3FX UT WOS:000394506100011 PM 27541081 ER PT J AU Charaziak, KK Shera, CA AF Charaziak, Karolina K. Shera, Christopher A. TI Compensating for ear-canal acoustics when measuring otoacoustic emissions SO JOURNAL OF THE ACOUSTICAL SOCIETY OF AMERICA LA English DT Article ID IN-SITU CALIBRATION; TEST-RETEST RELIABILITY; DISTORTION-PRODUCT; NORMAL-HEARING; STANDING WAVES; MIDDLE-EAR; ENERGY REFLECTANCE; SOUND CALIBRATION; PRESSURE LEVEL; FINE-STRUCTURE AB Otoacoustic emissions (OAEs) provide an acoustic fingerprint of the inner ear, and changes in this fingerprint may indicate changes in cochlear function arising from efferent modulation, aging, noise trauma, and/or exposure to harmful agents. However, the reproducibility and diagnostic power of OAE measurements is compromised by the variable acoustics of the ear canal, in particular, by multiple reflections and the emergence of standing waves at relevant frequencies. Even when stimulus levels are controlled using methods that circumvent standing-wave problems (e.g., forward-pressure- level calibration), distortion-product otoacoustic emission (DPOAE) levels vary with probe location by 10-15 dB near half-wave resonant frequencies. The method presented here estimates the initial outgoing OAE pressure wave at the eardrum from measurements of the conventional OAE, allowing one to separate the emitted OAE from the many reflections trapped in the ear canal. The emitted pressure level (EPL) represents the OAE level that would be recorded were the ear canal replaced by an infinite tube with no reflections. When DPOAEs are expressed using EPL, their variation with probe location decreases to the test-retest repeatability of measurements obtained at similar probe positions. EPL provides a powerful way to reduce the variability of OAE measurements and improve their ability to detect cochlear changes.(C) 2017 Acoustical Society of America. C1 [Charaziak, Karolina K.; Shera, Christopher A.] Massachusetts Eye & Ear Infirm, Eaton Peabody Labs, 243 Charles St, Boston, MA 02114 USA. [Charaziak, Karolina K.] Univ Southern Calif, Caruso Dept Otolaryngol, Keck Sch Med, Los Angeles, CA 90033 USA. RP Charaziak, KK (reprint author), Massachusetts Eye & Ear Infirm, Eaton Peabody Labs, 243 Charles St, Boston, MA 02114 USA.; Charaziak, KK (reprint author), Univ Southern Calif, Caruso Dept Otolaryngol, Keck Sch Med, Los Angeles, CA 90033 USA. EM kcharaziak@u.northwestern.edu FU NIH [R01 DC003687] FX Supported by NIH Grant No. R01 DC003687 (to C.A.S.). Portions of this report were presented at the 171st ASA Meeting, Salt Lake City, UT. We thank Stephen Neely and Jonathan Siegel for many helpful discussions and Carolina Abdala and the anonymous reviewers for thoughtful comments on the manuscript. NR 74 TC 0 Z9 0 U1 0 U2 0 PU ACOUSTICAL SOC AMER AMER INST PHYSICS PI MELVILLE PA STE 1 NO 1, 2 HUNTINGTON QUADRANGLE, MELVILLE, NY 11747-4502 USA SN 0001-4966 EI 1520-8524 J9 J ACOUST SOC AM JI J. Acoust. Soc. Am. PD JAN PY 2017 VL 141 IS 1 BP 515 EP 531 DI 10.1121/1.4973618 PG 17 WC Acoustics; Audiology & Speech-Language Pathology SC Acoustics; Audiology & Speech-Language Pathology GA EM4UP UT WOS:000395308700062 PM 28147590 ER PT J AU Haberer, JE AF Haberer, Jessica E. TI Actionable adherence monitoring to optimise intervention SO LANCET HIV LA English DT Editorial Material ID ANTIRETROVIRAL THERAPY ADHERENCE; MEDICATION ADHERENCE; RURAL UGANDA C1 [Haberer, Jessica E.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Haberer, JE (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. EM jhaberer@partners.org FU US National Institutes of Health; Bill & Melinda Gates Foundation; USAID; WHO; Merck FX I receive grant funding through the US National Institutes of Health, the Bill & Melinda Gates Foundation, and USAID. I have received consultation fees from the US National Institutes of Health, WHO, and Merck. I own stock in Natera. I would like to thank David R Bangsberg for his critical review of this Comment. NR 13 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER INC PI SAN DIEGO PA 525 B STREET, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 2352-3018 J9 LANCET HIV JI Lancet HIV PD JAN PY 2017 VL 4 IS 1 BP E5 EP E6 DI 10.1016/S2352-3018(16)30191-6 PG 3 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA EP2BH UT WOS:000397187500004 PM 27864001 ER PT J AU Blum, W Sanford, BL Klisovic, R DeAngelo, DJ Uy, G Powell, BL Stock, W Baer, MR Kolitz, JE Wang, ES Hoke, E Mrozek, K Kohlschmidt, J Bloomfield, CD Geyer, S Marcucci, G Stone, RM Larson, RA AF Blum, W. Sanford, B. L. Klisovic, R. DeAngelo, D. J. Uy, G. Powell, B. L. Stock, W. Baer, M. R. Kolitz, J. E. Wang, E. S. Hoke, E. Mrozek, K. Kohlschmidt, J. Bloomfield, C. D. Geyer, S. Marcucci, G. Stone, R. M. Larson, R. A. CA Alliance Clinical Trials Oncology TI Maintenance therapy with decitabine in younger adults with acute myeloid leukemia in first remission: a phase 2 Cancer and Leukemia Group B Study (CALGB 10503) SO LEUKEMIA LA English DT Article ID ACUTE MYELOGENOUS LEUKEMIA; HIGH-DOSE CYTARABINE; MICRORNA-EXPRESSION SIGNATURES; CONVENTIONAL CARE REGIMENS; STEM-CELL TRANSPLANTATION; COOPERATIVE-GROUP; OLDER PATIENTS; RECOMBINANT INTERLEUKIN-2; MYELODYSPLASTIC SYNDROMES; PROLONGED MAINTENANCE AB In this prospective phase 2 clinical trial conducted by Cancer and Leukemia Group B (CALGB, now the Alliance), we studied decitabine as maintenance therapy for younger adults with acute myeloid leukemia (AML) who remained in first complete remission (CR1) following intensive induction and consolidation. Given that decitabine is clinically active in AML and with hypomethylating activity distinct from cytotoxic chemotherapy, we hypothesized that 1 year of maintenance therapy would improve disease-free survival (DFS) for AML patients <60 years, who did not receive allogeneic stem cell transplantation in CR1. After blood count recovery from final consolidation, patients received decitabine at 20 mg/m(2) intravenously daily for 4-5 days, every 6 weeks for eight cycles. One hundred and thirty-four patients received decitabine and 85 (63%) had favorable risk AML. The median number of cycles received was 7 (range: 1-8) and the primary reason for discontinuation was relapse. DFS at 1 year and 3 years was 79% and 54%, respectively. These results are similar to the outcomes in the historical control comprising similar patients treated on recent CALGB trials. Thus, maintenance with decitabine provided no benefit overall. Standard use of decitabine maintenance in younger AML patients in CR1 is not warranted. This trial was registered at www.clinicaltrials.gov as NCT00416598. C1 [Blum, W.; Klisovic, R.; Mrozek, K.; Kohlschmidt, J.; Bloomfield, C. D.] Ohio State Univ, Div Hematol, B312 Starling Loving Hall,320 West 10th Ave, Columbus, OH 43210 USA. [Blum, W.; Klisovic, R.; Mrozek, K.; Kohlschmidt, J.; Bloomfield, C. D.] Ohio State Univ, Ctr Comprehens Canc, B312 Starling Loving Hall,320 West 10th Ave, Columbus, OH 43210 USA. [Sanford, B. L.; Hoke, E.; Kohlschmidt, J.] Mayo Clin, Alliance Clin Trials Oncol Stat, Rochester, MN USA. [Sanford, B. L.; Hoke, E.; Kohlschmidt, J.] Mayo Clin, Ctr Data, Rochester, MN USA. [DeAngelo, D. J.; Stone, R. M.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Uy, G.] Washington Univ, Dept Med, St Louis, MO USA. [Powell, B. L.] Wake Forest Univ, Ctr Comprehens Canc, Winston Salem, NC 27109 USA. [Stock, W.] Univ Chicago, Dept Med, 5841 S Maryland Ave, Chicago, IL 60637 USA. [Baer, M. R.] Univ Maryland, Dept Med, Baltimore, MD 21201 USA. [Baer, M. R.] Univ Maryland, Greenebaum Canc Ctr, Baltimore, MD 21201 USA. [Kolitz, J. E.] Hofstra North Shore Long Isl Jewish Sch Med, Manhasset, NY USA. [Wang, E. S.] Roswell Pk Canc Inst, Dept Med, Buffalo, NY 14263 USA. [Geyer, S.] Univ S Florida, Hlth Informat Inst, Tampa, FL USA. [Marcucci, G.] City Hope Natl Med Ctr, Ctr Comprehens Canc, Gehr Family Leukemia Ctr, Duarte, CA USA. RP Blum, W (reprint author), Ohio State Univ, Div Hematol, B312 Starling Loving Hall,320 West 10th Ave, Columbus, OH 43210 USA.; Blum, W (reprint author), Ohio State Univ, Ctr Comprehens Canc, B312 Starling Loving Hall,320 West 10th Ave, Columbus, OH 43210 USA. EM william.blum@osumc.edu FU NCI Cancer Therapy Evaluation Program; National Cancer Institute of the National Institutes of Health [U10CA31946, U10CA33601, U10CA180821, U10CA180882]; NIH/NCI [K23CA120708]; [CA140158]; [CA016058]; [CA180850]; [CA101140]; [CA128377] FX We thank patients and their families, collaborators and staff in the CALGB and Alliance member institutions/data center and the Alliance Leukemia Tissue Bank/Ms Donna Bucci. We also thank John C Byrd, MD, and the team in the Leukemia and Leukemia Correlative Science Committees for the Alliance for review of the manuscript and assistance with molecular data. This trial was sponsored by the NCI Cancer Therapy Evaluation Program. We gratefully acknowledge the enormous contributions to this study and to the field of medicine by our friend Dr Meir Wetzler (deceased February 2015). Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under Award Numbers U10CA31946, U10CA33601 (to CALGB), U10CA180821 and U10CA180882 (to the Alliance for Clinical Trials in Oncology), and NIH/NCI K23CA120708. Additional support was provided under CA140158, CA016058, CA180850, CA101140 and CA128377. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 37 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 0887-6924 EI 1476-5551 J9 LEUKEMIA JI Leukemia PD JAN PY 2017 VL 31 IS 1 BP 34 EP 39 DI 10.1038/leu.2016.252 PG 6 WC Oncology; Hematology SC Oncology; Hematology GA EK6UD UT WOS:000394058700005 PM 27624549 ER PT J AU Etchin, J Berezovskaya, A Conway, AS Galinsky, IA Stone, RM Baloglu, E Senapedis, W Landesman, Y Kauffman, M Shacham, S Wang, JCY Look, AT AF Etchin, J. Berezovskaya, A. Conway, A. S. Galinsky, I. A. Stone, R. M. Baloglu, E. Senapedis, W. Landesman, Y. Kauffman, M. Shacham, S. Wang, J. C. Y. Look, A. T. TI KPT-8602, a second-generation inhibitor of XPO1-mediated nuclear export, is well tolerated and highly active against AML blasts and leukemia-initiating cells SO LEUKEMIA LA English DT Article ID ACUTE MYELOID-LEUKEMIA; CHRONIC LYMPHOCYTIC-LEUKEMIA; STEM-CELLS; SELECTIVE INHIBITORS; STRUCTURAL BASIS; CRM1; EXPRESSION; SELINEXOR; CANCER; SIGNAL AB Acute myeloid leukemia (AML) is a clonal hematologic malignant disease of developing myeloid cells that have acquired aberrant survival, uncontrolled proliferation and a block in normal hematopoietic cell differentiation. Standard chemotherapy often induces remissions in AML patients, but the disease frequently relapses due to incomplete targeting of leukemia-initiating cells (LICs), emphasizing the need for novel effective treatments. Exportin 1 (XPO1)-mediated nuclear export, which is inhibited by the drug selinexor, is an attractive new therapeutic target in AML. Selinexor has shown impressive activity in Phase I/II clinical trials for AML. Here we report the anti-leukemic efficacy and tolerability of KPT-8602, a second-generation XPO1 inhibitor. KPT-8602 demonstrates substantially reduced brain penetration compared to selinexor, with resultant attenuation of the central nervous system mediated side effects of anorexia and weight loss. Due to its improved tolerability profile, KPT-8602 can be given daily compared to the two or three times weekly regimen of selinexor, and exhibits greater anti-leukemic efficacy against both leukemic blasts and LICs in AML patient-derived xenograft models. Importantly, normal hematopoietic stem and progenitor cell (HSPC) frequency is not significantly reduced by KPT-8602, providing a therapeutic window for elimination of relapse-driving LICs while sparing normal HSPCs. These findings strongly endorse clinical testing of KPT-8602 in patients with relapsed and refractory AML. C1 [Etchin, J.; Berezovskaya, A.; Conway, A. S.; Look, A. T.] Dana Farber Canc Inst, Dept Pediat Oncol, Mayer Bldg,Room 630,450 Brookline Ave, Boston, MA 02115 USA. [Etchin, J.; Look, A. T.] Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USA. [Galinsky, I. A.; Stone, R. M.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Galinsky, I. A.; Stone, R. M.] Harvard Med Sch, Boston, MA USA. [Baloglu, E.; Senapedis, W.; Landesman, Y.; Kauffman, M.; Shacham, S.] Karyopharm Therapeut, Newton, MA USA. [Wang, J. C. Y.] Univ Hlth Network, Princess Margaret Canc Ctr, Toronto, ON, Canada. [Wang, J. C. Y.] Univ Toronto, Dept Med, Toronto, ON, Canada. RP Look, AT (reprint author), Dana Farber Canc Inst, Dept Pediat Oncol, Mayer Bldg,Room 630,450 Brookline Ave, Boston, MA 02115 USA. EM thomas_look@dfci.harvard.edu FU William Lawrence and Blanche Hughes Foundation; Leukemia and Lymphoma Society's Translational research grant; Alex's Lemonade Young Research Investigator grant; Luck2Tuck Foundation; Claudia Adams Barr Innovative Basic Science Research Grant; Wong Family Award in Translational Research FX We would like to thank Paul Kirschmeier and Prafulla Gokhale of the Lurie Family Imaging Center for assistance with the in vivo studies. We would like to thank the flow cytometry team led by John Daley and Suzan Lazo for their help with cell analysis. This research was supported by William Lawrence and Blanche Hughes Foundation (ATL), Leukemia and Lymphoma Society's Translational research grant (ATL), Alex's Lemonade Young Research Investigator grant (JE), Luck2Tuck Foundation (JE), Claudia Adams Barr Innovative Basic Science Research Grant (JE) and Wong Family Award in Translational Research (JE). NR 46 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 0887-6924 EI 1476-5551 J9 LEUKEMIA JI Leukemia PD JAN PY 2017 VL 31 IS 1 BP 143 EP 150 DI 10.1038/leu.2016.145 PG 8 WC Oncology; Hematology SC Oncology; Hematology GA EK6UD UT WOS:000394058700019 PM 27211268 ER PT J AU Liu, W Wu, M Huang, Z Lian, J Chen, J Wang, T Leung, AYH Liao, Y Zhang, Z Liu, Q Yen, K Lin, S Zon, L Wen, Z Zhang, Y Zhang, W AF Liu, W. Wu, M. Huang, Z. Lian, J. Chen, J. Wang, T. Leung, A. Y. H. Liao, Y. Zhang, Z. Liu, Q. Yen, K. Lin, S. Zon, Li Wen, Z. Zhang, Y. Zhang, W. TI c-myb hyperactivity leads to myeloid and lymphoid malignancies in zebrafish SO LEUKEMIA LA English DT Article ID ACUTE LYMPHOBLASTIC-LEUKEMIA; TRANSCRIPTION FACTOR; DIFFERENTIAL EXPRESSION; CELL DEVELOPMENT; SELF-RENEWAL; GENE; ONCOGENE; HEMATOPOIESIS; MYELOPOIESIS; PRODUCT AB The c-MYB transcription factor is a key regulator of hematopoietic cell proliferation and differentiation, and dysregulation of c-MYB activity often associates with various hematological disorders. Yet, its pathogenic role remains largely unknown due to lack of suitable animal models. Here, we report a detail characterization of a c-myb-gfp transgenic zebrafish harboring c-Myb hyperactivity (named c-myb(hyper)). This line exhibits abnormal granulocyte expansion that resembles human myelodysplastic syndrome (MDS) from embryonic stage to adulthood. Strikingly, a small portion of c-myb(hyper) adult fish develops acute myeloid leukemia-like or acute lymphoid leukemia-like disorders with age. The myeloid and lymphoid malignancies in c-myb(hyper) adult fish are likely caused by the hyperactivity of c-myb, resulting in the dysregulation of a number of cell-cycle-related genes and hyperproliferation of hematopoietic precursor cells. Finally, treatment with c-myb target drug flavopiridol can relieve the MDS-like symptoms in both c-myb(hyper) embryos and adult fish. Our study establishes a zebrafish model for studying the cellular and molecular mechanisms underlying c-Myb-associated leukemogenesis as well as for anti-leukemic drug screening. C1 [Liu, W.; Liao, Y.; Zhang, Z.; Zhang, W.] Southern Med Univ, State Key Lab Organ Failure Res, Guangzhou, Guangdong, Peoples R China. [Wu, M.; Huang, Z.; Lian, J.; Chen, J.; Yen, K.; Zhang, Y.; Zhang, W.] Southern Med Univ, Sch Basic Med Sci, Dept Dev Biol, Key Lab Zebrafish Modeling & Drug Screening Human, Guangzhou 510515, Guangdong, Peoples R China. [Wang, T.; Wen, Z.] Hong Kong Univ Sci & Technol, Div Life Sci, State Key Lab Mol Neurosci, Hong Kong, Hong Kong, Peoples R China. [Leung, A. Y. H.] Univ Hong Kong, Li Ka Shing Fac Med, Div Haematol, Dept Med, Hong Kong, Hong Kong, Peoples R China. [Liao, Y.] Southern Med Univ, Nanfang Hosp, Dept Cardiol, Guangzhou, Guangdong, Peoples R China. [Zhang, Z.] Southern Med Univ, Nanfang Hosp, Div Renal, Guangzhou, Guangdong, Peoples R China. [Liu, Q.] Southern Med Univ, Nanfang Hosp, Dept Haematol, Guangzhou, Guangdong, Peoples R China. [Lin, S.] Univ Calif Los Angeles, Dept Mol Cell & Dev Biol, Los Angeles, CA USA. [Zon, Li] Harvard Med Sch, Stem Cell Program, Boston, MA USA. [Zon, Li] Harvard Med Sch, Div Hematol Oncol, Childrens Hosp, Boston, MA USA. [Zon, Li] Harvard Med Sch, Dana Farber Canc Inst, Howard Hughes Med Inst, Harvard Stem Cell Inst, Boston, MA USA. RP Zhang, Y; Zhang, W (reprint author), Southern Med Univ, Sch Basic Med Sci, Dept Dev Biol, Key Lab Zebrafish Modeling & Drug Screening Human, Guangzhou 510515, Guangdong, Peoples R China. EM yiyue@smu.edu.cn; zzwwqq@smu.edu.cn FU National Natural Science Foundation of China [81470335, 81200340, 31229003]; Ministry of Science and Technology Project 863 [SS2015AA020309]; Team Program of Guangdong Natural Science Foundation [2014A030312002]; Talent Recruitment funding and Excellent Young Teacher funding of Guangdong Higher Education Institutes [Yq2013025]; Peal River S&T Nova Program of Guangzhou [2013J2200032] FX This work was supported by the National Natural Science Foundation of China (Grant Nos. 81470335, 81200340 and 31229003), The Ministry of Science and Technology Project 863 (SS2015AA020309), Team Program of Guangdong Natural Science Foundation (2014A030312002), Talent Recruitment funding and Excellent Young Teacher funding (Yq2013025) of Guangdong Higher Education Institutes and Peal River S&T Nova Program of Guangzhou (2013J2200032). NR 61 TC 0 Z9 0 U1 2 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0887-6924 EI 1476-5551 J9 LEUKEMIA JI Leukemia PD JAN PY 2017 VL 31 IS 1 BP 222 EP 233 DI 10.1038/leu.2016.170 PG 12 WC Oncology; Hematology SC Oncology; Hematology GA EK6UD UT WOS:000394058700028 PM 27457538 ER PT J AU Yang, K Li, XH Xu, XG Liu, B AF Yang, Kai Li, Xinhua Xu, X. George Liu, Bob TI Direct and fast measurement of CT beam filter profiles with simultaneous geometrical calibration SO MEDICAL PHYSICS LA English DT Article DE beam filtration; bowtie; computed tomography; geometrical calibration; transmission ID HALF-VALUE LAYER; X-RAY CT; SIMULATIONS; VALIDATION; SPECTRA AB Purpose: To accurately measure the beam filter profiles from a variety of CT scanner models and to provide reference data for Monte Carlo simulations of CT scanners. Methods: This study proposed a new method to measure CT beam filter profiles using a linear-array x-ray detector (X-Scan 0.8f3-512; Detection Technology Inc., Espoo, Finland) under gantry rotation mode. A robust geometrical calibration approach was developed to determine key geometrical parameters by considering the x-ray focal spot location relative to the linear-array detector and the gantry's angular increment at each acquisition point. CT beam intensity profiles were synthesized from continuously measured data during a 10 degrees gantry rotation range with calibrated detector response and system geometry information. Relative transmission profiles of nineteen sets of beam filters were then derived for nine different CT scanner models from three different manufacturers. Equivalent aluminum thickness profiles of these beam filters were determined by analytical calculation using the Spektr Matlab software package to match the measured transmission profiles. Three experiments were performed to validate the accuracy of the geometrical calibration, detector response modeling, and the derived equivalent aluminum thickness profiles. Results: The beam intensity profiles measured from gantry rotation mode showed very good agreement with those measured with gantry stationary mode, with a maximal difference of 3%. The equivalent aluminum thickness determined by this proposed method agreed well with what was measured by an ion chamber, with a mean difference of 0.4%. The determined HVL profiles matched well with data from a previous study (max difference of 4.7%). Conclusions: An accurate and robust method to directly measure profiles from a broad list of beam filters and CT scanner models was developed, implemented, and validated. Useful reference data was provided for future research on CT system modeling. (C) 2016 American Association of Physicists in Medicine. C1 [Yang, Kai; Li, Xinhua; Liu, Bob] Massachusetts Gen Hosp, Dept Radiol, Div Diagnost Imaging Phys, 55 Fruit St, Boston, MA 02114 USA. [Xu, X. George] Rensselaer Polytech Inst, Nucl Engn Program, Troy, NY 12180 USA. RP Yang, K (reprint author), Massachusetts Gen Hosp, Dept Radiol, Div Diagnost Imaging Phys, 55 Fruit St, Boston, MA 02114 USA. EM kyang11@mgh.harvard.edu FU National Institute of Biomedical Imaging and Bioengineering [R01EB015478]; Detection Technology, Inc FX This research is sponsored in part by the National Institute of Biomedical Imaging and Bioengineering (R01EB015478). The authors would like to acknowledge Tomi Falt from Detection Technology, Inc for the support of the linear-array detector. The authors would like to acknowledge Dr. Sarah McKenney, Dr. MauroTambasco, and Mr. Mitch Sommerville for constructive discussions and their generosity to provide data for comparison. The authors would also like to thank Mr. Matthew DeLorenzo for proofreading the manuscript. NR 21 TC 0 Z9 0 U1 0 U2 0 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0094-2405 EI 2473-4209 J9 MED PHYS JI Med. Phys. PD JAN PY 2017 VL 44 IS 1 BP 57 EP 70 DI 10.1002/mp.12024 PG 14 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA EO9WJ UT WOS:000397038500008 PM 28102951 ER PT J AU Ortega, JM Gonzalez, NG Tejero, PC Monedero, MP Tolani, NB Martin, LN Montero, RS AF Martinez Ortega, J. Gomez Gonzalez, N. Castro Tejero, P. Pinto Monedero, M. Tolani, N. B. Nunez Martin, L. Sanchez Montero, R. TI A portal dosimetry dose prediction method based on collapsed cone algorithm using the clinical beam model SO MEDICAL PHYSICS LA English DT Article DE amorphous silicon; EPID dosimetry; IMRT; portal image prediction ID MODULATED RADIATION-THERAPY; VIVO EPID DOSIMETRY; AMORPHOUS-SILICON; IMAGING DEVICE; IMRT VERIFICATION; PRETREATMENT VERIFICATION; OPTIMAL BACKSCATTER; SYSTEM; IMAGER; RADIOTHERAPY AB Purpose: Amorphous silicon electronical portal imaging devices (EPIDs) are widely used for dosimetric measurements in Radiation Therapy. The purpose of this work was to determine if a portal dose prediction method can be utilized for dose map calculations based on the linear accelerator model within a commercial treatment planning system (Pinnacle 3 v8.0 m). Methods: The method was developed for a 6 MV photon beam on the Varian Clinac 21-EX, at a nominal dose rate of 400 MU/min. The Varian aS1000 EPID was unmounted from the linear accelerator and scanned to acquire CT images of the EPID. The CT images were imported into Pinnacle 3 and were used as a quality assurance phantom to calculate dose on the EPID setup at a source to detector distance of 105 cm. The best match of the dose distributions was obtained considering the image plane located at 106 cm from the source to detector plane. The EPID was calibrated according to the manufacturer procedure and corrections were made for output factors. Arm-backscattering effect, based on profile correction curves, has been introduced. Five low-modulated and three high-modulated clinical planned treatments were predicted and measured with the method presented here and with MatriXX (IBA Dosimetry, Schwarzenbruck, Germany). Results: A portal dose prediction method based on Pinnacle 3 was developed without modifying the commissioned parameters of the model in use in the clinic. CT images of the EPID were acquired and used as a quality assurance phantom. The CT images indicated a mean density of 1.16 g/cm(3) for the sensitive area of the EPID. Output factor measured with the EPID were lower for small fields and larger for larger fields (beyond 10 x 10 cm(2)). Arm-backscatter correction showed a better agreement at the target side of the EPID. Analysis of Gamma index comparison (3%, 3 mm) indicated a minimum of 97.4% pass rate for low modulated and 98.3% for high modulated treatments. Pass rates were similar for MatriXX measurements. Conclusions: The method developed here can be easily implemented into clinic, as neither additional modeling of the clinical energy nor an independent image prediction algorithm are necessary. The main advantage of this method is that portal dose prediction is calculated with the same algorithm and beam model used for patient dose distribution calculation. This method was independently validated with an ionization chamber matrix. (C) 2016 American Association of Physicists in Medicine C1 [Martinez Ortega, J.; Gomez Gonzalez, N.; Pinto Monedero, M.; Nunez Martin, L.] Hosp Univ Puerta Hierro, Dept Med Phys, C Manuel de Falla 1, Majadahonda 28222, Madrid, Spain. [Castro Tejero, P.] Hosp Univ La Princesa, Dept Radiat Oncol, Radiat Phys, C Diego de Leon 62, Madrid 28006, Spain. [Tolani, N. B.] ME DeBakey VA Med Ctr, Dept Radiotherapy, 2002 Holcombe Blvd, Houston, TX 77030 USA. [Sanchez Montero, R.] Univ Alcala De Henares, Signal Theory & Commun Dept, Campus Univ,Km 33-600, Alcala De Henares 28805, Madrid, Spain. RP Ortega, JM (reprint author), Hosp Univ Puerta Hierro, Dept Med Phys, C Manuel de Falla 1, Majadahonda 28222, Madrid, Spain. EM jaime.martinez@salud.madrid.org NR 40 TC 0 Z9 0 U1 0 U2 0 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0094-2405 EI 2473-4209 J9 MED PHYS JI Med. Phys. PD JAN PY 2017 VL 44 IS 1 BP 333 EP 341 DI 10.1002/mp.12018 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA EO9WJ UT WOS:000397038500032 ER PT J AU Verma, S Cherayil, BJ AF Verma, Smriti Cherayil, Bobby J. TI Iron and inflammation - the gut reaction SO METALLOMICS LA English DT Review ID NECROSIS-FACTOR-ALPHA; HEREDITARY HEMOCHROMATOSIS PROTEIN; TRANSFERRIN RECEPTOR 2; BOWEL-DISEASE; HEPCIDIN EXPRESSION; IN-VIVO; INTESTINAL INFLAMMATION; SERUM HEPCIDIN; DEFICIENCY ANEMIA; CROHNS-DISEASE AB Anemia is a frequent complication of many inflammatory disorders, including inflammatory bowel disease. Although the pathogenesis of this problem is multifactorial, a key component is the abnormal elevation of the hormone hepcidin, the central regulator of systemic iron homeostasis. Investigations over the last decade have resulted in important insights into the role of hepcidin in iron metabolism and the mechanisms that lead to hepcidin dysregulation in the context of inflammation. These insights provide the foundation for novel strategies to prevent and treat the anemia associated with inflammatory diseases. C1 [Cherayil, Bobby J.] Massachusetts Gen Hosp, Dept Pediat, Mucosal Immunol & Biol Res Ctr, Bldg 114,16th St, Boston, MA 02129 USA. Harvard Med Sch, Bldg 114,16th St, Boston, MA 02129 USA. RP Cherayil, BJ (reprint author), Massachusetts Gen Hosp, Dept Pediat, Mucosal Immunol & Biol Res Ctr, Bldg 114,16th St, Boston, MA 02129 USA. EM cherayil@helix.mgh.harvard.edu FU United States National Institutes of Health [R01AI089700] FX Work in the authors' laboratory is supported by United States National Institutes of Health grant R01AI089700. NR 110 TC 0 Z9 0 U1 1 U2 1 PU ROYAL SOC CHEMISTRY PI CAMBRIDGE PA THOMAS GRAHAM HOUSE, SCIENCE PARK, MILTON RD, CAMBRIDGE CB4 0WF, CAMBS, ENGLAND SN 1756-5901 EI 1756-591X J9 METALLOMICS JI Metallomics PY 2017 VL 9 IS 2 BP 101 EP 111 DI 10.1039/c6mt00282j PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EP5RV UT WOS:000397437300001 PM 28067386 ER PT J AU Herrick, KS Woltjer, R Pham, T Chalupsky, M Hiller, AL AF Herrick, Kory S. Woltjer, Randy Thao Pham Chalupsky, Megan Hiller, Amie L. TI Central Hypoventilation in Progressive Supranuclear Palsy SO MOVEMENT DISORDERS CLINICAL PRACTICE LA English DT Article DE progressive supranuclear palsy; primary hypoventilation; tauopathy ID MULTIPLE SYSTEM ATROPHY AB Central hypoventilation, also known as Ondine's curse, results from an impairment of the autonomic respiratory drive. It is characterized by an attenuated or absent respiratory response to hypoxemia and hypercapnia with preservation of volitional respiratory function. R.J. was a 75-year-old woman with a diagnosis of probably PSP who developed central hypoventilation approximately 4 years after her initial onset of symptoms. Brain MRI showed no evidence of medullary lesions, one of the more common causes of adult-onset central hypoventilation. The respiratory centers in the medulla, especially the ventral respiratory group (VRG) containing Botzinger and pre-Botzinger complex of neurons, appear critical for normal respiratory rhythm generation. R.J. was maintained on a portable ventilator after her diagnosis of central hypoventilation. Ten months after being placed on ventilation, she passed of unclear causes. R.J. showed pathological features consistent with a diagnosis of PSP, specifically loss of neurons, secondary demyelination, and tau-positive inclusions in both astrocytes and neurons, chiefly in the globus pallidus, midbrain, and brainstem. R.J. showed significant tauopathy in the region of the VRG in particular. We also examined this region in 16 other cases of PSP and found similar tauopathy in all but 1 case, which had significantly less involvement of this area. We had limited clinical data on these cases, but 1 had two episodes of unexplained hypoxia shortly before being placed on hospice. Central hypoventilation associated with tauopathy involving the VRG may be more common than often appreciated. C1 [Herrick, Kory S.; Woltjer, Randy; Thao Pham; Chalupsky, Megan; Hiller, Amie L.] Oregon Hlth & Sci Univ, Dept Neurol, Mail Code 32,3181 Southwest Sam Jackson Pk Rd, Portland, OR 97239 USA. [Hiller, Amie L.] Portland VA Med Ctr, Portland, OR USA. RP Hiller, AL (reprint author), Oregon Hlth & Sci Univ, Dept Neurol, Mail Code 32,3181 Southwest Sam Jackson Pk Rd, Portland, OR 97239 USA. EM peterami@ohsu.edu FU Alzheimer's Disease Center Neuropathology Core-NIH [NIA P30AG8017]; Portland VA Career Development Award-The Effects of Vitamin D on Balance in Parkinson's Disease; NINDS-Udall Study [P50 NS052684]; Michael J. Fox Foundation FX Dr. Woltjer has funding through the Alzheimer's Disease Center Neuropathology Core-NIH NIA P30AG8017. Dr. Hiller had funding through the Portland VA Career Development Award-The Effects of Vitamin D on Balance in Parkinson's Disease until November 2015. Dr. Hiller also receives funding through NINDS-Udall Study P50 NS052684 and the Michael J. Fox Foundation. NR 9 TC 0 Z9 0 U1 0 U2 0 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2330-1619 J9 MOV DISORD CLIN PRAC JI MOV. DISORD. CLIN. PRACT. PD JAN-FEB PY 2017 VL 4 IS 1 BP 42 EP 45 DI 10.1002/mdc3.12348 PG 4 WC Clinical Neurology SC Neurosciences & Neurology GA EO0EF UT WOS:000396370400009 PM 28367478 ER PT J AU Collado-Torres, L Nellore, A Frazee, AC Wilks, C Love, MI Langmead, B Irizarry, RA Leek, JT Jaffe, AE AF Collado-Torres, Leonardo Nellore, Abhinav Frazee, Alyssa C. Wilks, Christopher Love, Michael I. Langmead, Ben Irizarry, Rafael A. Leek, Jeffrey T. Jaffe, Andrew E. TI Flexible expressed region analysis for RNA-seq with derfinder SO NUCLEIC ACIDS RESEARCH LA English DT Article ID DIFFERENTIAL EXPRESSION; GENE; TRANSCRIPTOME; RECONSTRUCTION; CONTRIBUTES; FEATURES; DATASETS; WEIGHTS; HUMANS; READS AB Differential expression analysis of RNA sequencing (RNA-seq) data typically relies on reconstructing transcripts or counting reads that overlap known gene structures. We previously introduced an intermediate statistical approach called differentially expressed region (DER) finder that seeks to identify contiguous regions of the genome showing differential expression signal at single base resolution without relying on existing annotation or potentially inaccurate transcript assembly. We present the derfinder software that improves our annotation-agnostic approach to RNA-seq analysis by: (i) implementing a computationally efficient bump-hunting approach to identify DERs that permits genome-scale analyses in a large number of samples, (ii) introducing a flexible statistical modeling framework, including multi-group and timecourse analyses and (iii) introducing a new set of data visualizations for expressed region analysis. We apply this approach to public RNA-seq data from the Genotype-Tissue Expression (GTEx) project and BrainSpan project to show that derfinder permits the analysis of hundreds of samples at base resolution in R, identifies expression outside of known gene boundaries and can be used to visualize expressed regions at base-resolution. In simulations, our base resolution approaches enable discovery in the presence of incomplete annotation and is nearly as powerful as feature-level methods when the annotation is complete. derfinder analysis using expressed region-level and single base-level approaches provides a compromise between full transcript reconstruction and feature-level analysis. C1 [Collado-Torres, Leonardo; Nellore, Abhinav; Frazee, Alyssa C.; Langmead, Ben; Leek, Jeffrey T.; Jaffe, Andrew E.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Biostat, Baltimore, MD 21205 USA. [Collado-Torres, Leonardo; Nellore, Abhinav; Frazee, Alyssa C.; Wilks, Christopher; Langmead, Ben; Leek, Jeffrey T.; Jaffe, Andrew E.] Johns Hopkins Univ, Ctr Computat Biol, Baltimore, MD 21205 USA. [Collado-Torres, Leonardo; Jaffe, Andrew E.] Lieber Inst Brain Dev, Johns Hopkins Med Campus, Baltimore, MD 21205 USA. [Nellore, Abhinav; Wilks, Christopher; Langmead, Ben] Johns Hopkins Univ, Dept Comp Sci, Baltimore, MD 21218 USA. [Love, Michael I.; Irizarry, Rafael A.] Harvard TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Love, Michael I.; Irizarry, Rafael A.] Harvard Univ, Dana Farber Canc Inst, Boston, MA 02215 USA. [Jaffe, Andrew E.] Johns Hopkins Univ, Dept Mental Hlth, Baltimore, MD 21205 USA. RP Leek, JT; Jaffe, AE (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, Dept Biostat, Baltimore, MD 21205 USA.; Leek, JT; Jaffe, AE (reprint author), Johns Hopkins Univ, Ctr Computat Biol, Baltimore, MD 21205 USA.; Jaffe, AE (reprint author), Lieber Inst Brain Dev, Johns Hopkins Med Campus, Baltimore, MD 21205 USA.; Jaffe, AE (reprint author), Johns Hopkins Univ, Dept Mental Hlth, Baltimore, MD 21205 USA. EM jtleek@gmail.com; andrew.jaffe@libd.org OI Collado-Torres, Leonardo/0000-0003-2140-308X FU NIH [1R01GM105705]; Consejo Nacional de Ciencia y Tecnologia Mexico [351535]; [1R21MH109956] FX NIH [1R01GM105705 to J.T.L.]; Consejo Nacional de Ciencia y Tecnologia Mexico [351535 to L.C.T.]; A.E.J.was supported by 1R21MH109956. NR 47 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 EI 1362-4962 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD JAN PY 2017 VL 45 IS 2 AR e9 DI 10.1093/nar/gkw852 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EO3DY UT WOS:000396576300004 PM 27694310 ER PT J AU Peppercorn, J AF Peppercorn, Jeffrey TI Financial Toxicity and Societal Costs of Cancer Care: Distinct Problems Require Distinct Solutions SO ONCOLOGIST LA English DT Editorial Material ID CLINICAL ONCOLOGY; AMERICAN SOCIETY; UNITED-STATES; CHEMOTHERAPY; EXPERIENCE; BURDEN C1 [Peppercorn, Jeffrey] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. RP Peppercorn, J (reprint author), Massachusetts Gen Hosp, Canc Survivorship Program, 55 Fruit St, Boston, MA 02114 USA. EM jpeppercorn@mgh.harvard.edu FU Greenwall Foundation FX This work was supported by a grant from The Greenwall Foundation. NR 27 TC 0 Z9 0 U1 0 U2 0 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1083-7159 EI 1549-490X J9 ONCOLOGIST JI Oncologist PY 2017 VL 22 IS 2 BP 123 EP 125 DI 10.1634/theoncologist.2016-0301 PG 3 WC Oncology SC Oncology GA EM9XC UT WOS:000395663800001 PM 28167570 ER PT J AU Ter-Minassian, M Zhang, S Brooks, NV Brais, LK Chan, JA Christiani, DC Lin, XH Gabriel, S Dinet, J Kulke, MH AF Ter-Minassian, Monica Zhang, Sui Brooks, Nichole V. Brais, Lauren K. Chan, Jennifer A. Christiani, David C. Lin, Xihong Gabriel, Sylvie Dinet, Jerome Kulke, Matthew H. TI Association Between Tumor Progression Endpoints and Overall Survival in Patients with Advanced Neuroendocrine Tumors SO ONCOLOGIST LA English DT Article DE Neuroendocrine tumors; Somatostatin analogs; Progression-free survival; Overall survival; Landmark analysis ID METASTATIC COLORECTAL-CANCER; 1ST-LINE CHEMOTHERAPY; TRIAL-LEVEL; SURROGATE; EVEROLIMUS; THERAPIES; DATABASE; PHASE-3; LUNG AB Endpoints related to tumor progression are commonly used in clinical trials of novel therapeutic agents for neuroendocrine tumors (NETs). Whether improved tumor control translates into improved overall survival (OS), however, is uncertain. We assessed associations between tumor progression endpoints and OS in observational cohorts of patients with advanced neuroendocrine tumors treated with somatostatin analogs or with everolimus. We identified 440 patients with advanced NET who had received treatment with single-agent somatostatin analogs and 109 patients treated with everolimus, all of whom were treated at our institution and were evaluable for both tumor progression and survival. We assessed associations between progression-free survival (PFS) and OS by using the Kendall tau test, and we assessed associations between tumor progression and OS by using a landmark analysis. In the 440 patients treated with somatostatin analogs, we observed a significant correlation between PFS and OS by using the Kendall tau test (0.31; p<.0001). Additionally, the development of progressive disease was associated with OS in a landmark analysis, at landmark times of 6, 12, 18, and 24 months. In the 109 patients treated with everolimus, we similarly observed a significant correlation between PFS and OS by using the Kendall tau test (0.44; p<.0001) and associations between progressive disease and OS by using a landmark analysis at 3, 6, and 12 months. In these observational cohorts of patients with metastatic NET treated with single-agent somatostatin analogs or everolimus, longer times to disease progression and longer PFS were both associated with improved OS. Our findings support the continued use of disease progression endpoints in NET clinical trials. C1 [Ter-Minassian, Monica; Zhang, Sui; Brooks, Nichole V.; Brais, Lauren K.; Chan, Jennifer A.; Kulke, Matthew H.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Ter-Minassian, Monica; Christiani, David C.] Harvard Sch Publ Hlth, Dept Environm Hlth, Boston, MA USA. [Lin, Xihong] Harvard Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Gabriel, Sylvie; Dinet, Jerome] Ipsen Pharma, Boulogne, France. [Ter-Minassian, Monica] Kaiser Permanente, Rockville, MD USA. RP Kulke, MH (reprint author), Dana Farber Canc Inst, D1220,450 Brookline Ave, Boston, MA 02215 USA. EM matthew_kulke@dfci.harvard.edu FU Gitta and Saul Kurlat Fund for Neuroendocrine Tumor Research; Jane Dybowski Fund for Neuroendocrine Cancer; McIntyre Family Fund for Neuroendocrine Tumor Research; Lipson Family Fund; Goldhirsh-Yellin Foundation Fund for Neuroendocrine Tumor Research; Murphy Family Fund for Carcinoid Tumor Research; Caring for Carcinoid Foundation; Ipsen Pharmaceuticals; U.S. National Institutes of Health [R01 CA151532] FX We are grateful for support from the Gitta and Saul Kurlat Fund for Neuroendocrine Tumor Research, Jane Dybowski Fund for Neuroendocrine Cancer, McIntyre Family Fund for Neuroendocrine Tumor Research, Lipson Family Fund, Goldhirsh-Yellin Foundation Fund for Neuroendocrine Tumor Research, the Murphy Family Fund for Carcinoid Tumor Research, and the Caring for Carcinoid Foundation. This study was funded in part with a grant from Ipsen Pharmaceuticals. This work was also supported by U.S. National Institutes of Health Grant R01 CA151532 to M.H.K. The abstract was submitted for presentation and accepted for publication at the 2015 American Society of Clinical Oncology annual meeting in Chicago, Illinois. NR 26 TC 0 Z9 0 U1 0 U2 0 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1083-7159 EI 1549-490X J9 ONCOLOGIST JI Oncologist PY 2017 VL 22 IS 2 BP 165 EP 172 DI 10.1634/theoncologist.2016-0175 PG 8 WC Oncology SC Oncology GA EM9XC UT WOS:000395663800009 PM 28179574 ER PT J AU Selt, F Hohloch, J Hielscher, T Sahm, F Capper, D Korshunov, A Usta, D Brabetz, S Ridinger, J Ecker, J Oehme, I Gronych, J Marquardt, V Pauck, D Bachli, H Stiles, CD von Deimling, A Remke, M Schuhmann, MU Pfister, SM Brummer, T Jones, DTW Witt, O Milde, T AF Selt, Florian Hohloch, Juliane Hielscher, Thomas Sahm, Felix Capper, David Korshunov, Andrey Usta, Diren Brabetz, Sebastian Ridinger, Johannes Ecker, Jonas Oehme, Ina Gronych, Jan Marquardt, Viktoria Pauck, David Baechli, Heidi Stiles, Charles D. von Deimling, Andreas Remke, Marc Schuhmann, Martin U. Pfister, Stefan M. Brummer, Tilman Jones, David T. W. Witt, Olaf Milde, Till TI Establishment and application of a novel patient-derived KIAA1549: BRAF-driven pediatric pilocytic astrocytoma model for preclinical drug testing SO ONCOTARGET LA English DT Article DE pediatric low grade glioma; pilocytic astrocytoma; KIAA1549: BRAF-fusion; oncogene-induced senescence (OIS); MAPK-inhibitors ID ONCOGENE-INDUCED SENESCENCE; LOW-GRADE GLIOMAS; MAPK PATHWAY ACTIVATION; NORMAL HUMAN-CELLS; IN-VIVO; ACQUIRED-RESISTANCE; TELOMERASE ACTIVITY; INHIBITOR TAK-632; LINEAR-MODELS; TUMOR-ANTIGEN AB Pilocytic astrocytoma (PA) is the most frequent pediatric brain tumor. Activation of the MAPK pathway is well established as the oncogenic driver of the disease. It is most frequently caused by KIAA1549: BRAF fusions, and leads to oncogene induced senescence (OIS). OIS is thought to be a major reason for growth arrest of PA cells in vitro and in vivo, preventing establishment of PA cultures. Hence, valid preclinical models are currently very limited, but preclinical testing of new compounds is urgently needed. We transduced the PA short-term culture DKFZ-BT66 derived from the PA of a 2-year old patient with a doxycycline-inducible system coding for Simian Vacuolating Virus 40 Large T Antigen (SV40-TAg). SV40-TAg inhibits TP53/CDKN1A and CDKN2A/RB1, two pathways critical for OIS induction and maintenance. DNA methylation array and KIAA1549: BRAF fusion analysis confirmed pilocytic astrocytoma identity of DKFZ-BT66 cells after establishment. Readouts were analyzed in proliferating as well as senescent states, including cell counts, viability, cell cycle analysis, expression of SV40-Tag, CDKN2A (p16), CDKN1A (p21), and TP53 (p53) protein, and geneexpression profiling. Selected MAPK inhibitors (MAPKi) including clinically available MEK inhibitors (MEKi) were tested in vitro. Expression of SV40-TAg enabled the cells to bypass OIS and to resume proliferation with a mean doubling time of 45h allowing for propagation and long-term culture. Withdrawal of doxycycline led to an immediate decrease of SV40-TAg expression, appearance of senescent morphology, upregulation of CDKI proteins and a subsequent G1 growth arrest in line with the re-induction of senescence. DKFZ-BT66 cells still underwent replicative senescence that was overcome by TERT expression. Testing of a set of MAPKi revealed differential responses in DKFZ-BT66. MEKi efficiently inhibited MAPK signaling at clinically achievable concentrations, while BRAF V600E-and RAF Type II inhibitors showed paradoxical activation. Taken together, we have established the first patient-derived long term expandable PA cell line expressing the KIAA1549: BRAF-fusion suitable for preclinical drug testing. C1 [Selt, Florian; Hohloch, Juliane; Usta, Diren; Ridinger, Johannes; Ecker, Jonas; Oehme, Ina; Witt, Olaf; Milde, Till] German Canc Res Ctr, Clin Cooperat Unit Pediat Oncol G340, Heidelberg, Germany. [Selt, Florian; Hohloch, Juliane; Usta, Diren; Brabetz, Sebastian; Ridinger, Johannes; Ecker, Jonas; Oehme, Ina; Gronych, Jan; Pfister, Stefan M.; Jones, David T. W.; Witt, Olaf; Milde, Till] German Canc Consortium DKTK, Heidelberg, Germany. [Selt, Florian; Ecker, Jonas; Pfister, Stefan M.; Witt, Olaf; Milde, Till] Univ Heidelberg Hosp, Dept Pediat Oncol Hematol & Immunol, Ctr Individualized Pediat Oncol ZIPO, Heidelberg, Germany. [Selt, Florian; Ecker, Jonas; Pfister, Stefan M.; Witt, Olaf; Milde, Till] Univ Heidelberg Hosp, Sect Pediat Brain Tumors, Heidelberg, Germany. [Hielscher, Thomas] German Canc Res Ctr, Div Biostat C060, Heidelberg, Germany. [Sahm, Felix; Capper, David; Korshunov, Andrey; von Deimling, Andreas] Univ Heidelberg Hosp, Dept Neuropathol, Heidelberg, Germany. [Sahm, Felix; Capper, David; Korshunov, Andrey; von Deimling, Andreas] German Canc Res Ctr, Clin Cooperat Unit Neuropathol G380, Heidelberg, Germany. [Sahm, Felix; Capper, David; Korshunov, Andrey; von Deimling, Andreas] German Canc Consortium DKTK, Heidelberg, Germany. [Brabetz, Sebastian; Pfister, Stefan M.; Jones, David T. W.] German Canc Res Ctr, Div Pediat Neurooncol B062, Heidelberg, Germany. [Gronych, Jan] German Canc Res Ctr, Div Mol Genet B060, Heidelberg, Germany. [Gronych, Jan] AbbVie Deutschland GmbH & Co KG, Med Immunol, Wiesbaden, Germany. [Marquardt, Viktoria; Pauck, David; Remke, Marc] Univ Hosp Dusseldorf, Fac Med, Dept Pediat Oncol Hematol & Clin Immunol, Dusseldorf, Germany. [Marquardt, Viktoria; Pauck, David; Remke, Marc] German Canc Consortium DKTK, Dept Pediat Neurooncogen, Heidelberg, Germany. [Marquardt, Viktoria; Pauck, David; Remke, Marc] German Canc Res Ctr, Heidelberg, Germany. [Baechli, Heidi] Univ Heidelberg Hosp, Dept Neurosurg, Heidelberg, Germany. [Stiles, Charles D.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Schuhmann, Martin U.] Univ Hosp Tubingen, Dept Neurosurg, Tubingen, Germany. [Brummer, Tilman] Albert Ludwigs Univ, Inst Mol Med & Cell Res, Freiburg, Germany. [Brummer, Tilman] Univ Med Ctr, Freiburg, Germany. RP Selt, F (reprint author), German Canc Res Ctr, Clin Cooperat Unit Pediat Oncol G340, Heidelberg, Germany.; Selt, F (reprint author), German Canc Consortium DKTK, Heidelberg, Germany.; Selt, F (reprint author), Univ Heidelberg Hosp, Dept Pediat Oncol Hematol & Immunol, Ctr Individualized Pediat Oncol ZIPO, Heidelberg, Germany.; Selt, F (reprint author), Univ Heidelberg Hosp, Sect Pediat Brain Tumors, Heidelberg, Germany. EM f.selt@dkfz.de RI von Deimling, Andreas/F-7774-2013; Brummer, Tilman/B-6218-2016 OI von Deimling, Andreas/0000-0002-5863-540X; Brummer, Tilman/0000-0003-4387-7905 FU A Kids' Brain Tumor Cure (PLGA) Foundation; Verein fur krebskranke Kinder Odenwald; Deutsche Forschungsgemeinschaft (DFG) [W1461/4-1, Oe542/2-1]; H.W. & J. Hector foundation [M71]; Dr. Mildred Scheel Foundation for Cancer Research; Kind-Philipp Stiftung; Dusseldorf School of Oncology (Medical Faculty, Heinrich-Heine University); DFG; Centre for Biological Signalling Studies BIOSS FX This study was funded by A Kids' Brain Tumor Cure (PLGA) Foundation (SP, DJ, AvD, OW), and the "Verein fur krebskranke Kinder Odenwald" (OW). OW (W1461/4-1) and IO (Oe542/2-1) are funded by the Deutsche Forschungsgemeinschaft (DFG). IO is supported by H.W. & J. Hector foundation (#M71). JG was supported by the Dr. Mildred Scheel Foundation for Cancer Research. MR together with DP or VM are funded by the Kind-Philipp Stiftung and the Dusseldorf School of Oncology (Medical Faculty, Heinrich-Heine University), respectively. TB is supported by the DFG via the Heisenberg program and the Centre for Biological Signalling Studies BIOSS. NR 68 TC 0 Z9 0 U1 0 U2 0 PU IMPACT JOURNALS LLC PI ORCHARD PARK PA 6666 E QUAKER ST, STE 1, ORCHARD PARK, NY 14127 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PY 2017 VL 8 IS 7 BP 11460 EP 11479 DI 10.18632/oncotarget.14004 PG 20 WC Oncology; Cell Biology SC Oncology; Cell Biology GA EK8QB UT WOS:000394187400067 ER PT J AU McNamara, A Geng, C Turner, R Mendez, JR Perl, J Held, K Faddegon, B Paganetti, H Schuemann, J AF McNamara, Aimee Geng, Changran Turner, Robert Mendez, Jose Ramos Perl, Joseph Held, Kathryn Faddegon, Bruce Paganetti, Harald Schuemann, Jan TI Validation of the radiobiology toolkit TOPAS-nBio in simple DNA geometries SO PHYSICA MEDICA-EUROPEAN JOURNAL OF MEDICAL PHYSICS LA English DT Article DE Monte Carlo simulation; Track structure; DNA strand break; Validation ID MONTE-CARLO-SIMULATION; TRACK STRUCTURE CODE; LIQUID WATER; GEANT4-DNA; ELECTRONS; ENERGY; DAMAGE; DISTRIBUTIONS; MITOCHONDRIA; IRRADIATION AB Computational simulations offer a powerful tool for quantitatively investigating radiation interactions with biological tissue and can help bridge the gap between physics, chemistry and biology. The TOPAS collaboration is tackling this challenge by extending the current Monte Carlo tool to allow for subcellular in silico simulations in a new extension, TOPAS-nBio. TOPAS wraps and extends the Geant4 Monte Carlo simulation toolkit and the new extension allows the modeling of particles down to vibrational energies (similar to 2 eV) within realistic biological geometries. Here we present a validation of biological geometries available in TOPAS-nBio, by comparing our results to two previously published studies. We compare the prediction of strand breaks in a simple linear DNA strand from TOPAS-nBio to a published Monte Carlo track structure simulation study. While TOPAS-nBio confirms the trend in strand break generation, it predicts a higher frequency of events below an energy of 17.5 eV compared to the alternative Monte Carlo track structure study. This is due to differences in the physics models used by each code. We also compare the experimental measurement of strand breaks from incident protons in DNA plasmids to TOPAS-nBio simulations. Our results show good agreement of single and double strand breaks predicting a similar increase in the strand break yield with increasing LET. (C) 2016 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved. C1 [McNamara, Aimee; Geng, Changran; Held, Kathryn; Paganetti, Harald; Schuemann, Jan] Massachusetts Gen Hosp, Boston, MA 02114 USA. [McNamara, Aimee; Geng, Changran; Held, Kathryn; Paganetti, Harald; Schuemann, Jan] Harvard Med Sch, Boston, MA 02115 USA. [Turner, Robert] Univ Tennessee, Knoxville, TN USA. [Perl, Joseph] SLAC Natl Accelerator Lab, Menlo Pk, CA USA. [Mendez, Jose Ramos; Faddegon, Bruce] Univ Calif San Francisco, Ctr Comprehens Canc, San Francisco, CA 94143 USA. RP McNamara, A (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA.; McNamara, A (reprint author), Harvard Med Sch, Boston, MA 02115 USA. EM amcnamara2@mgh.harvard.edu RI McNamara, Aimee/C-9432-2009 OI McNamara, Aimee/0000-0001-8792-0464 FU National Institutes of Health (NIH)/National Cancer Institute (NCI) grant [R01 CA187003] FX This work was supported by the National Institutes of Health (NIH)/National Cancer Institute (NCI) grant R01 CA187003. The authors wish to thank Dudley Goodhead, Katerina P Brabcova and Vaclav Stepen for helpful discussions concerning the study. NR 36 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1120-1797 EI 1724-191X J9 PHYS MEDICA JI Phys. Medica PD JAN PY 2017 VL 33 BP 207 EP 215 DI 10.1016/j.ejmp.2016.12.010 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA EM5RP UT WOS:000395370400024 PM 28017738 ER PT J AU Lutz, S Balboni, T Jones, J Lo, S Petit, J Rich, SE Wong, R Hahn, C AF Lutz, Stephen Balboni, Tracy Jones, Joshua Lo, Simon Petit, Joshua Rich, Shayna E. Wong, Rebecca Hahn, Carol TI Palliative radiation therapy for bone metastases: Update of an ASTRO Evidence-Based Guideline SO PRACTICAL RADIATION ONCOLOGY LA English DT Article ID RESISTANT PROSTATE-CANCER; CLINICAL-PRACTICE GUIDELINES; SPINAL-CORD COMPRESSION; ADVANCED BREAST-CANCER; RANDOMIZED-TRIAL; DOUBLE-BLIND; ZOLEDRONIC ACID; RADIUM-223 CHLORIDE; SINGLE-FRACTION; PHASE-II AB Purpose: The purpose is to provide an update the Bone Metastases Guideline published in 2011 based on evidence complemented by expert opinion. The update will discuss new high-quality literature for the 8 key questions from the original guideline and implications for practice. Methods and materials: A systematic PubMed search from the last date included in the original Guideline yielded 414 relevant articles. Ultimately, 20 randomized controlled trials, 32 prospective nonrandomized studies, and 4meta-analyses/pooled analyses were selected and abstracted into evidence tables. The authors synthesized the evidence and reached consensus on the included recommendations. Results: Available literature continues to support pain relief equivalency between single and multiple fraction regimens for bone metastases. High-quality data confirmsingle fraction radiation therapy may be delivered to spine lesions with acceptable late toxicity. One prospective, randomized trial confirms both peripheral and spine-based painful metastases can be successfully and safely palliated with retreatment for recurrence pain with adherence to published dosing constraints. Advanced radiation therapy techniques such as stereotactic body radiation therapy lack high-quality data, leading the panel to favor its use on a clinical trial or when results will be collected in a registry. The panel's conclusion remains that surgery, radionuclides, bisphosphonates, and kyphoplasty/vertebroplasty do not obviate the need for external beam radiation therapy. Conclusion: Updated data analysis confirms that radiation therapy provides excellent palliation for painful bone metastases and that retreatment is safe and effective. Although adherence to evidence-based medicine is critical, thorough expert radiation oncology physician judgment and discretion regarding number of fractions and advanced techniques are also essential to optimize outcomes when considering the patient's overall health, life expectancy, comorbidities, tumor biology, anatomy, previous treatment including prior radiation at or near current site of treatment, tumor and normal tissue response history to local and systemic therapies, and other factors related to the patient, tumor characteristics, or treatment. (C) 2016 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved. C1 [Lutz, Stephen] Eastern Woods Radiat Oncol, Dept Radiat Oncol, 15990 Med Dr South, Findlay, OH 45840 USA. [Balboni, Tracy] Brigham & Womens Hosp, Dept Radiat Oncol, Boston, MA USA. [Balboni, Tracy] Brigham & Womens Hosp, Dept Psychosocial Oncol & Palliat Care, Boston, MA USA. [Balboni, Tracy] Dana Farber Canc Inst, Boston, MA 02115 USA. [Jones, Joshua] Univ Penn Hlth Syst, Dept Radiat Oncol, Philadelphia, PA USA. [Lo, Simon] Univ Washington, Sch Med, Dept Radiat Oncol, Seattle, WA 98195 USA. [Petit, Joshua] Univ Colorado Hlth, Dept Radiat Oncol, Ft Collins, CO USA. [Rich, Shayna E.] Mayo Clin, Coll Med, Hosp & Palliat Med, Jacksonville, FL USA. [Wong, Rebecca] Princess Margaret Hosp, Dept Radiat Oncol, Toronto, ON, Canada. [Hahn, Carol] Duke Univ, Med Ctr, Dept Radiat Oncol, Durham, NC USA. RP Lutz, S (reprint author), Eastern Woods Radiat Oncol, 15990 Med Dr South, Findlay, OH 45840 USA. EM slutz@bvhealthsystem.org FU Templeton Foundation; Elekta FX Before initiating work on this guideline, all panelists completed disclosure statements and pertinent disclosures are published within this report. Where potential conflicts are detected, remedial measures to address them are taken and noted here. TB received research funding from Templeton Foundation and leads ongoing bone metastases study. S.Lo. participated in international oligometastases consortium partially funded by Elekta and received honoraria and travel expenses from Accuray and Varian. These disclosures were shared with the panel. The panel and guideline subcommittee chair reviewed these relationships and determined that the disclosure here is sufficient to manage potential conflicts. NR 39 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 1879-8500 J9 PRACT RADIAT ONCOL JI Pract. Radiat. Oncol. PD JAN-FEB PY 2017 VL 7 IS 1 BP 4 EP 12 DI 10.1016/j.prro.2016.08.001 PG 9 WC Oncology SC Oncology GA EO0NY UT WOS:000396396100017 PM 27663933 ER PT J AU Le Cook, B Trinh, NH Li, ZH Hou, SSY Progovac, AM AF Le Cook, Benjamin Nhi-Ha Trinh Li, Zhihui Hou, Sherry Shu-Yeu Progovac, Ana M. TI Trends in Racial-Ethnic Disparities in Access to Mental Health Care, 2004-2012 SO PSYCHIATRIC SERVICES LA English DT Article ID UNITED-STATES; AFRICAN-AMERICANS; CONTROLLED-TRIAL; ASIAN-AMERICANS; RACE-ETHNICITY; SERVICES; DEPRESSION; ATTITUDES; GENDER; RISK AB Objective: This study compared trends in racial-ethnic disparities in mental health care access among whites, blacks, Hispanics, and Asians by using the Institute of Medicine definition of disparities as all differences except those due to clinical appropriateness, clinical need, and patient preferences. Methods: Racial-ethnic disparities in mental health care access were examined by using data from a nationally representative sample of 214,597 adults from the 2004-2012 Medical Expenditure Panel Surveys. The main outcome measures included three mental health care access measures (use of any mental health care, any outpatient care, and any psychotropic medication in the past year). Results: Significant disparities were found in 2004-2005 and in 2011-2012 for all three racial-ethnic minority groups compared with whites in all three measures of access. Between 2004 and 2012, black-white disparities in any mental health care and any psychotropic medication use increased, respectively, from 8.2% to 10.8% and from 7.6% to 10.0%. Similarly, Hispanic-white disparities in any mental health care and any psychotropic medication use increased, respectively, from 8.4% to 10.9% and 7.3% to 10.3%. Conclusions: No reductions in racial-ethnic disparities in access to mental health care were identified between 2004 and 2012. For blacks and Hispanics, disparities were exacerbated over this period. Clinical interventions that improve identification of symptoms of mental illness, expansion of health insurance, and other policy interventions that remove financial barriers to access may help to reduce these disparities. C1 [Le Cook, Benjamin] Harvard Med Sch, Dept Psychiat, Boston, MA 02115 USA. [Le Cook, Benjamin; Hou, Sherry Shu-Yeu; Progovac, Ana M.] Cambridge Hlth Alliance, Ctr Multicultural Mental Hlth Res, Cambridge, MA USA. [Progovac, Ana M.] Harvard Med Sch, Dept Hlth Care Policy, Boston, MA USA. [Nhi-Ha Trinh] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Li, Zhihui] Harvard Sch Publ Hlth, Dept Global Hlth & Populat, Boston, MA USA. RP Le Cook, B (reprint author), Harvard Med Sch, Dept Psychiat, Boston, MA 02115 USA. EM bcook@cha.harvard.edu FU Agency for Healthcare Research and Quality [R01 HS021486]; National Institute of Mental Health [T32 MH019733] FX This research was supported by the Agency for Healthcare Research and Quality (R01 HS021486 PI Cook) and the National Institute of Mental Health (T32 MH019733). The content is solely the responsibility of the authors and does not necessarily represent the official views of the Agency for Healthcare Research and Quality or the National Institutes of Health. NR 62 TC 0 Z9 0 U1 0 U2 0 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 1075-2730 EI 1557-9700 J9 PSYCHIAT SERV JI Psychiatr. Serv. PD JAN 1 PY 2017 VL 68 IS 1 BP 9 EP 16 DI 10.1176/appi.ps.201500453 PG 8 WC Health Policy & Services; Public, Environmental & Occupational Health; Psychiatry SC Health Care Sciences & Services; Public, Environmental & Occupational Health; Psychiatry GA EP0PQ UT WOS:000397089600004 ER PT J AU Lillemoe, KD AF Lillemoe, Keith D. TI Invited Commentary on "Tumor-Vessel Relationships in Pancreatic Ductal Adenocarcinoma at Multidetector CT," with Response from Dr Zaky and Colleagues SO RADIOGRAPHICS LA English DT Editorial Material ID CANCER; FOLFIRINOX C1 [Lillemoe, Keith D.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Surg, Boston, MA 02115 USA. RP Lillemoe, KD (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Dept Surg, Boston, MA 02115 USA. NR 7 TC 0 Z9 0 U1 0 U2 0 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0271-5333 J9 RADIOGRAPHICS JI Radiographics PD JAN-FEB PY 2017 VL 37 IS 1 BP 113 EP 114 DI 10.1148/rg.2017160205 PG 2 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA EP2HY UT WOS:000397205200008 PM 28076018 ER PT J AU Lewis, RC Minguez-Alarcon, L Meeker, JD Williams, PL Mezei, G Ford, JB Hauser, R AF Lewis, Ryan C. Minguez-Alarcon, Lidia Meeker, John D. Williams, Paige L. Mezei, Gabor Ford, Jennifer B. Hauser, Russ CA EARTH Study Team TI Self-reported mobile phone use and semen parameters among men from a fertility clinic SO REPRODUCTIVE TOXICOLOGY LA English DT Article DE Mobile phones; Electromagnetic fields; Semen quality; Reproductive health; Epidemiology Longitudinal studies ID SPERM DNA-DAMAGE; URINARY BISPHENOL-A; CELL PHONE; TESTOSTERONE LEVELS; TESTICULAR FUNCTION; HEALTHY-MEN; QUALITY; EXPOSURE; RATS; METAANALYSIS AB There is increasing concern that use of mobile phones, a source of low-level radio-frequency electromagnetic fields, may be associated with poor semen quality, but the epidemiologic evidence is limited and conflicting. The relationship between mobile phone use patterns and markers of semen quality was explored in a longitudinal cohort study of 153 men that attended an academic fertility clinic in Boston, Massachusetts. Information on mobile phone use duration, headset or earpiece use, and the body location in which the mobile phone was carried was ascertained via nurse -administered questionnaire. Semen samples (n = 350) were collected and analyzed onsite. To account for multiple semen samples per man, linear mixed models with random intercepts were used to investigate the association between mobile phone use and semen parameters. Overall, there was no evidence for a relationship between mobile phone use and semen quality.(C) 2016 Elsevier Inc. All rights reserved. C1 [Lewis, Ryan C.] Exponent Inc, Ctr Hlth Sci, 475 14th St,Suite 400, Oakland, CA 94612 USA. [Minguez-Alarcon, Lidia; Ford, Jennifer B.; Hauser, Russ] Harvard TH Chan Sch Publ Hlth, Dept Environm Hlth, 665 Huntington Ave, Boston, MA 02115 USA. [Meeker, John D.] Univ Michigan, Sch Publ Hlth, Dept Environm Hlth Sci, 1415 Washington Hts, Ann Arbor, MI 48109 USA. [Williams, Paige L.] Harvard TH Chan Sch Publ Hlth, Dept Biostat, 665 Huntington Ave, Boston, MA 02115 USA. [Williams, Paige L.; Hauser, Russ] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, 665 Huntington Ave, Boston, MA 02115 USA. [Mezei, Gabor] Exponent Inc, Ctr Hlth Sci, 149 Commonwealth Dr, Menlo Pk, CA 94025 USA. [Hauser, Russ; EARTH Study Team] Massachusetts Gen Hosp, Vincent Mem Obstet & Gynecol Serv, 55 Fruit St, Boston, MA 02114 USA. RP Lewis, RC (reprint author), Exponent Inc, Ctr Hlth Sci, 475 14th St,Suite 400, Oakland, CA 94612 USA. EM rlewis@exponent.com FU National Institute of Environmental Health Sciences, National Institutes of Health [R01 ES009718]; Electric Power Research Institute [1-SP0239] FX This research was supported by grant R01 ES009718 from the National Institute of Environmental Health Sciences, National Institutes of Health, and project 1-SP0239 from the Electric Power Research Institute. The authors also acknowledge all other members of the EARTH team, specifically Ramace Dadd, Myra Keller, and Patricia Morey at the Harvard T.H. Chan School of Public Health and physicians and staff at MGH, and especially thank all of the study participants. NR 42 TC 0 Z9 0 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0890-6238 J9 REPROD TOXICOL JI Reprod. Toxicol. PD JAN PY 2017 VL 67 BP 42 EP 47 DI 10.1016/j.reProtox.2016.11.008 PG 6 WC Reproductive Biology; Toxicology SC Reproductive Biology; Toxicology GA EK8SV UT WOS:000394195700006 PM 27838386 ER PT J AU Dudzinski, DM Horowitz, JM AF Dudzinski, David M. Horowitz, James M. TI Start-up, Organization and Performance of a Multidisciplinary Pulmonary Embolism Response Team for the Diagnosis and Treatment of Acute Pulmonary Embolism SO REVISTA ESPANOLA DE CARDIOLOGIA LA Spanish DT Editorial Material ID MANAGEMENT; GUIDELINES; CARE; VTE C1 [Dudzinski, David M.] Massachusetts Gen Hosp, Div Cardiovasc, Pulm Embolism Response Team, Cardiac Intens Care Unit, Boston, MA 02115 USA. [Dudzinski, David M.] Massachusetts Gen Hosp, Dept Echocardiog, Boston, MA 02115 USA. [Dudzinski, David M.] Massachusetts Gen Hosp, Dept Crit Care, Boston, MA 02115 USA. [Horowitz, James M.] Weill Cornell Med Ctr, New York Presbyterian Hosp, Pulm Embolism Adv Care Team, Cardiac Intens Care Unit,Cardiol Div, New York, NY USA. RP Dudzinski, DM (reprint author), Massachusetts Gen Hosp, Div Cardiovasc, Pulm Embolism Response Team, Cardiac Intens Care Unit, Boston, MA 02115 USA.; Dudzinski, DM (reprint author), Massachusetts Gen Hosp, Dept Echocardiog, Boston, MA 02115 USA.; Dudzinski, DM (reprint author), Massachusetts Gen Hosp, Dept Crit Care, Boston, MA 02115 USA. EM ddudzinski@partners.org NR 16 TC 1 Z9 1 U1 0 U2 0 PU EDICIONES DOYMA S A PI BARCELONA PA TRAV DE GRACIA 17-21, 08021 BARCELONA, SPAIN SN 0300-8932 EI 1579-2242 J9 REV ESP CARDIOL JI Rev. Esp. Cardiol. PD JAN PY 2017 VL 70 IS 1 BP 9 EP 13 DI 10.1016/j.recesp.2016.05.028 PG 5 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EO2CG UT WOS:000396503600005 PM 27567494 ER PT J AU Singh, JA Bharat, A Khanna, D Aquino-Beaton, C Persselin, JE Duffy, E Elashoff, D Khanna, PP AF Singh, Jasvinder A. Bharat, Aseem Khanna, Dinesh Aquino-Beaton, Cleopatra Persselin, Jay E. Duffy, Erin Elashoff, David Khanna, Puja P. TI Racial differences in health-related quality of life and functional ability in patients with gout SO RHEUMATOLOGY LA English DT Article DE health-related quality of life; HRQOL; function; gout; race; disparity; racial ID RHEUMATOID-ARTHRITIS; ASSESSMENT QUESTIONNAIRE; RESOURCE USE; VETERANS-AFFAIRS; LOWERING THERAPY; CONTROLLED-TRIAL; OLDER-ADULTS; HYPERURICEMIA; HYPERTENSION; METHOTREXATE AB Objective. To compare the health-related quality of life (HRQOL) and the functional ability by race in patients with gout. Methods. In a 9-month prospective cohort multicentre study, patients with gout self-reported race, dichotomized as Caucasian or African American (others excluded). We calculated HRQOL/function scores adjusted for age, study site and college education for Short Form-36 (SF-36; generic HRQOL), Gout Impact Scale (GIS; disease-specific HRQOL) and HAQ-disability index (HAQ-DI; functional ability). Longitudinally adjusted scores were computed using multivariable mixed-effect regression models with a random patient effect and fixed sequential visit effect (3-monthly visits). Results. Compared with Caucasians (n = 107), African Americans (n = 60) with gout were younger (61.1 vs 67.3 years) and had higher median baseline serum urate (9.0 vs 7.9 mg/dl) (P < 0.01). African Americans with gout had worse HRQOL scores on three SF-36 domains, the mental component summary (MCS) and two of the five GIS scales than Caucasians [mean (S.E.); P <= 0.02 for all]: SF-36 mental health, 39.7 (1.1) vs 45.2 (0.9); SF-36 role emotional, 42.1 (4.2) vs 51.4 (4.2); SF-36 social functioning, 36.0 (1.1) vs 40.0 (0.9) (P = 0.04); SF-36 MCS, 43.2 (3.1) vs 50.0 (3.2); GIS unmet treatment need, 37.6 (1.6) vs 31.5 (1.4); and GIS concern during attacks, 53.3 (3.7) vs 47.4 (3.7). Differences between the respective HAQ-DI total scores were not statistically significant; 0.98 (0.1) vs 0.80 (1.0) (P = 0.11). Racial differences in SF-36 mental health, role emotional and MCS scales exceeded, and for HAQ-DI approached, the minimal clinically important difference thresholds. Conclusions. African Americans with gout have significantly worse HRQOL compared with Caucasians. Further research is necessary in the form of studies targeted at African Americans on how best to improve these outcomes. C1 [Singh, Jasvinder A.] Univ Alabama Birmingham, Birmingham VA Med Ctr, Med Serv, Birmingham, AL 35294 USA. [Singh, Jasvinder A.; Bharat, Aseem] Univ Alabama Birmingham, Sch Med, Dept Med, Birmingham, AL 35294 USA. [Singh, Jasvinder A.; Bharat, Aseem] Univ Alabama Birmingham, Sch Publ Hlth, Div Epidemiol, Birmingham, AL 35294 USA. [Singh, Jasvinder A.] Mayo Clin, Coll Med, Dept Orthoped Surg, Rochester, MN USA. [Khanna, Dinesh; Khanna, Puja P.] Univ Michigan, Dept Med, Ann Arbor, MI 48109 USA. [Aquino-Beaton, Cleopatra; Persselin, Jay E.] VA Greater Los Angeles Healthcare Syst, Dept Biostat, Los Angeles, CA USA. [Duffy, Erin; Elashoff, David] Univ Calif Los Angeles, Dept Med, Los Angeles, CA 90024 USA. [Khanna, Puja P.] VA Ann Arbor Healthcare Syst, Dept Med, Ann Arbor, MI USA. RP Singh, JA (reprint author), Univ Alabama Birmingham, Fac Off Tower 805B,510 20th St S, Birmingham, AL 35294 USA. EM Jasvinder.md@gmail.com FU Savient Pharmaceuticals Inc. FX This study was sponsored in part by an investigator-initiated study from Savient Pharmaceuticals Inc. NR 43 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1462-0324 EI 1462-0332 J9 RHEUMATOLOGY JI RHEUMATOLOGY PD JAN PY 2017 VL 56 IS 1 BP 103 EP 112 DI 10.1093/rheumatology/kew356 PG 10 WC Rheumatology SC Rheumatology GA EP0AN UT WOS:000397049300014 PM 28028159 ER PT J AU Barrett, LF AF Barrett, Lisa Feldman TI The theory of constructed emotion: an active inference account of interoception and categorization SO SOCIAL COGNITIVE AND AFFECTIVE NEUROSCIENCE LA English DT Article DE emotion; predictive coding; construction; interoception; categorization; concepts; affect ID THALAMIC RETICULAR NUCLEUS; CLASSICAL RECEPTIVE-FIELD; BILATERAL AMYGDALA DAMAGE; LARGE-SCALE BRAIN; PREFRONTAL CORTEX; FUNCTIONAL CONNECTIVITY; DECISION-MAKING; BASIC EMOTIONS; PSYCHOLOGICAL CONSTRUCTION; BASOLATERAL AMYGDALA AB The science of emotion has been using folk psychology categories derived from philosophy to search for the brain basis of emotion. The last two decades of neuroscience research have brought us to the brink of a paradigm shift in understanding the workings of the brain, however, setting the stage to revolutionize our understanding of what emotions are and how they work. In this article, we begin with the structure and function of the brain, and from there deduce what the biological basis of emotions might be. The answer is a brain-based, computational account called the theory of constructed emotion. C1 [Barrett, Lisa Feldman] Northeastern Univ, Dept Psychol, Boston, MA 02115 USA. [Barrett, Lisa Feldman] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Barrett, Lisa Feldman] Massachusetts Gen Hosp, Psychiat Neuroimaging Div, Dept Psychiat, Charlestown, MA USA. [Barrett, Lisa Feldman] Harvard Med Sch, Charlestown, MA USA. RP Barrett, LF (reprint author), Northeastern Univ, Dept Psychol, Boston, MA 02115 USA. EM l.barrett@neu.edu FU National Institute on Aging [R01 AG030311]; National Cancer Institute [U01 CA193632]; National Science Foundation [CMMI 1638234]; US Army Research Institute for the Behavioral and Social Sciences [W911NF-15-1-0647, W911NF-16-1-0191] FX This article was prepared with support from the National Institute on Aging (R01 AG030311), the National Cancer Institute (U01 CA193632), the National Science Foundation (CMMI 1638234) and the US Army Research Institute for the Behavioral and Social Sciences (W911NF-15-1-0647 and W911NF-16-1-0191). The views, opinions, and/or findings contained in this paper are those of the authors and shall not be construed as an official Department of the Army position, policy, or decision, unless so designated by other documents. NR 255 TC 0 Z9 0 U1 1 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1749-5016 EI 1749-5024 J9 SOC COGN AFFECT NEUR JI Soc. Cogn. Affect. Neurosci. PD JAN PY 2017 VL 12 IS 1 BP 1 EP 23 DI 10.1093/scan/nsw154 PG 23 WC Neurosciences; Psychology; Psychology, Experimental SC Neurosciences & Neurology; Psychology GA EO2CO UT WOS:000396504400001 ER PT J AU Barrett, LF AF Barrett, Lisa Feldman TI Functionalism cannot save the classical view of emotion SO SOCIAL COGNITIVE AND AFFECTIVE NEUROSCIENCE LA English DT Editorial Material C1 [Barrett, Lisa Feldman] Northeastern Univ, Dept Psychol, Boston, MA 02115 USA. [Barrett, Lisa Feldman] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Barrett, Lisa Feldman] Massachusetts Gen Hosp, Dept Psychiat, Psychiat Neuroimaging Div, Charlestown, MA 02129 USA. RP Barrett, LF (reprint author), Northeastern Univ, Dept Psychol, Boston, MA 02115 USA.; Barrett, LF (reprint author), Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA.; Barrett, LF (reprint author), Massachusetts Gen Hosp, Dept Psychiat, Psychiat Neuroimaging Div, Charlestown, MA 02129 USA. EM l.barrett@neu.edu FU National Institutes on Aging [R01 AG030311]; National Cancer Institute [U01 CA193632]; National Science Foundation [CMMI 1638234]; US Army Research Institute for the Behavioral and Social Sciences [W911NF-15-1-0647, W911NF-16-1-0191] FX This paper was prepared with support from the National Institutes on Aging (R01 AG030311), the National Cancer Institute (U01 CA193632), the National Science Foundation (CMMI 1638234) and the US Army Research Institute for the Behavioral and Social Sciences (W911NF-15-1-0647 and W911NF-16-1-0191). NR 10 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1749-5016 EI 1749-5024 J9 SOC COGN AFFECT NEUR JI Soc. Cogn. Affect. Neurosci. PD JAN PY 2017 VL 12 IS 1 BP 34 EP 36 DI 10.1093/scan/nsw156 PG 3 WC Neurosciences; Psychology; Psychology, Experimental SC Neurosciences & Neurology; Psychology GA EO2CO UT WOS:000396504400004 ER PT J AU Li, C Liu, SW Yan, RP Han, N Wong, KK Li, L AF Li, Chong Liu, Shengwu Yan, Ruping Han, Ning Wong, Kwok-Kin Li, Lei TI CD54-NOTCH1 axis controls tumor initiation and cancer stem cell functions in human prostate cancer SO THERANOSTICS LA English DT Article DE prostate cancer; CD54; cancer stem cells; NOTCH1 ID ADHESION MOLECULE-1; BREAST-CANCER; ENDOTHELIAL-CELLS; TARGETING NOTCH; GROWTH-FACTOR; SELF-RENEWAL; KAPPA-B; ICAM-1; PATHWAY; THERAPY AB Cancer stem cells (CSCs) are considered one of the key contributors to chemoresistance and tumor recurrence. Therefore, the precise identification of reliable CSC markers and clarification of the intracellular signaling involved in CSCs remains a great challenge in fields relating to cancer biology. Here, we implemented a novel chemoresistant prostate cancer patient-derived xenograft (PDX) model in NOD/SCID mice and identified CD54 as a candidate gene among the most highly enriched gene expression profiles in prostate tumors exposed to chronic cisplatin administration. Additional in vitro and in vivo assays showed that CD54 played a critical role in the self-renewal and tumorigenesis of prostate CSCs. Moreover, silencing CD54 greatly reduced the tumorigenesis of prostate cancers both in vitro and in vivo and significantly extended the survival time of tumor-bearing mice in a prostate cancer xenograft model. Dissection of the molecular mechanism revealed that the p38-Notch1 axis was the main downstream signaling pathway in CD54-mediated regulation of CSCs in prostate cancers. Together, these results established that CD54 could be a novel reliable prostate CSC marker and provided a new potential therapeutic target in prostate cancer via CD54-Notch1 signaling. C1 [Li, Chong; Li, Lei] Xi An Jiao Tong Univ, Dept Urol, Affiliated Hosp 1, Xian 710061, Peoples R China. [Li, Chong] Chinese Acad Sci, Inst Biophys, Core Facil Prot Res, Beijing 100101, Peoples R China. [Liu, Shengwu; Wong, Kwok-Kin] Harvard Med Sch, Dept Med, Boston, MA 02115 USA. [Yan, Ruping] Kunming Med Coll, Dept Urol, Affiliated Hosp 2, Kunming 650101, Peoples R China. [Liu, Shengwu; Wong, Kwok-Kin] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Han, Ning] China Pharmaceut Univ, Dept Life Sci & Technol, Nanjing 211198, Jiangsu, Peoples R China. [Li, Chong] Beijing Jianlan Inst Med, Beijing 100190, Peoples R China. RP Li, L (reprint author), Xi An Jiao Tong Univ, Dept Urol, Affiliated Hosp 1, Xian 710061, Peoples R China. EM lilydr@163.com FU National Natural Science Foundation of China [81672956, 81472413, 81130041, 81472679]; Shenzhen Science and Technology Development Funds Program [CXZZ20130516153248144]; Shenzhen Strategic Emerging Industry Development Special Funds Program [JSGG20130411091246833]; Major Program of Scientific Research Foundation from Yunnan Provincial Department of Education [2014Z052]; Science and Technology Program of Yunnan Province [2014RA067] FX This work was supported by the National Natural Science Foundation of China (81672956, 81472413, 81130041, 81472679), Shenzhen Science and Technology Development Funds Program (CXZZ20130516153248144); Shenzhen Strategic Emerging Industry Development Special Funds Program (JSGG20130411091246833); Major Program of Scientific Research Foundation from Yunnan Provincial Department of Education (2014Z052); Science and Technology Program of Yunnan Province (2014RA067). NR 53 TC 0 Z9 0 U1 0 U2 0 PU IVYSPRING INT PUBL PI LAKE HAVEN PA PO BOX 4546, LAKE HAVEN, NSW 2263, AUSTRALIA SN 1838-7640 J9 THERANOSTICS JI Theranostics PY 2017 VL 7 IS 1 BP 67 EP 80 DI 10.7150/thno.16752 PG 14 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EO2VK UT WOS:000396553900007 PM 28042317 ER PT J AU Shi, J Bei, YH Kong, XQ Liu, XJ Lei, ZY Xu, TZ Wang, H Xuan, QK Chen, P Xu, JH Che, L Liu, H Zhong, JC Sluijter, JPG Li, XL Rosenzweig, A Xiao, JJ AF Shi, Jing Bei, Yihua Kong, Xiangqing Liu, Xiaojun Lei, Zhiyong Xu, Tianzhao Wang, Hui Xuan, Qinkao Chen, Ping Xu, Jiahong Che, Lin Liu, Hui Zhong, Jiuchang Sluijter, Joost P. G. Li, Xinli Rosenzweig, Anthony Xiao, Junjie TI miR-17-3p Contributes to Exercise-Induced Cardiac Growth and Protects against Myocardial Ischemia Reperfusion Injury SO THERANOSTICS LA English DT Article DE Exercise; Cardiac growth; microRNA ID CARDIOMYOCYTE PROLIFERATION; HEART-FAILURE; HYPERTROPHY; MECHANISM; APOPTOSIS AB Limited microRNAs (miRNAs, miRs) have been reported to be necessary for exercise-induced cardiac growth and essential for protection against pathological cardiac remodeling. Here we determined members of the miR-17-92 cluster and their passenger miRNAs expressions in two distinct murine exercise models and found that miR-17-3p was increased in both. miR-17-3p promoted cardiomyocyte hypertrophy, proliferation, and survival. TIMP-3 was identified as a direct target gene of miR-17-3p whereas PTEN was indirectly inhibited by miR-17-3p. Inhibition of miR-17-3p in vivo attenuated exercise-induced cardiac growth including cardiomyocyte hypertrophy and expression of markers of myocyte proliferation. Importantly, mice injected with miR-17-3p agomir were protected from adverse remodeling after cardiac ischemia/reperfusion injury. Collectively, these data suggest that miR-17-3p contributes to exercise-induced cardiac growth and protects against adverse ventricular remodeling. miR-17-3p may represent a novel therapeutic target to promote functional recovery after cardiac ischemia/reperfusion. C1 [Shi, Jing; Kong, Xiangqing; Wang, Hui; Xuan, Qinkao; Liu, Hui; Li, Xinli] Nanjing Med Univ, Affiliated Hosp 1, Dept Cardiol, 300 Guangzhou Rd, Nanjing 210029, Jiangsu, Peoples R China. [Bei, Yihua; Xu, Tianzhao; Chen, Ping; Xiao, Junjie] Shanghai Univ, Sch Life Sci, Cardiac Regenerat & Ageing Lab, 333 Nan Chen Rd, Shanghai 200444, Peoples R China. [Liu, Xiaojun; Rosenzweig, Anthony] Massachusetts Gen Hosp, Div Cardiovasc, Boston, MA 02115 USA. [Liu, Xiaojun; Rosenzweig, Anthony] Harvard Med Sch, Boston, MA 02115 USA. [Lei, Zhiyong; Sluijter, Joost P. G.] Univ Med Ctr Utrecht, Lab Expt Cardiol, NL-3508 GA Utrecht, Netherlands. [Xu, Jiahong; Che, Lin] Tongji Univ, Tongji Hosp, Sch Med, Dept Cardiol, Shanghai 200065, Peoples R China. [Zhong, Jiuchang] Shanghai Jiao Tong Univ, Ruijin Hosp, Sch Med, State Key Lab Med Genom, Shanghai 200025, Peoples R China. [Zhong, Jiuchang] Shanghai Jiao Tong Univ, Ruijin Hosp, Sch Med, Shanghai Inst Hypertens, Shanghai 200025, Peoples R China. RP Kong, XQ (reprint author), Nanjing Med Univ, Affiliated Hosp 1, Dept Cardiol, 300 Guangzhou Rd, Nanjing 210029, Jiangsu, Peoples R China.; Xiao, JJ (reprint author), Shanghai Univ, Sch Life Sci, Cardiac Regenerat & Ageing Lab, 333 Nan Chen Rd, Shanghai 200444, Peoples R China. EM xiangqingkong_nj@163.com; junjiexiao@shu.edu.cn FU National Natural Science Foundation of China [81570362, 91639101, 81200169, 81370332, 81170201, 81400647, 81370362]; NIH [R21HL114352, 1UH2TR000901, R01HL110733]; Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD) [20102013]; Netherlands Cardiovascular Research Initiative (CVON); Dutch Heart Foundation, Dutch Federation of University Medical Centers; N