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; Netherlands Organization for Health Research and Development; Royal Netherlands Academy of Science; National Basic Research Program of China [2014CB542300]; National Major Research Plan Training Program [91339108]; Shanghai Municipal Education Commission-Gaofeng Clinical Medicine [20152509] FX This work was supported by the grants from National Natural Science Foundation of China (81570362, 91639101, and 81200169 to JJ Xiao, 81370332 and 81170201 to XL Li, 81400647 to Y Bei, 81370362 to JC Zhong), NIH (R21HL114352, 1UH2TR000901, R01HL110733 to A Rosenzweig), the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD20102013 to XL Li), the Netherlands Cardiovascular Research Initiative (CVON): the Dutch Heart Foundation, Dutch Federation of University Medical Centers, the Netherlands Organization for Health Research and Development, and the Royal Netherlands Academy of Science (to JPG Sluijter), the National Basic Research Program of China (2014CB542300), the National Major Research Plan Training Program (91339108), Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant (20152509). Dr XQ Kong is a Fellow and Dr XL Li is an Associate Fellow at the Collaborative Innovation Center For Cardiovascular Disease Translational Medicine. NR 28 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 3 BP 664 EP 676 DI 10.7150/thno.15162 PG 13 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EO2WS UT WOS:000396557300013 PM 28255358 ER PT J AU Chen, HH Yuan, HS Cho, HS Feng, Y Ngoy, S Kumar, ATN Liao, RL Chao, W Josephson, L Sosnovik, DE AF Chen, Howard H. Yuan, Hushan Cho, Hoonsung Feng, Yan Ngoy, Soeun Kumar, Anand T. N. Liao, Ronglih Chao, Wei Josephson, Lee Sosnovik, David E. TI Theranostic Nucleic Acid Binding Nanoprobe Exerts Anti-inflammatory and Cytoprotective Effects in Ischemic Injury SO THERANOSTICS LA English DT Article DE DNA; RNA; Inflammation; Ischemia; Nanoprobe; Imaging ID TOLL-LIKE RECEPTOR-3; DNA CF-DNA/NETS; MYOCARDIAL-INFARCTION; RNA; ACTIVATION; MONOCYTES; NECROSIS; CELLS; MICE; NANOPARTICLES AB Extracellular nucleic acids are proinflammatory molecules that have been implicated in a diverse range of diseases. We report here the development of a multivalent nucleic acid scavenging nanoprobe, where the fluorochrome thiazole orange (TO) is conjugated to a polymeric 40 kDa dextran carrier. Dextran-TO (Dex-TO) has nanomolar affinity for mammalian and bacterial nucleic acids and attenuates the production of inflammatory cytokines from activated macrophages exposed to DNA and RNA. Mice with myocardial ischemia reperfusion that were treated with Dex-TO showed a decrease in myocardial macrophage infiltration at 24 hours (p<0.05) and a decrease in infarct size (18% +/- 9%, p<0.01) on day 7. Dex-TO allows sites of injury to be identified with fluorescence imaging, while simultaneously exerting an anti-inflammatory and cytoprotective effect. Dex-TO could be of significant diagnostic and therapeutic (theranostic) utility in a broad range of conditions including ischemia, trauma, burns, sepsis and autoimmune disease. C1 [Chen, Howard H.; Kumar, Anand T. N.; Josephson, Lee; Sosnovik, David E.] Massachusetts Gen Hosp, Harvard Med Sch, Martinos Ctr Biomed Imaging, Boston, MA 02114 USA. [Chen, Howard H.] Massachusetts Gen Hosp, Harvard Med Sch, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Cho, Hoonsung; Josephson, Lee] Massachusetts Gen Hosp, Harvard Med Sch, Dept Radiol, Boston, MA 02114 USA. [Yuan, Hushan; Josephson, Lee] Chonnam Natl Univ, Sch Mat Sci & Engn, Gwangju, South Korea. [Feng, Yan; Chao, Wei] Massachusetts Gen Hosp, Harvard Med Sch, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. [Feng, Yan; Chao, Wei] Univ Maryland, Sch Med, Dept Anesthesiol, Baltimore, MD 21201 USA. [Ngoy, Soeun; Liao, Ronglih] Brigham & Womens Hosp, Harvard Med Sch, Div Genet, Boston, MA 02115 USA. [Ngoy, Soeun; Liao, Ronglih] Brigham & Womens Hosp, Harvard Med Sch, Div Cardiovasc Med, Boston, MA 02115 USA. RP Sosnovik, DE (reprint author), Massachusetts Gen Hosp, Martinos Ctr Biomed Imaging, 149 13th St, Boston, MA 02129 USA.; Sosnovik, DE (reprint author), Harvard Med Sch, 149 13th St, Boston, MA 02129 USA. EM sosnovik@nmr.mgh.harvard.edu FU National Institutes of Health [K99HL121152, R01HL093038, R01HL112831, R01EB011996, P41RR14075] FX This research was supported in part by the following National Institutes of Health grants: K99HL121152 (H.H.C.), R01HL093038 (D.E.S.), R01HL112831 (D.E.S.), R01EB011996 (L.J.) and P41RR14075 to the Martinos Center for Biomedical Imaging. NR 35 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 4 BP 814 EP 825 DI 10.7150/thno.17366 PG 12 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EO2XP UT WOS:000396559600002 PM 28382156 ER PT J AU Kim, H Choi, HS Kim, SK Il Lee, B Choi, Y AF Kim, Hyunjin Choi, Hak Soo Kim, Seok-Ki Il Lee, Byung Choi, Yongdoo TI Antigen-responsive molecular sensor enables real-time tumor-specific imaging SO THERANOSTICS LA English DT Article DE Antigen-responsive; near-infrared fluorescence imaging; real-time imaging ID MONOCLONAL-ANTIBODIES; BREAST-CANCER; FLUORESCENCE; SURGERY AB Antibody-fluorophore conjugates have high potential for the specific fluorescence detection of target cancer cells in vitro and in vivo. However, the antibody-fluorophore conjugates described to date are inappropriate for real-time imaging of target cells because removal of unbound antibody is required to reduce background fluorescence before quantifiable analysis by microscopy. In addition, clinical applications of the conjugates have been limited by persistent background retention due to their long systemic circulation and nonspecific uptake. Here we report fast and real-time near-infrared fluorescence imaging of target cancer cells using an antigen-responsive molecular "on-off" sensor: the fluorescence of trastuzumab-ATTO680 conjugate is dark (i.e., turned off) in the extracellular region, while it becomes highly fluorescent (i.e., turned on) upon binding to the target antigen HER2 on cancer cell surface. This molecular switch enables fast and real-time imaging of target cancer cells in vitro and in vivo. C1 [Kim, Hyunjin; Kim, Seok-Ki; Choi, Yongdoo] Natl Canc Ctr, Mol Imaging & Therapy Branch, 323 Ilsan Ro, Goyang 10408, Gyeonggi, South Korea. [Choi, Hak Soo] Massachusetts Gen Hosp, Gordon Ctr Med Imaging, Div Nucl Med & Mol Imaging, Dept Radiol, Boston, MA 02114 USA. [Choi, Hak Soo] Harvard Med Sch, Boston, MA 02114 USA. [Il Lee, Byung] Natl Canc Ctr, Biomol Funct Res Branch, 323 Ilsan Ro, Goyang 10408, Gyeonggi, South Korea. RP Choi, Y (reprint author), Natl Canc Ctr, Mol Imaging & Therapy Branch, 323 Ilsan Ro, Goyang 10408, Gyeonggi, South Korea. EM ydchoi@ncc.re.kr FU National Cancer Center grant [1610150]; National Research Foundation of Korea (NRF) grant-Korea government (MSIP), Republic of Korea [NRF-2014R1A2A1A11050923] FX This work was supported by the National Cancer Center grant (1610150), and by the National Research Foundation of Korea (NRF) grant (NRF-2014R1A2A1A11050923) funded by the Korea government (MSIP), Republic of Korea. NR 23 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 4 BP 952 EP 961 DI 10.7150/thno.16647 PG 10 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EO2XP UT WOS:000396559600013 PM 28382167 ER PT J AU Mikula, H Stapleton, S Kohler, RH Vinegoni, C Weissleder, R AF Mikula, Hannes Stapleton, Shawn Kohler, Rainer H. Vinegoni, Claudio Weissleder, Ralph TI Design and Development of Fluorescent Vemurafenib Analogs for In Vivo Imaging SO THERANOSTICS LA English DT Article DE fluorescence microscopy; imaging agents; kinase inhibitor; BRAF ID RAF INHIBITOR RESISTANCE; B-RAF; SINGLE-CELL; THERAPEUTIC TARGET; TYROSINE KINASE; MELANOMA-CELLS; MUTANT CANCER; SI-RHODAMINE; BRAF; BRAF(V600E) AB Herein we describe fluorescent derivatives of vemurafenib to probe therapeutic BRAF inhibition in live cells and in vivo. The compounds were evaluated and compared by determining target binding, inhibition of mutant BRAF melanoma cell lines and live cell imaging. We show that vemurafenib-BODIPY is a superior imaging drug to visualize the targets of vemurafenib in live cells and in vivo in non-resistant and resistant melanoma tumors. C1 [Mikula, Hannes; Stapleton, Shawn; Kohler, Rainer H.; Vinegoni, Claudio; Weissleder, Ralph] Massachusetts Gen Hosp, Ctr Syst Biol, 185 Cambridge St,CPZN 5206, Boston, MA 02114 USA. [Weissleder, Ralph] Harvard Med Sch, Dept Syst Biol, 200 Longwood Ave, Boston, MA 02115 USA. RP Weissleder, R (reprint author), Massachusetts Gen Hosp, Ctr Syst Biol, 185 Cambridge St,CPZN 5206, Boston, MA 02114 USA.; Weissleder, R (reprint author), Harvard Med Sch, Dept Syst Biol, 200 Longwood Ave, Boston, MA 02115 USA. EM rweissleder@mgh.harvard.edu FU Schrodinger Fellowship of the Austrian Science Fund (FWF) [J 3586]; National Science and Engineering Research Council of Canada (NSERC); [P50GM107618]; [R01EB010011]; [R01HL122208]; [1R01CA164448] FX We thank Katy Yang for providing the construct used to transduce the melanoma cell lines, David Pirovich for assistance with the window chamber surgery, and Zhenyu Ji and Hensin Tsao for kindly providing resistant A375 and SK-MEL-28 cells. This work was supported in parts by P50GM107618, R01EB010011, R01HL122208, and 1R01CA164448. H.M. was supported by a Schrodinger Fellowship of the Austrian Science Fund (FWF, J 3586) and S. S. was supported by the National Science and Engineering Research Council of Canada (NSERC) Post-Doctoral Fellowship. NR 51 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 5 BP 1257 EP 1265 DI 10.7150/thno.18238 PG 9 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EO3DD UT WOS:000396574200017 ER PT J AU Iezzoni, LI Wint, AJ Smeltzer, SC Ecker, JL AF Iezzoni, Lisa I. Wint, Amy J. Smeltzer, Suzanne C. Ecker, Jeffrey L. TI Recommendations about Pregnancy from Women with Mobility Disability to Their Peers SO WOMENS HEALTH ISSUES LA English DT Article ID CHRONIC PHYSICAL-DISABILITIES; RISK-FACTORS; US WOMEN; HEALTH; EXPERIENCES; DISPARITIES; OUTCOMES; CARE AB Background: Although growing numbers of women with mobility disability are becoming pregnant and desiring motherhood, relatively little is known about their pregnancy experiences or what they might recommend to other women with mobility disability contemplating pregnancy. Methods: Using a semistructured, open-ended interview protocol, we conducted 2-hour telephone interviews with 22 women who had a significant mobility disability before becoming pregnant and had delivered babies within the prior 10 years. We recruited most interviewees through online social networks. We used NVivo software to sort interview transcript texts and performed conventional content analyses to identify major themes. Results: Participants' mean +/- standard deviation age was 34.8 +/- 5.3 years; most were White, well-educated, and middle income and 18 used wheeled mobility aids. Recommendations for other women with mobility disability coalesced around five themes: recognizing the possibility of giving birth, advocacy and support, being informed, approaches toward obstetrical practitioners, and managing fears about losing custody of their child. Lacking information about what to expect during their pregnancy was a significant problem. Women got information about pregnancy from diverse sources, but questions arose about accuracy and relevance of this information to individual circumstances. Women urged their peers to advocate for their preferences and needs with obstetrical practitioners. Conclusions: Women with mobility disability who had delivered babies offered constructive advice for their peers who desire pregnancy. Increasing availability of accurate and relevant information about pregnancy among women with mobility disability is critically important, as is training obstetrical practitioners to provide patient-centered care to these women during pregnancy. (C) 2016 Jacobs Institute of Women's Health. Published by Elsevier Inc. C1 [Iezzoni, Lisa I.; Wint, Amy J.] Massachusetts Gen Hosp, Mongan Inst Hlth Policy Ctr, 50 Staniford St,Room 901B, Boston, MA 02114 USA. [Iezzoni, Lisa I.] Harvard Med Sch, Dept Med, Boston, MA USA. [Smeltzer, Suzanne C.] Villanova Univ, Ctr Nursing Res, Coll Nursing, Villanova, PA 19085 USA. [Ecker, Jeffrey L.] Massachusetts Gen Hosp, Dept Obstet & Gynecol, Boston, MA 02114 USA. [Ecker, Jeffrey L.] Harvard Med Sch, Dept Obstet & Gynecol, Boston, MA USA. RP Iezzoni, LI (reprint author), Massachusetts Gen Hosp, Mongan Inst Hlth Policy Ctr, 50 Staniford St,Room 901B, Boston, MA 02114 USA. EM liezzoni@mgh.harvard.edu FU Eunice Kennedy Shriver National Institute of Child Health and Human Development in the National Institutes of Health fund [1R21HD068756-02] FX The Eunice Kennedy Shriver National Institute of Child Health and Human Development in the National Institutes of Health funded this study (Grant No. 1R21HD068756-02). NR 23 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 1049-3867 EI 1878-4321 J9 WOMEN HEALTH ISS JI Womens Health Iss. PD JAN-FEB PY 2017 VL 27 IS 1 BP 75 EP 82 DI 10.1016/j.whi.2016.09.004 PG 8 WC Public, Environmental & Occupational Health; Women's Studies SC Public, Environmental & Occupational Health; Women's Studies GA EO1EX UT WOS:000396442300011 PM 27773531 ER PT J AU Barros, MA Fernandes, TL Dimitriou, D Pedrinelli, A Hernandez, AJ AF Barros, Marcos Amstalden Fernandes, Tiago Lazzaretti Dimitriou, Dimitris Pedrinelli, Andre Hernandez, Arnaldo Jose TI COMPARISON BETWEEN RENDERING 3D-CT AND TRANSPARENT 3D-CT IN ACL TUNNEL POSITIONING SO ACTA ORTOPEDICA BRASILEIRA LA English DT Article DE Anterior cruciate ligament reconstruction; Imaging; Three-Dimensional; Image processing; computer-assisted ID ANTERIOR CRUCIATE LIGAMENT; 3-DIMENSIONAL COMPUTED-TOMOGRAPHY; POSTEROLATERAL BUNDLES; RECONSTRUCTION; INSERTIONS; SERIES AB Objective: To compare the transparent 3D computed tomography (CT) image protocol against conventional 3D-CT image-rendering protocol to assess femoral tunnel position in anatomic anterior cruciate ligament (ACL) reconstructions. Methods: Eight knee CT scans from cadavers were analyzed by image rendering 3D-CT protocol, using Rhinoceros (R) software. The central point of the ACL tunnel was set using the sagittal plane. Same CT scans were analyzed using transparent 3D-CT measurement protocol with OsiriX (R) software. Central point of the ACL tunnel was set using sagittal, coronal and axial planes. The grid system described by Bernard and Hertel was used to compare tunnel positions between protocols, using height and length parameters. Results: There was a significant difference between measurements using image rendering 3D-CT and transparent 3D-CT protocol for height (23.8 +/- 7.9mm and 33.0 +/- 5.0mm, respectively; p=0.017) and no differences for length (18.6 +/- 4.2mm and 18.3 +/- 4.5mm, respectively; p=0.560). Conclusion: Height in transparent CT protocol was different and length was the same as compared to 3D-CT rendering protocol in Bernard and Hertel method for tunnel measurements. C1 [Barros, Marcos Amstalden; Fernandes, Tiago Lazzaretti; Pedrinelli, Andre; Hernandez, Arnaldo Jose] Univ Sao Paulo, Inst Ortopedia & Traumatol, Hosp Clin, Fac Med, Sao Paulo, SP, Brazil. [Dimitriou, Dimitris] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Dimitriou, Dimitris] Harvard Med Sch, Dept Orthoped Surg, Bioengn Lab, Boston, MA USA. RP Barros, MA (reprint author), Rua Joao Moura,860,Apto 121, BR-05412002 Sao Paulo, SP, Brazil. EM marcos.barros@usp.br NR 20 TC 0 Z9 0 U1 0 U2 0 PU ATHA COMUNICACAO & EDITORA PI SAO PAULO SP PA RUA MACHADO BITTENCOURT, 190-40 ANDAR, CONJ 410, SAO PAULO SP, 00000, BRAZIL SN 1413-7852 EI 1809-4406 J9 ACTA ORTOP BRAS JI Acta Ortop. Bras. PD JAN-FEB PY 2017 VL 25 IS 1 BP 30 EP 33 DI 10.1590/1413-785220172501167914 PG 4 WC Orthopedics SC Orthopedics GA EO4AX UT WOS:000396637400005 ER PT J AU Blair, A Manian, FA AF Blair, Alex Manian, Farrin A. TI Coexisting Systemic Infections in Patients Who Present With a Fall SO AMERICAN JOURNAL OF THE MEDICAL SCIENCES LA English DT Article DE Fall; Infections; Sepsis; Bacteremia ID INFLAMMATORY RESPONSE SYNDROME; C-REACTIVE PROTEIN; SEVERE SEPSIS; OLDER-ADULTS; RISK-FACTORS; MANAGEMENT; PEOPLE AB Background: Although the causes of falls are legion, infectious disease related factors are not commonly reported in the published literature. We investigated the characteristics of patients presenting to the hospital because of a fall and who were subsequently found to have a coexisting systemic infection (CSI). Materials and Methods: This was a retrospective study performed at Massachusetts General Hospital, using the electronic database of adult patients receiving care during the period January 1, 2000 through December 31, 2014. Cases were initially screened by using billing codes for "fall," "sepsis," "bacteremia" and "systemic inflammatory response syndrome" (SIRS). Evaluable patients had documented CSI in the setting of a fall. Results: Of 161 evaluable patients, 84 (52.2%) were female. The mean age was 75. 2 years (range: 35-102 years, median = 78 years). Fall was considered "mechanical" (e.g., tripped by a rug) in 106 (65.8%) cases, with 126 (78.3%) patients living at home. SIRS criteria were met on initial healthcare encounters of 66 (40.1%) patients. Urinary and lower respiratory tract infections were the most common infectious disease conditions (71 [44.1%] and 37 [23.0%] cases, respectively). Bacteremia was seen in 64 (39.8%) cases. Staphylococcus aureus was the most common cause of bacteremia (21 cases, 31.3% of bloodstream isolates). CSI was not initially suspected by providing clinicians in 64 (39.8%) patients. Conclusions: Falls associated with CSIs are often considered "mechanical" in nature, and they frequently fail to meet the SIRS criteria on initial presentation. Aside from its commonly recognized causes, falls may be an atypical manifestation of a systemic infection. C1 [Blair, Alex; Manian, Farrin A.] Harvard Med Sch, Boston, MA USA. [Manian, Farrin A.] Massachusetts Gen Hosp, Dept Med, 503B Staniford, Boston, MA 02114 USA. RP Manian, FA (reprint author), Massachusetts Gen Hosp, Dept Med, 503B Staniford, Boston, MA 02114 USA. EM fmanian@mgh.Harvard.edu NR 23 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9629 EI 1538-2990 J9 AM J MED SCI JI Am. J. Med. Sci. PD JAN PY 2017 VL 353 IS 1 BP 22 EP 26 PG 5 WC Medicine, General & Internal SC General & Internal Medicine GA EO2HE UT WOS:000396516400006 PM 28104099 ER PT J AU Padole, A Digumarthy, S Flores, E Madan, R Mishra, S Sharma, A Kalra, MK AF Padole, Atul Digumarthy, Subba Flores, Efren Madan, Rachna Mishra, Shelly Sharma, Amita Kalra, Mannudeep K. TI Assessment of chest CT at CTDIvol less than 1mGy with iterative reconstruction techniques SO BRITISH JOURNAL OF RADIOLOGY LA English DT Article ID FILTERED BACK-PROJECTION; RADIATION-DOSE OPTIMIZATION; COMPUTED-TOMOGRAPHY; PULMONARY NODULES; IMAGE QUALITY; GUIDELINES; MANAGEMENT; SOCIETY AB Objective: To assess the image quality of chest CT reconstructed with image-based iterative reconstruction (SafeCT; MedicVision (R), Tirat Carmel, Israel), adaptive statistical iterative reconstruction (ASIR; GE Healthcare, Waukesha, WI) and model-based iterative reconstruction (MBIR; GE Healthcare, Waukesha, WI) techniques at CT dose index volume (CTDIvol)<1mGy. Methods: In an institutional review board-approved study, 25 patients gave written informed consent for acquisition of three reduced dose (0.25-, 0.4-and 0.8-mGy) chest CT after standard of care CT (8mGy) on a 64-channel multidetector CT (MDCT) and reconstructed with SafeCT, ASIR and MBIR. Two board-certified thoracic radiologists evaluated images fromthe lowest to the highest dose of the reduced dose CT series and subsequently for standard of care CT. Results: Out of the 182 detected lesions, the missed lesions were 35 at 0.25, 24 at 0.4 and 9 at 0.8mGy with SafeCT, ASIR and MBIR, respectively. The most missed lesions were non-calcified lung nodules (NCLNs) 25/112 (<5mm) at 0.25, 18/112 (<5mm) at 0.4 and 3/112 (<4mm) at 0.8mGy. There were 78%, 84% and 97% lung nodules detected at 0.25, 0.4 and 0.8mGy, respectively regardless of iterative reconstruction techniques (IRTs), Most mediastinum structures were not sufficiently seen at 0.25-0.8mGy. Conclusion: NCLNs can be missed in chest CT at CTDIvol of <1mGy (0.25, 0.4 and 0.8mGy) regardless of IRTs. The most lung nodules (97%) were detected at CTDIvol of 0.8mGy. The most mediastinum structures were not sufficiently seen at 0.25-0.8mGy. Advances in knowledge: NCLNs can be missed regardless of IRTs in chest CT at CTDIvol of <1mGy. The performance of ASIR, SafeCT and MBIR was similar for lung nodule detection at 0.25, 0.4 and 0.8mGy. C1 [Padole, Atul; Digumarthy, Subba; Flores, Efren; Mishra, Shelly; Sharma, Amita; Kalra, Mannudeep K.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Madan, Rachna] Brigham & Womens Hosp, Dept Radiol, 75 Francis St, Boston, MA 02115 USA. RP Padole, A (reprint author), Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. EM apadole@mgh.harvard.edu NR 20 TC 0 Z9 0 U1 0 U2 0 PU BRITISH INST RADIOLOGY PI LONDON PA 36 PORTLAND PLACE, LONDON W1N 4AT, ENGLAND SN 0007-1285 EI 1748-880X J9 BRIT J RADIOL JI Br. J. Radiol. PY 2017 VL 90 IS 1071 AR 20160625 DI 10.1259/bjr.20160625 PG 11 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA EO3LW UT WOS:000396597200021 PM 28055250 ER PT J AU Soeda, T Higuma, T Abe, N Yamada, M Yokoyama, H Shibutani, S Ong, DS Vergallo, R Minami, Y Lee, H Okumura, K Jang, IK AF Soeda, Tsunenari Higuma, Takumi Abe, Naoki Yamada, Masahiro Yokoyama, Hiroaki Shibutani, Shuji Ong, Daniel S. Vergallo, Rocco Minami, Yoshiyasu Lee, Hang Okumura, Ken Jang, Ik-Kyung TI Morphological predictors for no reflow phenomenon after primary percutaneous coronary intervention in patients with ST-segment elevation myocardial infarction caused by plaque rupture SO EUROPEAN HEART JOURNAL-CARDIOVASCULAR IMAGING LA English DT Article DE ST-segment elevation myocardial infarction; optical coherence tomography; plaque rupture; no reflow ID OPTICAL COHERENCE TOMOGRAPHY; INTRAVASCULAR ULTRASOUND; ATHEROSCLEROTIC PLAQUE; DISTAL EMBOLIZATION; CALCIFIED NODULE; OUTCOMES; EROSION; IMPACT; FLOW; THROMBOLYSIS AB Aims Myocardial no reflow after percutaneous coronary intervention (PCI) is associated with poor outcome. Patients with ST-segment elevation myocardial infarction (STEMI) caused by plaque rupture are at high risk for no reflow. However, specific morphologic characteristics associated with no reflow are unknown in this population. The aim of this study is to identify the morphological characteristics of culprit plaques associated with no reflow in patients with STEMI caused by plaque rupture using both optical coherence tomography (OCT) and intravascular ultrasound (IVUS). Methods and results We enrolled 145 patients with STEMI who underwent both OCT and IVUS within 12 h of symptom onset. Among these patients, we excluded those with plaque erosion and calcified nodule and included 72 patients who had plaque rupture as an underlying mechanism for STEMI. Myocardial no reflow, defined as Thrombolysis in Myocardial Infarction flow grade 0-2 and/or myocardial blush grade 0-1 after PCI, was observed in 28 patients (38.9%). Onset to recanalization time was similar between the groups with and without no reflow. Receiver-operating curve analysis revealed OCT-derived lipid index > 3500 [area under curve (AUC) 077, P < 0.001] and IVUS-derived plaque burden > 81.5% (AUC 0.70, P = 0.002) were the best discriminators for myocardial no reflow. Conclusion No reflow occurred in nearly 40% of patients with STEMI caused by plaque rupture. Large lipid index and plaque burden were critical morphological discriminators between no reflow and normal flow. C1 [Soeda, Tsunenari; Ong, Daniel S.; Vergallo, Rocco; Minami, Yoshiyasu; Jang, Ik-Kyung] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Soeda, Tsunenari; Ong, Daniel S.; Vergallo, Rocco; Minami, Yoshiyasu; Lee, Hang; Jang, Ik-Kyung] Harvard Med Sch, Boston, MA USA. [Higuma, Takumi; Abe, Naoki; Yamada, Masahiro; Yokoyama, Hiroaki; Shibutani, Shuji; Okumura, Ken] Hirosaki Univ, Dept Cardiol, Grad Sch Med, Hirosaki, Aomori, Japan. [Lee, Hang] Massachusetts Gen Hosp, Ctr Biostat, Boston, MA 02114 USA. [Jang, Ik-Kyung] Kyung Hee Univ, Div Cardiol, Seoul, South Korea. RP Jang, IK (reprint author), Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA.; Jang, IK (reprint author), Harvard Med Sch, Boston, MA USA.; Jang, IK (reprint author), Kyung Hee Univ, Div Cardiol, Seoul, South Korea. EM ijang@mgh.harvard.edu FU Italian Society of Cardiology Award for Research Abroad FX R.V. was funded in part by the 2013 Italian Society of Cardiology Award for Research Abroad. I.-K.J.'s research was supported by 'Mr. and Mrs. Michael and Kathryn Park' and by 'Mr. and Mrs. Allan and Gillian Gray'. NR 28 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 2047-2404 EI 2047-2412 J9 EUR HEART J-CARD IMG JI Eur. Heart J.-Cardiovasc. Imaging PD JAN PY 2017 VL 18 IS 1 BP 103 EP 110 DI 10.1093/ehjci/jev341 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EP0GS UT WOS:000397065800015 PM 26800769 ER PT J AU Li, HY Feng, BJ Miron, A Chen, XQ Beesley, J Bimeh, E Barrowdale, D John, EM Daly, MB Andrulis, IL Buys, SS Kraft, P Thorne, H Chenevix-Trench, G Southey, MC Antoniou, AC James, PA Terry, MB Phillips, KA Hopper, JL Mitchell, G Goldgar, DE AF Li, Hongyan Feng, Bingjian Miron, Alexander Chen, Xiaoqing Beesley, Jonathan Bimeh, Emmanuella Barrowdale, Daniel John, Esther M. Daly, Mary B. Andrulis, Irene L. Buys, Saundra S. Kraft, Peter Thorne, Heather Chenevix-Trench, Georgia Southey, Melissa C. Antoniou, Antonis C. James, Paul A. Terry, Mary Beth Phillips, Kelly-Anne Hopper, John L. Mitchell, Gillian Goldgar, David E. CA KConFab Investigators TI Breast cancer risk prediction using a polygenic risk score in the familial setting: a prospective study from the Breast Cancer Family Registry and kConFab SO GENETICS IN MEDICINE LA English DT Article DE breast cancer; cancer screening; non-BRCA-associated; polygenic risk score; risk prediction ID SUSCEPTIBILITY; LOCI AB Purpose: This study examined the utility of sets of single-nucleotide polymorphisms (SNPs) in familial but non-BRCA-associated breast cancer (BC). Methods: We derived a polygenic risk score (PRS) based on 24 known BC risk SNPs for 4,365 women from the Breast Cancer Family Registry and Kathleen Cuningham Consortium Foundation for Research into Familial Breast Cancer familial BC cohorts. We compared scores for women based on cancer status at baseline; 2,599 women unaffected at enrollment were followed-up for an average of 7.4 years. Cox proportional hazards regression was used to analyze the association of PRS with BC risk. The BOADICEA risk prediction algorithm was used to measure risk based on family history alone. Results: The mean PRS at baseline was 2.25 (SD, 0.35) for affected women and was 2.17 (SD, 0.35) for unaffected women from combined cohorts (P < 10-6). During follow-up, 205 BC cases occurred. The hazard ratios for continuous PRS (per SD) and upper versus lower quintiles were 1.38 (95% confidence interval: 1.22-1.56) and 3.18 (95% confidence interval: 1.84-5.23) respectively. Based on their PRS-based predicted risk, management for up to 23% of women could be altered. Conclusion: Including BC-associated SNPs in risk assessment can provide more accurate risk prediction than family history alone and can influence recommendations for cancer screening and prevention modalities for high-risk women. C1 [Li, Hongyan; Goldgar, David E.] Univ Utah, Huntsman Canc Inst, Canc Control & Populat Sci, Salt Lake City, UT 84112 USA. [Feng, Bingjian; Goldgar, David E.] Univ Utah, Huntsman Canc Inst, Dept Dermatol, Sch Med, Salt Lake City, UT 84112 USA. [Miron, Alexander] Dana Farber Canc Inst, Boston, MA 02115 USA. [Miron, Alexander] Case Western Reserve Univ, Dept Genet & Genome Sci, Cleveland, OH 44106 USA. [Chen, Xiaoqing; Beesley, Jonathan; Chenevix-Trench, Georgia] QIMR Berghofer Med Res Inst, Canc Div, Brisbane, Qld, Australia. [Bimeh, Emmanuella] Univ Utah, Div Family & Prevent Med, Salt Lake City, UT USA. [Barrowdale, Daniel; Antoniou, Antonis C.] Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge, England. [John, Esther M.] Canc Prevent Inst Calif, Fremont, CA USA. [John, Esther M.] Stanford Univ, Sch Med, Dept Hlth Res & Policy Epidemiol, Stanford, CA 94305 USA. [John, Esther M.] Stanford Univ, Stanford Canc Inst, Sch Med, Stanford, CA 94305 USA. [Daly, Mary B.] Fox Chase Canc Ctr, Dept Clin Genet, 7701 Burholme Ave, Philadelphia, PA 19111 USA. [Andrulis, Irene L.] Univ Toronto, Lunenfeld Tanenbaum Res Inst, Mt Sinai Hosp, Dept Mol Genet, Toronto, ON, Canada. [Buys, Saundra S.] Univ Utah, Sch Med, Dept Med, Huntsman Canc Inst, Salt Lake City, UT USA. [Kraft, Peter] Harvard Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Thorne, Heather; KConFab Investigators] Peter MacCallum Canc Ctr, Div Res, East Melbourne, Vic, Australia. [Southey, Melissa C.] Univ Melbourne, Dept Pathol, Genet Epidemiol Lab, Melbourne, Vic, Australia. [James, Paul A.; Phillips, Kelly-Anne; Mitchell, Gillian] Peter MacCallum Canc Ctr, Familial Canc Ctr, East Melbourne, Vic, Australia. [James, Paul A.; Phillips, Kelly-Anne; Mitchell, Gillian] Univ Melbourne, Sir Peter MacCallum Dept Oncol, Parkville, Vic, Australia. [Terry, Mary Beth] Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY USA. [Terry, Mary Beth] Columbia Univ, Med Ctr, Herbert Irving Comprehens Canc Ctr, New York, NY USA. [Phillips, Kelly-Anne; Hopper, John L.] Univ Melbourne, Melbourne Sch Populat Hlth, Ctr Mol Environm Genet & Analyt Epidemiol, Melbourne, Vic, Australia. RP Goldgar, DE (reprint author), Univ Utah, Huntsman Canc Inst, Canc Control & Populat Sci, Salt Lake City, UT 84112 USA.; Goldgar, DE (reprint author), Univ Utah, Huntsman Canc Inst, Dept Dermatol, Sch Med, Salt Lake City, UT 84112 USA. EM david.goldgar@hsc.utah.edu FU Cancer Australia's Priority-driven Collaborative Cancer Research Scheme [566791]; NIH [U19 CA 148065-01, R01CA155767]; NIH from the National Cancer Institute [R01 CA159868, UM1 CA164920]; NHMRC; National Breast Cancer Foundation; Cancer Australia; US National Institutes of Health; National Health and Medical Research Council (NHMRC); Queensland Cancer Fund; Cancer Council of New South Wales; Cancer Council of Victoria; Cancer Council of Tasmania; Cancer Council of South Australia; Cancer Foundation of Western Australia FX This research was supported by a grant from Cancer Australia's Priority-driven Collaborative Cancer Research Scheme no. 566791 (to G.M.) and by NIH grant U19 CA 148065-01 (DRIVE, part of the GAME-ON initiative) and NIH grant R01CA155767 (to D.E.G.). The Breast Cancer Family Registry is supported by NIH grants R01 CA159868 and UM1 CA164920 from the National Cancer Institute.; We thank Eveline Niedermayr, all the kConFab research nurses and staff, the heads and staff of the Family Cancer Clinics, and the investigators and staff of the kConFab Clinical Follow-Up Study, which has received funding from the NHMRC, the National Breast Cancer Foundation, Cancer Australia, and the US National Institutes of Health, for their contributions to this resource. kConFab is supported by a grant from the National Breast Cancer Foundation and was previously supported by the National Health and Medical Research Council (NHMRC); the Queensland Cancer Fund; the Cancer Councils of New South Wales, Victoria, Tasmania, and South Australia; and the Cancer Foundation of Western Australia. Most importantly, the authors thank all the families enrolled in the BCFR and kConFab resources for their willingness to participate in research; without them, the work presented here would not be possible. NR 17 TC 1 Z9 1 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1098-3600 EI 1530-0366 J9 GENET MED JI Genet. Med. PD JAN PY 2017 VL 19 IS 1 BP 30 EP 35 DI 10.1038/gim.2016.43 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA EH6VD UT WOS:000391911100005 PM 27171545 ER PT J AU Scheuner, MT Peredo, J Tangney, K Schoeff, D Sale, T Lubick-Goldzweig, C Hamilton, A Hilborne, L Lee, M Mittman, B Yano, EM Lubin, IM AF Scheuner, Maren T. Peredo, Jane Tangney, Kelly Schoeff, Diane Sale, Taylor Lubick-Goldzweig, Caroline Hamilton, Alison Hilborne, Lee Lee, Martin Mittman, Brian Yano, Elizabeth M. Lubin, Ira M. TI Electronic health record interventions at the point of care improve documentation of care processes and decrease orders for genetic tests commonly ordered by nongeneticists SO GENETICS IN MEDICINE LA English DT Article ID FACTOR-V-LEIDEN; AXIAL SPONDYLOARTHRITIS; MANAGEMENT RECOMMENDATIONS; VENOUS THROMBOEMBOLISM; GENOMIC MEDICINE; CLINICAL UTILITY; CANCER-RISK; HEMOCHROMATOSIS; COMMUNICATION; VALIDATION AB Objective: To determine whether electronic health record (EHR) tools improve documentation of pre- and postanalytic care processes for genetic tests ordered by nongeneticists. Methods: We conducted a nonrandomized, controlled, pre-/postintervention study of EHR point-of-care tools (informational messages and template report) for three genetic tests. Chart review assessed documentation of genetic testing processes of care, with points assigned for each documented item. Multiple linear and logistic regressions assessed factors associated with documentation. Results: Preimplementation, there were no significant site differences (P > 0.05). Postimplementation, mean documentation scores increased (5.9 (2.1) vs. 5.0 (2.2); P = 0.0001) and records with clinically meaningful documentation increased (score >5: 59 vs. 47%; P = 0.02) at the intervention versus the control site. Pre and postimplementation, a score >5 was positively associated with abnormal test results (OR = 4.0; 95% CI: 1.8-9.2) and trainee provider (OR = 2.3; 95% CI: 1.2-4.6). Postimplementation, a score >5 was also positively associated with intervention site (OR = 2.3; 95% CI: 1.1-5.1) and specialty clinic (OR = 2.0; 95% CI: 1.1-3.6). There were also significantly fewer tests ordered after implementation (264/100,000 vs. 204/100,000; P = 0.03), with no significant change at the control site (280/100,000 vs. 257/100,000; P = 0.50). Conclusions: EHR point-of-care tools improved documentation of genetic testing processes and decreased utilization of genetic tests commonly ordered by nongeneticists. C1 [Scheuner, Maren T.; Peredo, Jane; Tangney, Kelly; Schoeff, Diane; Sale, Taylor; Lubick-Goldzweig, Caroline; Hamilton, Alison; Lee, Martin; Mittman, Brian; Yano, Elizabeth M.] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA 90073 USA. [Scheuner, Maren T.; Lubick-Goldzweig, Caroline] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA. [Hamilton, Alison] Univ Calif Los Angeles, David Geffen Sch Med, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90095 USA. [Hilborne, Lee] Univ Calif Los Angeles, David Geffen Sch Med, Dept Pathol & Lab Med, Los Angeles, CA 90095 USA. [Hilborne, Lee] Quest Diagnost, Madison, NJ USA. [Yano, Elizabeth M.] Univ Calif Los Angeles, Fielding Sch Publ Hlth, Dept Hlth Policy & Management, Los Angeles, CA USA. [Lubin, Ira M.] Ctr Dis Control & Prevent, Atlanta, GA USA. RP Scheuner, MT (reprint author), VA Greater Los Angeles Healthcare Syst, Los Angeles, CA 90073 USA.; Scheuner, MT (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA. EM maren.scheuner@va.gov FU Centers for Disease Control and Prevention Laboratory Training, Evaluation, and Quality Assurance Programs [CDC-RFA-CI10-100503CONT12, 5U47CI000823]; Centers for Disease Prevention and Control; VA HSR&D Senior Research Career Scientist Award [RCS 05-195] FX This study was funded by the Centers for Disease Control and Prevention Laboratory Training, Evaluation, and Quality Assurance Programs (CDC-RFA-CI10-100503CONT12; grant 5U47CI000823). This publication was supported by a cooperative agreement from the Centers for Disease Prevention and Control. E.M.Y.'s work was supported by a VA HSR&D Senior Research Career Scientist Award (RCS 05-195). The authors thank the VA staff who supported this project, including the following research team members: Albert Aparicio, Nui Brown, Austin Jones, Erica Ma, Russell Madison, Brian Tran, and Claudia Vaughn. The authors also thank the following members of the Advisory Board: Joanne Armstrong, Hawazin Faruki, W. Andrew Faucett, Matthew Goetz, Wayne Grody, Elaine Lyon, Laurence Meyer, Victoria Pratt, Sue Richards, Paul Schneider, Indira Subramanian, Tracy Trotter, Vickie Venne, An Weinreb, and Marc Williams. NR 40 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 1098-3600 EI 1530-0366 J9 GENET MED JI Genet. Med. PD JAN PY 2017 VL 19 IS 1 BP 112 EP 120 DI 10.1038/gim.2016.73 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA EH6VD UT WOS:000391911100016 PM 27362912 ER PT J AU Livingston, NA AF Livingston, Nicholas A. TI Avenues for Future Minority Stress and Substance Use Research among Sexual and Gender Minority Populations SO JOURNAL OF LGBT ISSUES IN COUNSELING LA English DT Article DE Ecological momentary assessment; experience sampling; LGBT; minority stress; substance use ID ECOLOGICAL MOMENTARY ASSESSMENT; ALCOHOL-USE; COLLEGE-STUDENTS; MENTAL-HEALTH; BISEXUAL POPULATIONS; UNITED-STATES; DAILY DIARY; RISK; GAY; INTERNET AB Sexual and gender minority individuals (lesbian, gay, bisexual, transgender, queer [LGBTQ]) experience elevated rates of minority stress and associated substance use relative to their heterosexual and cisgender counterparts. Although theminority stress substance use relationship is well documented, less is currently known regarding day-to-day minority stress and substance use risk processes. Rather than criticize existing literature, this review highlights future directions and advocates for the use of experience sampling methodology as a valuable research tool regarding real-time data capture. Greater utilization of this methodology is encouraged and expected to improve understanding of daily minority stress processes, and provide insight into real-time risk monitoring and intervention strategies. C1 [Livingston, Nicholas A.] Univ Montana, Dept Psychol, Skaggs Bldg Room 143,32 Campus Dr, Missoula, MT 59812 USA. [Livingston, Nicholas A.] VA Boston Hlth Care Syst, Boston, MA USA. RP Livingston, NA (reprint author), Univ Montana, Dept Psychol, Skaggs Bldg Room 143,32 Campus Dr, Missoula, MT 59812 USA. EM nicholas.livingston@umontana.edu NR 65 TC 0 Z9 0 U1 0 U2 0 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1553-8605 EI 1553-8338 J9 J LGBT ISS COUNS JI J. LGBT Iss. Couns. PY 2017 VL 11 IS 1 BP 52 EP 62 DI 10.1080/15538605.2017.1273164 PG 11 WC Psychology, Applied SC Psychology GA EO3PV UT WOS:000396607600005 ER PT J AU Tave, TT Wyers, DR Schreiber-Jones, C Fogger, SA McGuinness, TM AF Tave, Tristan T. Wyers, Daniel R. Schreiber-Jones, Catherine Fogger, Susanne A. McGuinness, Teena M. TI Improving Quality Outcomes in Veteran-Centric Care SO JOURNAL OF PSYCHOSOCIAL NURSING AND MENTAL HEALTH SERVICES LA English DT Article ID POSTTRAUMATIC-STRESS-DISORDER; MENTAL-HEALTH-CARE; SUBSTANCE USE; PREVALENCE; SOLDIERS; SUICIDE; COMBAT; IRAQ AB The University of Alabama at Birmingham (UAB) School of Nursing and the Birmingham Veterans Affairs Medical Center (BVAMC) created a Psychiatric-Mental Health Nurse Practitioner (PMHNP) Residency Continuity Clinic tasked with providing Veteran-centric mental health outpatient treatment informed by measurement-based care (MBC) to provide quality outcomes. Approved by the BVAMC, the UAB Institutional Review Board also approved and exempted the project as quality improvement. PMHNP residents administered the Patient Stress Questionnaire (PSQ)-an MBC tool that incorporates validated tools for assessing depression, anxiety, posttraumatic stress, alcohol use, and pain-to each Veteran from March to August 2016. Patient outcomes focused on depression and anxiety. PSQ scores were reviewed retrospectively via descriptive statistics, paired t tests, and Wilcoxon signed ranks tests. Analysis showed improvement in depression and anxiety that approached significance, and in several national Veterans Affairs mental health performance measures, reinforcing the importance of using MBC in psychiatric assessment. C1 [Tave, Tristan T.] Alta Point Hlth Syst Adult Outpatient Serv, PMHNP, Mobile, AL 36617 USA. [Wyers, Daniel R.] Northwest Alabama Psychiat Services PC, PMHNP, Huntsville, AL USA. [Schreiber-Jones, Catherine] Birmingham Vet Affairs Med Ctr, PMHNP, 700 19th St South, Birmingham, AL USA. [Fogger, Susanne A.; McGuinness, Teena M.] Univ Alabama Birmingham, Dept Family Commun & Hlth Syst, Birmingham, AL USA. RP Schreiber-Jones, C (reprint author), Birmingham Vet Affairs Med Ctr, PMHNP, 700 19th St South, Birmingham, AL USA. EM Catherine.Schreiber-Jones2@va.gov FU Office of Academic Affiliations (OAA) through the Veterans Affairs (VA) Nursing Academy; Birmingham Veterans Affairs Medical Center; University of Alabama at Birmingham School of Nursing; VA's OAA, a component of the VA Nursing Academic Partnership-Graduate Education program FX The authors have disclosed no potential conflicts of interest, financial or otherwise. This publication was supported in part by the Office of Academic Affiliations (OAA) through the Veterans Affairs (VA) Nursing Academy, a partnership between the Birmingham Veterans Affairs Medical Center and University of Alabama at Birmingham School of Nursing. The content is solely the responsibility of the authors and does not necessarily represent the official views of the Veterans Health Administration.; The PMHNP residents in the Resident Continuity Clinic were funded by trainee stipends from the VA's OAA, a component of the VA Nursing Academic Partnership-Graduate Education program. The OAA encourages scholarly work by NP residents in mental health or primary care settings. An OAA representative reviewed and approved this project, and made recommendations regarding dissemination. NR 31 TC 0 Z9 0 U1 1 U2 1 PU SLACK INC PI THOROFARE PA 6900 GROVE RD, THOROFARE, NJ 08086 USA SN 0279-3695 EI 1938-2413 J9 J PSYCHOSOC NURS MEN JI J. Psychosoc. Nurs. Ment. Health Serv. PD JAN PY 2017 VL 55 IS 1 BP 37 EP 44 DI 10.3928/02793695-20170119-07 PG 8 WC Nursing SC Nursing GA EO9QP UT WOS:000397023500006 PM 28135390 ER PT J AU Valente, SM AF Valente, Sharon M. TI Managing Professional and Nurse-Patient Relationship Boundaries in Mental Health SO JOURNAL OF PSYCHOSOCIAL NURSING AND MENTAL HEALTH SERVICES LA English DT Article ID VIOLATIONS; WORK AB Caring nurse-patient relationships in mental health settings are key components in helping patients recover. These professional relationships provide a safe, trustworthy, reliable, and secure foundation for therapeutic interactions; however, nurses face challenges in setting and maintaining relationship boundaries. Although patients ask for special privileges, romantic interactions, and social media befriending, or offer expensive gifts, nurses must recognize that these boundary violations may erode trust and harm patients. These violations may also trigger discipline for nurses. Professional relationship guidelines must be applied with thoughtful consideration, and nurses must monitor their emotions and reactions in these relationships. The current article is a sharing of personal experiences about boundaries augmented by evidence in the literature, and focuses on managing potential boundary violations (i. e., social media, sexuality, over-involvement, and gift giving) in mental health settings. C1 [Valente, Sharon M.] Greater Los Angeles Vet Adm Healthcare Syst, Res Continuum Care, 11301 Wilshire Blvd,Bldg 500, Los Angeles, CA 90073 USA. RP Valente, SM (reprint author), Greater Los Angeles Vet Adm Healthcare Syst, Res Continuum Care, 11301 Wilshire Blvd,Bldg 500, Los Angeles, CA 90073 USA. EM sharon.valente@va.gov NR 19 TC 0 Z9 0 U1 1 U2 1 PU SLACK INC PI THOROFARE PA 6900 GROVE RD, THOROFARE, NJ 08086 USA SN 0279-3695 EI 1938-2413 J9 J PSYCHOSOC NURS MEN JI J. Psychosoc. Nurs. Ment. Health Serv. PD JAN PY 2017 VL 55 IS 1 BP 45 EP 51 DI 10.3928/02793695-20170119-09 PG 7 WC Nursing SC Nursing GA EO9QP UT WOS:000397023500007 PM 28135391 ER PT J AU Romero, K Goparaju, B Russo, K Westover, MB Bianchi, MT AF Romero, Kate Goparaju, Balaji Russo, Kathryn Westover, M. Brandon Bianchi, Matt T. TI Alternative remedies for insomnia: a proposed method for personalized therapeutic trials SO NATURE AND SCIENCE OF SLEEP LA English DT Article DE insomnia; over the counter; alternative remedy; herbal; supplement ID COGNITIVE-BEHAVIORAL THERAPY; RANDOMIZED CONTROLLED-TRIAL; EXOGENOUS MELATONIN; DIETARY-SUPPLEMENTS; SLEEP VARIABILITY; N-OF-1 TRIALS; GUIDED ONLINE; OLDER-ADULTS; US ADULTS; METAANALYSIS AB Insomnia is a common symptom, with chronic insomnia being diagnosed in 5-10% of adults. Although many insomnia patients use prescription therapy for insomnia, the health benefits remain uncertain and adverse risks remain a concern. While similar effectiveness and risk concerns exist for herbal remedies, many individuals turn to such alternatives to prescriptions for insomnia. Like prescription hypnotics, herbal remedies that have undergone clinical testing often show subjective sleep improvements that exceed objective measures, which may relate to interindividual heterogeneity and/or placebo effects. Response heterogeneity can undermine traditional randomized trial approaches, which in some fields has prompted a shift toward stratified trials based on genotype or phenotype, or the so-called n-of-1 method of testing placebo versus active drug in within-person alternating blocks. We reviewed six independent compendiums of herbal agents to assemble a group of over 70 reported to benefit sleep. To bridge the gap between the unfeasible expectation of formal evidence in this space and the reality of common self-medication by those with insomnia, we propose a method for guided self-testing that overcomes certain operational barriers related to inter-and intraindividual sources of phenotypic variability. Patient-chosen outcomes drive a general statistical model that allows personalized self-assessment that can augment the open-label nature of routine practice. The potential advantages of this method include flexibility to implement for other (nonherbal) insomnia interventions. C1 [Romero, Kate; Goparaju, Balaji; Russo, Kathryn; Westover, M. Brandon; Bianchi, Matt T.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Romero, Kate; Goparaju, Balaji; Russo, Kathryn; Bianchi, Matt T.] Harvard Med Sch, Div Sleep Med, Boston, MA USA. RP Bianchi, MT (reprint author), Massachusetts Gen Hosp, Wang Neurol 7, 55 Fruit St, Boston, MA 02114 USA. EM mtbianchi@partners.org FU Department of Neurology, Massachusetts General Hospital; Center for Integration of Medicine and Innovative Technology; Milton Family Foundation; MGH-MIT Grand Challenge; American Sleep Medicine Foundation; NIH [NIH-NINDS 1K23NS090900] FX Dr Bianchi has received funding from the Department of Neurology, Massachusetts General Hospital, the Center for Integration of Medicine and Innovative Technology, the Milton Family Foundation, the MGH-MIT Grand Challenge, and the American Sleep Medicine Foundation. Dr Bianchi has a patent pending on a home sleep monitoring device. Dr Bianchi has research contracts with MC10 and Insomnisolv, a consulting agreement with McKesson and International Flavors and Fragrances, received payment for educational material from Oakstone Publishing, and has provided expert testimony in sleep medicine. Dr Bianchi serves as a medical monitor for Pfizer. Dr Westover has received funding from the NIH (NIH-NINDS 1K23NS090900). The other authors report no conflicts of interest in this work. NR 43 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 1179-1608 J9 NAT SCI SLEEP JI NAT. SCI. SLEEP PY 2017 VL 9 BP 97 EP 108 DI 10.2147/NSS.S128095 PG 12 WC Clinical Neurology SC Neurosciences & Neurology GA EO3XI UT WOS:000396627600001 PM 28360539 ER PT J AU Shapiro, M Nandi, B Gonzalez, G Prabhala, RH Mashimo, H Huang, Q Frank, NY Munshi, NC Gold, JS AF Shapiro, Mia Nandi, Bisweswar Gonzalez, Gabriel Prabhala, Rao H. Mashimo, Hiroshi Huang, Qin Frank, Natasha Y. Munshi, Nikhil C. Gold, Jason S. TI Deficiency of the immunostimulatory cytokine IL-21 promotes intestinal neoplasia via dysregulation of the Th1/Th17 axis SO ONCOIMMUNOLOGY LA English DT Article DE Adenoma; carcinogenesis; colorectal neoplasms; IL-21; mice; Th1 cells; Th17 cells ID EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; TUMOR-INFILTRATING LYMPHOCYTES; TH17 CELLS; COLORECTAL-CANCER; INTERLEUKIN 21; HELPER-CELLS; T(H)17 CELLS; COLON-CANCER; T-CELLS; DIFFERENTIATION AB IL-21 has reported activity in promoting both Th1 and Th17 immune responses. Its role in sporadic human colorectal cancer is unknown. We aimed to delineate the role of IL-21 in a model of sporadic intestinal carcinogenesis. We found that in APC(MIN/C) mice, ablation of IL-21 increased intestinal tumorigenesis. Expression of pro-inflammatory Th17-associated genes, including RORgt and IL-17A, was increased in the intestine in the absence of IL-21, while expression of antitumor Th1-associated genes Tbet, IFN gamma, granzyme B, and perforin was decreased. Similarly, the IL-21-deficient APC(MIN/C) mouse intestines had fewer infiltrating T cells as well as decreased effector memory T cells, NK cells, and granzyme B-expressing cells. Finally, our data suggest that IL-21 impairs Th17 immune responses as mesenteric lymph nodes from IL-21-deficient mice had increased IL-17A expression, and naive helper T cells from IL-21-deficient mice were more prone to differentiate into IL-17Asecreting cells. C1 [Shapiro, Mia; Nandi, Bisweswar; Gonzalez, Gabriel; Prabhala, Rao H.] VA Boston Healthcare Syst, Res Serv, W Roxbury, MA USA. [Shapiro, Mia; Nandi, Bisweswar; Gonzalez, Gabriel; Prabhala, Rao H.; Mashimo, Hiroshi; Huang, Qin; Frank, Natasha Y.; Munshi, Nikhil C.; Gold, Jason S.] Harvard Med Sch, Boston, MA USA. [Prabhala, Rao H.; Munshi, Nikhil C.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Mashimo, Hiroshi; Frank, Natasha Y.; Munshi, Nikhil C.] VA Boston Healthcare Syst, Med Serv, W Roxbury, MA USA. [Mashimo, Hiroshi; Frank, Natasha Y.; Gold, Jason S.] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. [Huang, Qin] VA Boston Healthcare Syst, Pathol Serv, W Roxbury, MA USA. [Gold, Jason S.] VA Boston Healthcare Syst, Surg Serv, W Roxbury, MA USA. RP Gold, JS (reprint author), VA Boston Healthcare Syst 112, 1400 VFW Pkwy, W Roxbury, MA USA. EM jgold@bwh.harvard.edu NR 34 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 2162-402X J9 ONCOIMMUNOLOGY JI OncoImmunology PY 2017 VL 6 IS 1 AR e1261776 DI 10.1080/2162402X.2016.1261776 PG 7 WC Oncology; Immunology SC Oncology; Immunology GA EP0IB UT WOS:000397069400007 PM 28197386 ER PT J AU Kono, Y Lyshchik, A Cosgrove, D Dietrich, CF Jang, HJ Kim, TK Piscaglia, F Willmann, JK Wilson, SR Santillan, C Kambadakone, A Mitchell, D Vezeridis, A Sirlin, CB AF Kono, Yuko Lyshchik, Andrej Cosgrove, David Dietrich, Christoph F. Jang, Hyun-Jung Kim, Tae Kyoung Piscaglia, Fabio Willmann, Juergen K. Wilson, Stephanie R. Santillan, Cynthia Kambadakone, Avinash Mitchell, Donald Vezeridis, Alexander Sirlin, Claude B. TI Contrast Enhanced Ultrasound (CEUS) Liver Imaging Reporting and Data System (LI-RADS (R)): the official version by the American College of Radiology (ACR) SO ULTRASCHALL IN DER MEDIZIN LA English DT Letter C1 [Kono, Yuko] Univ Calif San Diego, Dept Med, San Diego, CA 92103 USA. [Lyshchik, Andrej; Mitchell, Donald] Thomas Jefferson Univ Hosp, Dept Radiol, Philadelphia, PA 19107 USA. [Cosgrove, David] Imperial Coll, London, England. [Cosgrove, David] Kings Coll London, London, England. [Dietrich, Christoph F.] Caritas Krankenhaus, Innere Med 2, Bad Mergentheim, Germany. [Jang, Hyun-Jung; Kim, Tae Kyoung] Univ Toronto, Dept Med Imaging, Toronto, ON, Canada. [Piscaglia, Fabio] Dept Med & Surg Sci, Div Internal Med, Bologna, Italy. [Willmann, Juergen K.] Stanford Univ, Dept Radiol, Stanford, CA 94305 USA. [Wilson, Stephanie R.] Univ Calgary, Radiol & Med, Div Gastroenterol, Calgary, AB, Canada. [Santillan, Cynthia; Vezeridis, Alexander; Sirlin, Claude B.] Univ Calif San Diego, Radiol, San Diego, CA 92103 USA. [Kambadakone, Avinash] Massachusetts Gen Hosp, Radiol, Boston, MA 02114 USA. RP Kono, Y (reprint author), Univ Calif San Diego, Dept Med & Radiol, 200 W WArbor Dr,MC 8413, San Diego, CA 92103 USA. EM ykono@ucsd.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU GEORG THIEME VERLAG KG PI STUTTGART PA RUDIGERSTR 14, D-70469 STUTTGART, GERMANY SN 0172-4614 EI 1438-8782 J9 ULTRASCHALL MED JI Ultraschall Med. PD JAN PY 2017 VL 38 IS 1 BP 85 EP 86 DI 10.1055/s-0042-124369 PG 2 WC Acoustics; Radiology, Nuclear Medicine & Medical Imaging SC Acoustics; Radiology, Nuclear Medicine & Medical Imaging GA EO1PC UT WOS:000396469400012 PM 28249328 ER PT J AU Levey, EJ Oppenheim, CE Lange, BCL Plasky, NS Harris, BL Lekpeh, GG Kekulah, I Henderson, DC Borba, CPC AF Levey, Elizabeth J. Oppenheim, Claire E. Lange, Brittany C. L. Plasky, Naomi S. Harris, Benjamin L. Lekpeh, G. Gondah Kekulah, Isaac Henderson, David C. Borba, Christina P. C. TI A qualitative analysis of parental loss and family separation among youth in post-conflict Liberia SO VULNERABLE CHILDREN AND YOUTH STUDIES LA English DT Article DE Liberia; sub-Saharan Africa; post-conflict; trauma; child; orphan ID ADVERSE CHILDHOOD EXPERIENCES; MENTAL-HEALTH; CHILDREN; AIDS; ADULTHOOD; RISK; RESILIENCE; ORPHANS; AFRICA; TRAUMA AB Between 1989 and 2003, the Republic of Liberia experienced a brutal civil war. In 2008, the population was approximately 3.5million people, and there were an estimated 340,000 orphans. Nearly 6000 more children were orphaned by the Ebola epidemic from 2014-2015. The goal of this research was to explore the impact of parental loss, identify moderating factors, and consider interventions that could help vulnerable youth in post-conflict societies following the loss of a parent. Seventy-five young people (age 13-18 years) in Monrovia, the capital city of Liberia, were recruited in 2012. Semi-structured interviews were conducted, and demographic data were collected. Interviews were then transcribed and coded thematically. The loss of a parent or other primary caregiver had a significant impact on psychosocial and emotional health. The timing of the loss, strength of connection with the deceased parent, and relationship with surviving parent or substitute caregiver were all relevant factors. Children separated from living parents were functioning better than those whose parents were deceased. The case of Liberian children underscores the importance of early caregiver relationships and the difficulties children face when such relationships are disrupted. Children who did not experience stable early relationships suffered disconnection from their families and communities. C1 [Levey, Elizabeth J.] Massachusetts Gen Hosp, Div Global Psychiat, 5 Longfellow Pl,Suite 215, Boston, MA 02114 USA. [Levey, Elizabeth J.] Harvard Med Sch, Dept Psychiat, Boston, MA USA. [Levey, Elizabeth J.] Univ Illinois, Coll Med, Dept Psychiat, Chicago, IL USA. [Oppenheim, Claire E.; Henderson, David C.; Borba, Christina P. C.] Boston Med Ctr, Dept Psychiat, Boston, MA USA. [Lange, Brittany C. L.] Univ Oxford, Dept Social Policy & Intervent, Oxford, England. [Plasky, Naomi S.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Harris, Benjamin L.; Lekpeh, G. Gondah; Kekulah, Isaac] Univ Liberia, AM Dogliotti Coll Med, Monrovia, Liberia. [Henderson, David C.; Borba, Christina P. C.] Boston Univ, Sch Med, Dept Psychiat, Boston, MA 02118 USA. RP Levey, EJ (reprint author), Massachusetts Gen Hosp, Div Global Psychiat, 5 Longfellow Pl,Suite 215, Boston, MA 02114 USA. EM elevey@partners.org FU National Institutes of Health [T32-MH-093310]; Partners Healthcare Center of Expertise in Global Health Travel Award FX This work was supported by the National Institutes of Health [T32-MH-093310] and Partners Healthcare Center of Expertise in Global Health Travel Award. NR 34 TC 0 Z9 0 U1 1 U2 1 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1745-0128 EI 1745-0136 J9 VULNERABLE CHILD YOU JI Vulnerable Child. Youth Stud. PY 2017 VL 12 IS 1 BP 1 EP 16 DI 10.1080/17450128.2016.1262978 PG 16 WC Family Studies SC Family Studies GA EO2ZC UT WOS:000396563600001 PM 28163770 ER PT J AU Deng, J AF Deng, Jing TI How to unleash mitochondrial apoptotic blockades to kill cancers? SO ACTA PHARMACEUTICA SINICA B LA English DT Review DE Apaptosis; BCL-2 family; Mitochondrial priming; BH3 profiling; Targeted therapy; Combination therapy ID CHRONIC LYMPHOCYTIC-LEUKEMIA; BCL-X-L; CELL LUNG-CANCER; HUMAN HEPATOCELLULAR-CARCINOMA; OBATOCLAX MESYLATE GX15-070; CRITICAL SURVIVAL FACTOR; BRUTONS TYROSINE KINASE; MULTIPLE-MYELOMA; MCL-1 EXPRESSION; PROSTATE-CANCER AB Apoptosis, especially the intrinsic mitochondrial cell death pathway, is regulated by the BCL-2 family of proteins. Defects in apoptotic machinery are one of the main mechanisms that cells employ to evade cell death and become cancerous. Targeting the apoptotic defects, either by direct inhibition of BCL-2 family proteins or through modulation of regulatory pathways, can restore cell sensitivity to cell death. This review will focus on the aspects of BCL-2 family proteins, their interactions with kinase pathways, and how novel targeted agents can help overcome the apoptotic blockades. Furthermore, functional assays, such as BH3 profiling, may help in predicting responses to chemotherapies and aid in the selection of combination therapies by determining the mitochondrial threshold for initiating cell death. (C) 2017 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V. C1 [Deng, Jing] Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. RP Deng, J (reprint author), Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. EM jing_deng@dfci.harvard.edu FU Letai group (Dana-Farber Cancer Institute, Harvard Medical School, USA) FX The author would like to thank Dr. Anthony Letai and the Letai group (Dana-Farber Cancer Institute, Harvard Medical School, USA) for their support, helpful discussion and the research cited in this review; and Dr. Patrick Bhola and Ms. Alexandra Pourzia for their critical review of this manuscript. NR 117 TC 0 Z9 0 U1 1 U2 1 PU INST MATERIA MEDICA, CHINESE ACAD MEDICAL SCIENCES PI BEIJING PA C/O EDITORIAL BOARD OF ACTA PHARMACEUTICA SINICA, 1 XIANNONGTAN ST, BEIJING, 100050, PEOPLES R CHINA SN 2211-3835 EI 2211-3843 J9 ACTA PHARMACOL SIN B JI Acta Pharm. Sin. B PD JAN PY 2017 VL 7 IS 1 BP 18 EP 26 DI 10.1016/j.apsb.2016.08.005 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EO1FB UT WOS:000396442700004 PM 28119805 ER PT J AU Ortega, SP Chouchani, ET Boudina, S AF Ortega, Sara P. Chouchani, Edward T. Boudina, Sihem TI Stress turns on the heat: Regulation of mitochondrial biogenesis and UCP1 by ROS in adipocytes SO ADIPOCYTE LA English DT Editorial Material DE mitochondria; brown adipose tissue; MnSOD; oxidative modification; proton leak; superoxide; ROS; Uncoupling protein 1 (UCP1) ID BROWN ADIPOSE-TISSUE; DIET-INDUCED OBESITY; MANGANESE SUPEROXIDE-DISMUTASE; OXIDATIVE STRESS; HYDROGEN-PEROXIDE; UNCOUPLING PROTEINS; ENERGY-EXPENDITURE; FAT MITOCHONDRIA; MICE; DEFICIENCY AB Reactive oxygen species (ROS) production and oxidative stress (OS) in adipose tissue are associated with obesity and insulin resistance (IR). The nature of this relationship i.e., cause and effect or consequence has not been clearly determined. We provide evidence that elevated mitochondrial ROS generated by adipocytes from mice with diet-induced obesity (DIO) represents an adaptive mechanism that precipitates fatty acid oxidation, mitochondrial biogenesis, and mitochondrial uncoupling in an effort to defend against weight gain. Consistent with that, mice with adipocyte-specific deletion of manganese superoxide dismutase (MnSOD) exhibit increased adipocyte superoxide generation and are protected from weight gain and insulin resistance which otherwise develops in wild-type (WT) mice that consume an obesogenic diet. The defense mechanism displayed by MnSOD-deficiency in fat cells appears to be mediated by a dual effect of ROS on inefficient substrate oxidation through uncoupling of oxidative phosphorylation and enhanced mitochondrial biogenesis. The aim of this commentary is to summarize and contextualize additional evidence supporting the importance of mitochondrial ROS in the regulation of mitochondrial biogenesis and the modulation of uncoupling protein 1 (UCP1) expression and activation in both white and brown adipocytes. C1 [Ortega, Sara P.; Boudina, Sihem] Univ Utah, Sch Med, Dept Nutr & Integrat Physiol, Salt Lake City, UT USA. [Ortega, Sara P.; Boudina, Sihem] Univ Utah, Sch Med, Div Endocrinol Metab & Diabet, Salt Lake City, UT USA. [Ortega, Sara P.; Boudina, Sihem] Univ Utah, Sch Med, Program Mol Med, Salt Lake City, UT USA. [Chouchani, Edward T.] Harvard Med Sch, Dana Farber Canc Inst, Boston, MA USA. [Chouchani, Edward T.] Harvard Med Sch, Dept Cell Biol, Boston, MA USA. RP Boudina, S (reprint author), Univ Utah, Program Mol Med, 15 N 2030 Bldg,533 Rm 3410B, Salt Lake City, UT 84112 USA. EM sihem.boudina@hmbg.utah.edu FU National Institute of Diabetes and Digestive and Kidney Diseases [1-R01-DK-098646-01A1]; Human Frontiers Science Foundation FX This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases grants 1-R01-DK-098646-01A1 to SB and by the Human Frontiers Science Foundation to ETC. NR 44 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 2162-3945 EI 2162-397X J9 ADIPOCYTE JI Adipocyte PY 2017 VL 6 IS 1 BP 56 EP 61 DI 10.1080/21623945.2016.1273298 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EN6ZZ UT WOS:000396153200007 ER PT J AU Katz, I Pichelin, M Montesantos, S Murdock, A Fromont, S Venegas, J Caillibotte, G AF Katz, Ira Pichelin, Marine Montesantos, Spyridon Murdock, Alexander Fromont, Samuel Venegas, Jose Caillibotte, Georges TI The influence of lung volume during imaging on CFD within realistic airway models SO AEROSOL SCIENCE AND TECHNOLOGY LA English DT Article ID COMPUTATIONAL FLUID-DYNAMICS; COMPUTED-TOMOGRAPHY; AEROSOL DEPOSITION; PARTICLE-TRANSPORT; RESPIRATORY-TRACT; HELIUM-OXYGEN; FLOW; SIMULATION; VENTILATION; VALIDATION AB In this article, we address a fundamental question regarding computational fluid dynamics ( CFD) modeling within lung airways: does the inhaled volume during imaging have a significant effect on CFD computations of aerosol deposition? High resolution computed tomography ( HRCT) images taken at mean lung volume ( MLV) and at total lung capacity ( TLC) obtained as part of a previous study of ventilation and aerosol deposition using positron emission tomography ( PET) in challenged asthmatics were utilized to construct two airway models for each subject, and the differences in CFD calculated deposition metrics were subsequently quantified. These models included all the airway generations that could be rendered from the HRCT images. CFD calculations for three inhalation flow rates and four monodisperse aerosol sizes used images at MLV and at TLC from 24 volunteer subjects. Both large scale and detailed measures of particle deposition distribution were used in the analysis. The influence of lung volume during imaging is to increase airway dimensions in realistic models and thus reduce flow velocity and deposition due to impaction in the upper airways as calculated by CFD. However, large-scale deposition measures are confounded when the TLC models include deeper generations in the lung that increase the total airway deposition. These trends are modulated by the flow and particle characteristics of the aerosol, making consistent quantifiable differences between MLV and TLC difficult to predict unless both models consider the same anatomical airways. C1 [Katz, Ira; Pichelin, Marine; Montesantos, Spyridon; Murdock, Alexander; Fromont, Samuel; Caillibotte, Georges] Air Liquide Sante Int, Med R&D, F-78354 Loges Josas, France. [Katz, Ira] Lafayette Coll, Dept Mech Engn, Easton, PA USA. [Venegas, Jose] Massachusetts Gen Hosp, Boston, MA USA. [Venegas, Jose] Harvard Med Sch, Boston, MA USA. RP Katz, I (reprint author), Air Liquide Sante Int, Med R&D, F-78354 Loges Josas, France. EM ira.katz@airliquide.com NR 44 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 0278-6826 EI 1521-7388 J9 AEROSOL SCI TECH JI Aerosol Sci. Technol. PY 2017 VL 51 IS 2 BP 214 EP 223 DI 10.1080/02786826.2016.1254721 PG 10 WC Engineering, Chemical; Engineering, Mechanical; Environmental Sciences; Meteorology & Atmospheric Sciences SC Engineering; Environmental Sciences & Ecology; Meteorology & Atmospheric Sciences GA EL5LC UT WOS:000394661600010 ER PT J AU Grelottia, DJ Grelotti, DJ Hammer, GP Dilley, JW Karasic, DH Sorensen, JL Bangsberg, DR Tsai, AC AF Grelottia, David J. Grelotti, David J. Hammer, Gwendolyn P. Dilley, James W. Karasic, Dan H. Sorensen, James L. Bangsberg, David R. Tsai, Alexander C. TI Does substance use compromise depression treatment in persons with HIV? Findings from a randomized controlled trial SO AIDS CARE-PSYCHOLOGICAL AND SOCIO-MEDICAL ASPECTS OF AIDS/HIV LA English DT Article DE Depression; substance abuse; HIV; syndemics; directly observed therapy ID ACTIVE ANTIRETROVIRAL THERAPY; ANTIDEPRESSANT MEDICATION TREATMENT; PLACEBO-CONTROLLED TRIAL; ALCOHOL-USE DISORDERS; MENTAL-HEALTH; UNITED-STATES; INFECTED INDIVIDUALS; TREATMENT OUTCOMES; MAJOR DEPRESSION; HOMELESS ADULTS AB Depression and substance use are significant obstacles to effective HIV care. Using data derived from a randomized controlled trial of persons with HIV who are homeless or marginally housed, this study assesses the utility of antidepressant treatment among persons with HIV, depression, and active substance use. Participants were diagnosed with depressive disorders and randomly assigned to receive directly observed therapy with fluoxetine or a referral to community mental health treatment. Assessments, conducted at baseline and every 3 months over a 9-month period, included the Hamilton Rating Scale for Depression, the Beck Depression Inventory II, and self-report of alcohol, crack, cocaine, heroin, or methamphetamine use in the past 90 days. To investigate the effect of antidepressant treatment in the setting of active substance use, the authors fit mixed-effects linear regression models to estimate the effect of directly observed fluoxetine on depressive symptom severity after stratifying by any alcohol use or any illicit drug use. To investigate whether alcohol use or illicit drug use moderated the antidepressant treatment response, the authors examined the interaction terms. The effect of directly observed fluoxetine treatment on depression symptom severity was statistically significant irrespective of alcohol use status. When stratified by illicit drug use status, the effect of directly observed fluoxetine treatment on depression symptom severity was statistically significant only among persons who did not use illicit drugs. The interaction terms were not statistically significant. This study found a benefit of antidepressant treatment in persons with HIV, depression, and alcohol use. In addition, this study found no evidence that either alcohol use or illicit drug use moderates the antidepressant treatment response. Altogether, these findings support the use of antidepressant medication in this population. The public health impact of research in this area is significant given the known adverse effects of depression on HIV-related health outcomes. ClinicalTrials. gov Identifier: NCT00338767. C1 [Grelottia, David J.] Univ Calif San Diego, Dept Psychiat, San Diego, CA 92103 USA. [Grelottia, David J.; Tsai, Alexander C.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Hammer, Gwendolyn P.] Calif Dept Publ Hlth, Richmond, CA USA. [Dilley, James W.; Karasic, Dan H.; Sorensen, James L.] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA. [Bangsberg, David R.; Tsai, Alexander C.] Massachusetts Gen Hosp, Ctr Global Hlth, Boston, MA 02114 USA. [Bangsberg, David R.; Tsai, Alexander C.] Harvard Med Sch, Boston, MA USA. [Bangsberg, David R.; Tsai, Alexander C.] Mbarara Univ Sci & Technol, Mbarara, Uganda. RP Grelottia, DJ (reprint author), Univ Calif San Diego, Dept Psychiat, 9500 Gilman Dr,MC 0603, La Jolla, CA 92093 USA. EM dgrelotti@ucsd.edu FU U.S. National Institutes of Health (NIH) [R01MH063011]; NIH [R01MH054907, T32MH017119, K23MH096620, K24MH087227] FX This study was funded by the U.S. National Institutes of Health (NIH) [grant number R01MH063011] (PI: Bangsberg). The Research in Access to Care for the Homeless cohort, from whom some of the study participants were drawn, was funded by the NIH [grant number R01MH054907] (PI: Bangsberg). Members of the research team also acknowledge the following additional funding support from the NIH: [grant number T32MH017119] (Grelotti), [grant number K23MH096620] (Tsai), and [grant number K24MH087227] (Bangsberg). HIV RNA kits were donated by Roche. Study doses of Prozac Weekly(R) were donated by Eil Lilly from 2002 through 2005. No funding source was involved in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the article for publication. NR 41 TC 0 Z9 0 U1 0 U2 0 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 0954-0121 EI 1360-0451 J9 AIDS CARE JI Aids Care-Psychol. Socio-Med. Asp. Aids-Hiv PY 2017 VL 29 IS 3 BP 273 EP 279 DI 10.1080/09540121.2016.1226479 PG 7 WC Health Policy & Services; Public, Environmental & Occupational Health; Psychology, Multidisciplinary; Respiratory System; Social Sciences, Biomedical SC Health Care Sciences & Services; Public, Environmental & Occupational Health; Psychology; Respiratory System; Biomedical Social Sciences GA EL4TG UT WOS:000394613200001 PM 27590273 ER PT J AU Dale, SK Weber, KM Cohen, MH Brody, LR AF Dale, Sannisha K. Weber, Kathleen M. Cohen, Mardge H. Brody, Leslie R. TI Abuse, nocturnal stress hormones, and coronary heart disease risk among women with HIV SO AIDS CARE-PSYCHOLOGICAL AND SOCIO-MEDICAL ASPECTS OF AIDS/HIV LA English DT Article DE Abuse; HIV; women; norepinephrine; cortisol ID CHILDHOOD SEXUAL-ABUSE; CORTISOL PRODUCTION; INTERAGENCY HIV; PTSD; NOREPINEPHRINE; EXPERIENCES; DISORDER; TRAUMA; SLEEP AB This study investigated the relationshipsamong abuse, nocturnal levels of cortisol and norepinephrine (NE), and coronary heart disease (CHD) risk as measured by the Framingham risk score among women with human immunodeficiency virus (HIV). Participants (n = 53) from the Chicago Women's Interagency HIV Study (WIHS), a longitudinal prospective cohort study initiated in 1994, were enrolled in this study during 2012. At WIHS baseline and annual follow-up visits, women were asked about recent experiences of abuse. Summary variables captured the proportion of visits for which women reported recent (past 12 months) physical, sexual, and domestic abuse. Cortisol and NE were assayed in overnight urine samples and adjusted for creatinine levels. Recent abuse was not significantly associated with levels of cortisol, NE, or NE/cortisol ratio. However, higher NE/ cortisol ratio was significantly related to higher CHD risk score, higher cortisol was significantly related to lower CHD risk score, and NE was not associated with CHD risk score. In addition, higher proportions of visits with recent sexual abuse, physical abuse, and domestic abuse were significantly related to higher CHD risk score. The association between abuse exposure and CHD risk in the context of HIV infection is likely complex and may involve dysregulation of multiple neurobiological systems. Future research is needed to better understand these relationships and prevention and intervention efforts are needed to address abuse among women with HIV. C1 [Dale, Sannisha K.] Massachusetts Gen Hosp, One Bowdoin Sq,Suite 701, Boston, MA 02114 USA. [Dale, Sannisha K.] Harvard Med Sch, Boston, MA USA. [Weber, Kathleen M.; Cohen, Mardge H.] Cook Cty Hlth & Hosp Syst, Chicago, IL USA. [Dale, Sannisha K.; Brody, Leslie R.] Boston Univ, Dept Psychol & Brain Sci, Boston, MA 02215 USA. RP Dale, SK (reprint author), Massachusetts Gen Hosp, Behav Med Serv, One Bowdoin Sq,Suite 701, Boston, MA 02114 USA. EM skdale@mgh.harvard.edu FU National Institute of Allergy and Infectious Diseases [U01-AI-34994]; National Cancer Institute, National Institute of Drug Abuse; Eunice Kennedy Shriver National Institute of Child Health & Human Development; National Research Service Award from the National Institute of Mental Health [F31MH095510]; [P30-AI082151] FX Data in this manuscript were collected by the Chicago site of the Women's Interagency HIV study (WIHS), which is funded by the National Institute of Allergy and Infectious Diseases [grant number U01-AI-34994] (PI, Mardge Cohen) with co-funding from the National Cancer Institute, National Institute of Drug Abuse, and the Eunice Kennedy Shriver National Institute of Child Health & Human Development. Sannisha K. Dale was funded by a National Research Service Award (#F31MH095510) from the National Institute of Mental Health. Kathleen Weber was also funded in part by P30-AI082151. NR 26 TC 0 Z9 0 U1 0 U2 0 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 0954-0121 EI 1360-0451 J9 AIDS CARE JI Aids Care-Psychol. Socio-Med. Asp. Aids-Hiv PY 2017 VL 29 IS 5 BP 598 EP 602 DI 10.1080/09540121.2016.1241378 PG 5 WC Health Policy & Services; Public, Environmental & Occupational Health; Psychology, Multidisciplinary; Respiratory System; Social Sciences, Biomedical SC Health Care Sciences & Services; Public, Environmental & Occupational Health; Psychology; Respiratory System; Biomedical Social Sciences GA EO6BF UT WOS:000396776000012 PM 27733045 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 AMERICAN JOURNAL OF GASTROENTEROLOGY 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, White River Jct, VT 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, 215N Main St, White River Jct, VT 05009 USA. EM douglas.robertson@va.gov FU Olympus; Endochoice FX This authors discloses 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 Kaltenback served as Consultant for Olympus America. The remaining authors disclose no conflicts. NR 118 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 0002-9270 EI 1572-0241 J9 AM J GASTROENTEROL JI Am. J. Gastroenterol. PD JAN PY 2017 VL 112 IS 1 BP 37 EP 53 DI 10.1038/ajg.2016.492 PG 17 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EK7UX UT WOS:000394131800013 PM 27753435 ER PT J AU Nagata, K Endo, S Honda, T Yasuda, T Hirayama, M Takahashi, S Kato, T Horita, S Furuya, K Kasai, K Matsumoto, H Kimura, Y Utano, K Sugimoto, H Kato, H Yamada, R Yamamichi, J Shimamoto, T Ryu, Y Matsui, O Kondo, H Doi, A Abe, T Yamano, H Takeuchi, K Hanai, H Saida, Y Fukuda, K Nappi, J Yoshida, H AF Nagata, Koichi Endo, Shungo Honda, Tetsuro Yasuda, Takaaki Hirayama, Michiaki Takahashi, Sho Kato, Takashi Horita, Shoichi Furuya, Ken Kasai, Kenji Matsumoto, Hiroshi Kimura, Yoshiki Utano, Kenichi Sugimoto, Hideharu Kato, Hiroyuki Yamada, Rieko Yamamichi, Junta Shimamoto, Takeshi Ryu, Yasuji Matsui, Osamu Kondo, Hitoshi Doi, Ayako Abe, Taro Yamano, Hiro-o Takeuchi, Ken Hanai, Hiroyuki Saida, Yukihisa Fukuda, Katsuyuki Nappi, Janne Yoshida, Hiroyuki TI Accuracy of CT Colonography for Detection of Polypoid and Nonpolypoid Neoplasia by Gastroenterologists and Radiologists: A Nationwide Multicenter Study in Japan SO AMERICAN JOURNAL OF GASTROENTEROLOGY LA English DT Article ID COMPUTED TOMOGRAPHIC COLONOGRAPHY; COLORECTAL-CANCER; ASYMPTOMATIC ADULTS; AIDED DETECTION; VIRTUAL COLONOSCOPY; DIAGNOSTIC-ACCURACY; LESIONS; TRIAL; FLAT; POPULATION AB OBJECTIVES: The objective of this study was to assess prospectively the diagnostic accuracy of computer-assisted computed tomographic colonography (CTC) in the detection of polypoid (pedunculated or sessile) and nonpolypoid neoplasms and compare the accuracy between gastroenterologists and radiologists. METHODS: This nationwide multicenter prospective controlled trial recruited 1,257 participants with average or high risk of colorectal cancer at 14 Japanese institutions. Participants had CTC and colonoscopy on the same day. CTC images were interpreted independently by trained gastroenterologists and radiologists. The main outcome was the accuracy of CTC in the detection of neoplasms >= 6 mm in diameter, with colonoscopy results as the reference standard. Detection sensitivities of polypoid vs. nonpolypoid lesions were also evaluated. RESULTS: Of the 1,257 participants, 1,177 were included in the final analysis: 42 (3.6%) were at average risk of colorectal cancer, 456 (38.7%) were at elevated risk, and 679 (57.7%) had recent positive immunochemical fecal occult blood tests. The overall per-participant sensitivity, specificity, and positive and negative predictive values for neoplasms >= 6 mm in diameter were 0.90, 0.93, 0.83, and 0.96, respectively, among gastroenterologists and 0.86, 0.90, 0.76, and 0.95 among radiologists (P<0.05 for gastroenterologists vs. radiologists). The sensitivity and specificity for neoplasms >= 10 mm in diameter were 0.93 and 0.99 among gastroenterologists and 0.91 and 0.98 among radiologists (not significant for gastroenterologists vs. radiologists). The CTC interpretation time by radiologists was shorter than that by gastroenterologists (9.97 vs. 15.8 min, P<0.05). Sensitivities for pedunculated and sessile lesions exceeded those for flat elevated lesions >= 10 mm in diameter in both groups (gastroenterologists 0.95, 0.92, and 0.68; radiologists: 0.94, 0.87, and 0.61; P<0.05 for polypoid vs. nonpolypoid), although not significant (P>0.05) for gastroenterologists vs. radiologists. CONCLUSIONS: CTC interpretation by gastroenterologists and radiologists was accurate for detection of polypoid neoplasms, but less so for nonpolypoid neoplasms. Gastroenterologists had a higher accuracy in the detection of neoplasms >= 6 mm than did radiologists, although their interpretation time was longer than that of radiologists. C1 [Nagata, Koichi; Endo, Shungo] Japanese CTC Soc, Boston, MA USA. [Yoshida, Hiroyuki] Massachusetts Gen Hosp, Dept Radiol, Imaging Res 3D, 25 New Chardon St,Suite 400C, Boston, MA 02114 USA. [Yoshida, Hiroyuki] Harvard Med Sch, 25 New Chardon St,Suite 400C, Boston, MA 02114 USA. [Endo, Shungo] Showa Univ, Ctr Digest Dis, Northern Yokohama Hosp, Yokohama, Kanagawa, Japan. [Honda, Tetsuro] Nagasaki Kamigoto Hosp, Dept Gastroenterol, Nagasaki, Japan. [Yasuda, Takaaki] Nagasaki Kamigoto Hosp, Radiol Sect, Nagasaki, Japan. [Hirayama, Michiaki; Takahashi, Sho] Otaru Kyokai Hosp, Dept Gastroenterol, Otaru, Hokkaido, Japan. [Kato, Takashi] Hokkaido Gastroenterol Hosp, Dept Gastroenterol, Sapporo, Hokkaido, Japan. [Horita, Shoichi] Hokkaido Gastroenteol Hosp, Dept Internal Med, Sapporo, Hokkaido, Japan. [Furuya, Ken] Hokkaido Hosp, Japan Community Hlth Care Org JCHO, Dept Gastroenterol & Hepatol, Sapporo, Hokkaido, Japan. [Kasai, Kenji] Hokkaido Hosp, Japan Community Hlth Care Org JCHO, Dept Radiol, Sapporo, Hokkaido, Japan. [Matsumoto, Hiroshi; Kimura, Yoshiki] Kawasaki Med Sch Hosp, Dept Gastroenterol, Kurashiki, Okayama, Japan. [Utano, Kenichi; Sugimoto, Hideharu] Jichi Med Univ Hosp, Dept Radiol, Shimotsuke, Tochigi, Japan. [Kato, Hiroyuki; Yamada, Rieko] Tokyo Womens Med Univ, Dept Clin Lab & Endoscopy, Med Ctr East, Tokyo, Japan. [Yamamichi, Junta] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Shimamoto, Takeshi] Kameda Med Ctr Makuhari, Dept Med Stat & Informat, Chiba, Chiba, Japan. [Ryu, Yasuji; Matsui, Osamu] Kanazawa Univ Hosp, Dept Radiol, Kanazawa, Ishikawa, Japan. [Kondo, Hitoshi; Doi, Ayako] Tonan Hosp, Ctr Digest Dis, Sapporo, Hokkaido, Japan. [Abe, Taro; Yamano, Hiro-o] Akita Red Cross Hosp, Ctr Digest Dis, Akita, Akita, Japan. [Takeuchi, Ken; Hanai, Hiroyuki] Hamamatsu South Hosp, Ctr Gastroenterol & IBD Res, Shizuoka, Japan. [Saida, Yukihisa] St Lukes Int Hosp, Dept Radiol, Tokyo, Japan. [Fukuda, Katsuyuki] St Lukes Int Hosp, Dept Gastroenterol, Tokyo, Japan. [Hirayama, Michiaki] Tonan Hosp, Dept Gastroenterol, Sapporo, Hokkaido, Japan. [Takahashi, Sho] Oji Gen Hosp, Dept Gastroenterol, Tomakomai, Hokkaido, Japan. [Kasai, Kenji] Sapporo Century Hosp, Dept Gastroenterol, Sapporo, Hokkaido, Japan. [Takeuchi, Ken] Toho Univ, Div Gastroenterol & Hepatol, Dept Internal Med, Sakura Med Ctr, Sakura, Chiba, Japan. RP Yoshida, H (reprint author), Massachusetts Gen Hosp, Dept Radiol, Imaging Res 3D, 25 New Chardon St,Suite 400C, Boston, MA 02114 USA.; Yoshida, H (reprint author), Harvard Med Sch, 25 New Chardon St,Suite 400C, Boston, MA 02114 USA. EM yoshida.hiro@mgh.harvard.edu FU Japanese CTC Society; Ajinomoto Pharmaceutical; National Institutes of Health, Bethesda, Maryland [R01CA095279]; National Institutes of Health [R01CA095279] FX This study was in part supported by the Japanese CTC Society, Ajinomoto Pharmaceutical, and R01CA095279 (Principal Investigator: Yoshida) from the National Institutes of Health, Bethesda, Maryland. The Japanese CTC Society did have a 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. The industry sponsor, Ajinomoto Pharmaceutical, had no role in the above aspects of the study. The National Institutes of Health had no role in the above aspects of the study, but had a role in supporting the development of computer-aided diagnosis soft ware for image interpretation used in the study through grant R01CA095279. NR 32 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 0002-9270 EI 1572-0241 J9 AM J GASTROENTEROL JI Am. J. Gastroenterol. PD JAN PY 2017 VL 112 IS 1 BP 163 EP 171 DI 10.1038/ajg.2016.478 PG 9 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EK7UX UT WOS:000394131800027 PM 27779195 ER PT J AU Melamed, A Keating, NL Clemmer, JT Bregar, AJ Wright, JD Boruta, DM Schorge, JO del Carmen, MG Rauh-Hain, JA AF Melamed, Alexander Keating, Nancy L. Clemmer, Joel T. Bregar, Amy J. Wright, Jason D. Boruta, David M. Schorge, John O. del Carmen, Marcela G. Rauh-Hain, J. Alejandro TI Laparoscopic staging for apparent stage I epithelial ovarian cancer SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE laparoscopy; laparotomy; ovarian cancer; staging ID FALLOPIAN-TUBE; SURGERY; DISPARITIES; LAPAROTOMY AB BACKGROUND: Whereas advances in minimally invasive surgery have made laparoscopic staging technically feasible in stage I epithelial ovarian cancer, the practice remains controversial because of an absence of randomized trials and lack of high-quality observational studies demonstrating equivalent outcomes. OBJECTIVE: This study seeks to evaluate the association of laparoscopic staging with survival among women with clinical stage I epithelial ovarian cancer. STUDY DESIGN: We used the National Cancer Data Base to identify all women who underwent surgical staging for clinical stage I epithelial ovarian cancer diagnosed from 2010 through 2012. The exposure of interest was planned surgical approach (laparoscopy vs laparotomy), and the primary outcome was overall survival. The primary analysis was based on an intention to treat: all women whose procedures were initiated laparoscopically were categorized as having had a planned laparoscopic procedure, regardless of subsequent conversion to laparotomy. We used propensity methods to match patients who underwent planned laparoscopic staging with similar patients who underwent planned laparotomy based on observed characteristics. We compared survival among the matched cohorts using the Kaplan-Meiermethod and Cox regression. We compared the extent of lymphadenectomy using the Wilcoxon rank-sum test. RESULTS: Among 4798 eligible patients, 1112 (23.2%) underwent procedures that were initiated laparoscopically, of which 190 (17%) were converted to laparotomy. Women who underwent planned laparoscopy were more frequently white, privately insured, from wealthier ZIP codes, received care in community cancer centers, and had smaller tumors that were more frequently of serous and less often of mucinous histology than those who underwent staging via planned laparotomy. After propensity score matching, time to death did not differ between patients undergoing planned laparoscopic vs open staging (hazard ratio, 0.77, 95% confidence interval, 0.54-1.09; P =.13). Planned laparoscopic staging was associated with a slightly higher median lymph node count (14 vs 12, P =.005). Planned laparoscopic staging was not associated with time to death after adjustment for receipt of adjuvant chemotherapy, histological type and grade, and pathological stage (hazard ratio, 0.82, 95% confidence interval, 0.57-1.16). CONCLUSION: Surgical staging via planned laparoscopy vs laparotomy was not associated with worse survival in women with apparent stage I epithelial ovarian cancer. C1 [Melamed, Alexander; Clemmer, Joel T.; Bregar, Amy J.; Boruta, David M.; Schorge, John O.; del Carmen, Marcela G.; Rauh-Hain, J. Alejandro] Massachusetts Gen Hosp, Harvard Med Sch, Div Gynecol Oncol, Vincent Obstetr & Gynecol, Boston, MA 02114 USA. [Keating, Nancy L.] Harvard Med Sch, Dept Hlth Care Policy, Boston, MA USA. [Keating, Nancy L.] Brigham & Womens Hosp, Div Gen Int Med, Boston, MA USA. [Wright, Jason D.] Columbia Univ, Dept Obstet & Gynecol, Columbia, MD USA. [Wright, Jason D.] Columbia Univ, Herbert Irving Comprehens Canc Ctr, Columbia, MD USA. [Wright, Jason D.] New York Presbyterian Hosp, New York, NY USA. RP Rauh-Hain, JA (reprint author), Massachusetts Gen Hosp, Harvard Med Sch, Div Gynecol Oncol, Vincent Obstetr & Gynecol, Boston, MA 02114 USA. EM jrauh-hain@partners.org FU National Cancer Institute at the National Institutes of Health [R25CA092203]; Deborah Kelly Center for Outcomes Research, Massachusetts General Hospital; National Cancer Institute [K24CA181510] FX This work was supported by grant R25CA092203 from the National Cancer Institute at the National Institutes of Health and The Deborah Kelly Center for Outcomes Research, Massachusetts General Hospital. Dr Keating is also supported by grant K24CA181510 from the National Cancer Institute. 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 0002-9378 EI 1097-6868 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JAN PY 2017 VL 216 IS 1 AR 50.e1 DI 10.1016/j.ajog.2016.08.030 PG 12 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA EO0II UT WOS:000396381100012 ER PT J AU Freytes, IM LeLaurin, JH Zickmund, SL Resende, RD Uphold, CR AF Freytes, I. Magaly LeLaurin, Jennifer H. Zickmund, Susan L. Resende, Rosana D. Uphold, Constance R. TI Exploring the Post-Deployment Reintegration Experiences of Veterans With PTSD and Their Significant Others SO AMERICAN JOURNAL OF ORTHOPSYCHIATRY LA English DT Article DE post-deployment; family reintegration; family functioning; PTSD; TBI ID FAMILY; SYMPTOMS; COMBAT; HOME AB Veterans with family support have better functional recovery and reintegration outcomes. However, families' ability to support the veteran with PTSD's rehabilitation and reintegration oftentimes is hindered by interpersonal challenges. We report findings of a qualitative study that examined OEF/OIF veterans with PTSD/TBI and their significant others' (SOs') perceptions of family functioning. We conducted 24 in-depth interviews with 12 veteran/SO dyads using an adapted version of the Family Assessment Device Structured Interview. Descriptive qualitative analytic methods were used to analyze the data. Data show that the impact of deployment and the resulting changes in the individuals and the family dynamics lingered years after the veterans returned home and had a lasting influence on veterans' and SOs' perceptions of family functioning. Most couples acknowledged growth in their relationships several years postdeployment. However, many continued to struggle with disruptions generated by deployment. Four themes emerged from the data: individual changes, coping strategies, relationship changes, and a "new normal." Postdeployment family functioning was influenced by a dynamic interplay of individual and relationship factors and the development of coping strategies and a new normal. This study contributes to the understanding of the prolonged postdeployment family reintegration experiences of veterans and their SOs. Findings underscore the importance of continuing to advance the current knowledge base about the long-term impact of deployment on veterans and their families, especially factors that contribute to positive postdeployment family functioning. Additional empirical studies are needed to provide more in-depth understanding of the long-term postdeployment reintegration experiences of veterans and their families. C1 [Freytes, I. Magaly; LeLaurin, Jennifer H.] North Florida South Georgia Vet Hlth Syst, Ctr Innovat Disabil & Rehabil Res CINDRR, Gainesville, FL USA. [Zickmund, Susan L.] VA Pittsburgh Hlth Care Syst, Ctr Hlth Equ Res & Promot, Pittsburgh, PA USA. [Resende, Rosana D.] Univ Florida, Ctr Latin Amer Studies, Gainesville, FL 32611 USA. [Uphold, Constance R.] North Florida South Georgia Vet Hlth Syst, Geriatr Res Educ & Clin Ctr, Gainesville, FL USA. [Uphold, Constance R.] Univ Florida, Coll Med, Dept Aging & Geriatr Res, Gainesville, FL 32611 USA. [Zickmund, Susan L.] VA Salt Lake City Informat Decis Enhancement & An, Ctr Innovat COIN, Salt Lake City, UT USA. [Zickmund, Susan L.] Univ Utah, Dept Med, Salt Lake City, UT 84112 USA. RP Freytes, IM (reprint author), North Florida South Georgia Vet Hlth Syst, 1601 SW Archer Rd 151B, Gainesville, FL 32608 USA. EM ivette.freytes@va.gov FU Department of Veterans Affairs, Veterans Health Administration, Rehabilitation Research and Development Service Merit Award [D7801-P] FX The research reported here was supported by the Department of Veterans Affairs, Veterans Health Administration, Rehabilitation Research and Development Service Merit Award D7801-P. We thank Justin Ahern, Latrice Jones, Tasnia Osmani, and Magda Schmitzberger for assistance with this research. NR 24 TC 1 Z9 1 U1 1 U2 1 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0002-9432 EI 1939-0025 J9 AM J ORTHOPSYCHIAT JI Am. J. Orthopsychiatr. PY 2017 VL 87 IS 2 SI SI BP 149 EP 156 DI 10.1037/ort0000211 PG 8 WC Psychiatry; Social Work SC Psychiatry; Social Work GA EN2SD UT WOS:000395859400005 PM 28206802 ER PT J AU Primack, JM Borsari, B Benz, MB Reddy, MK Shea, MT AF Primack, Jennifer M. Borsari, Brian Benz, Madeline B. Reddy, Madhavi K. Shea, M. Tracie TI Mental Health Treatment Utilization in OIF/OEF National Guard and Reserve Troops With and Without DSM Diagnoses SO AMERICAN JOURNAL OF ORTHOPSYCHIATRY LA English DT Article DE mental health; treatment utilization; military ID POSTTRAUMATIC-STRESS-DISORDER; TREATMENT ENGAGEMENT; TREATMENT-SEEKING; SOCIAL SUPPORT; PTSD TREATMENT; VETERANS; CARE; BARRIERS; IRAQ; SOLDIERS AB Military service members have an increased risk of developing mental health (MH) problems following deployment to Iraq or Afghanistan, yet only a small percentage seek mental health treatment. The aim of the present study was to explore patterns of MH service utilization within the first 12 months following return from combat deployment. Participants were 169 service members who had returned from war-zone deployment in either Iraq or Afghanistan and had assessments covering a 12-month period following their homecoming. The authors first examined the prevalence of mental health diagnoses and engagement with mental health treatment (e.g., visits to the emergency room, inpatient hospitalization, individual therapy, group therapy, family or couple therapy, medication appointments, and self-help). Regression analyses explored whether distress, functioning, diagnoses, or social support predicted treatment use. Findings indicated that 28 of 50 military service members (56%) who met diagnostic criteria for a mental health disorder accessed services in the year following their return from deployment. Individual treatment was the most common modality, and those with major depressive disorder (MDD) reported the most treatment contacts. Social support was not associated with use of mental health services. Baseline functioning and psychiatric distress predicted entry into treatment whereas only psychiatric distress predicted amount of mental health service use in the 12-month postdeployment period. Findings highlight the need for enhanced strategies to link those reporting psychiatric distress with MH treatment services and increase community connectedness regardless of whether they meet full criteria for a mental health diagnosis. C1 [Primack, Jennifer M.; Borsari, Brian; Shea, M. Tracie] Providence VA Med Ctr, 830 Chalkstone Ave, Providence, RI 02906 USA. [Primack, Jennifer M.; Reddy, Madhavi K.; Shea, M. Tracie] Brown Univ, Warren Alpert Sch Med, Providence, RI 02912 USA. [Borsari, Brian; Benz, Madeline B.] Brown Univ, Ctr Alcohol & Addict Studies, Providence, RI 02912 USA. [Reddy, Madhavi K.] Univ Texas Med Sch Houston, Houston, TX USA. [Borsari, Brian] Univ Calif San Francisco, San Francisco Vet Affairs Med Ctr, San Francisco, CA 94143 USA. RP Primack, JM (reprint author), Providence VA Med Ctr, 830 Chalkstone Ave, Providence, RI 02906 USA. EM Jennifer_Primack@brown.edu FU Department of Defense [W81XWH-06-1-0573] FX This work was supported by a grant from the Department of Defense awarded to Tracie Shea (W81XWH-06-1-0573). The authors express their appreciation to the participating members of the National Guard and Reserves, the leadership of the Rhode Island National Guard, and to Walter Musto, Lauren Slater, and Melissa Platt for their work on this study. The contents of this article do not represent the views of the Department of Veterans Affairs or the United States Government. NR 44 TC 1 Z9 1 U1 0 U2 0 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0002-9432 EI 1939-0025 J9 AM J ORTHOPSYCHIAT JI Am. J. Orthopsychiatr. PY 2017 VL 87 IS 2 SI SI BP 157 EP 165 DI 10.1037/ort0000226 PG 9 WC Psychiatry; Social Work SC Psychiatry; Social Work GA EN2SD UT WOS:000395859400006 PM 28206803 ER PT J AU Rundback, JH Armstrong, EJ Contos, B Iida, O Jacobs, D Jaff, MR Matsumoto, AH Mills, JL Montero-Baker, M Pena, C Tallian, A Uematsu, M Wilkins, LR Shishehbor, MH AF Rundback, John H. Armstrong, Ehrin J. Contos, Brian Iida, Osamu Jacobs, Donald Jaff, Michael R. Matsumoto, Alan H. Mills, Joseph L., Sr. Montero-Baker, Miguel Pena, Constantino Tallian, Alexander Uematsu, Masaaki Wilkins, Luke R. Shishehbor, Mehdi H. TI Key Concepts in Critical Limb Ischemia: Selected Proceedings from the 2015 Vascular Interventional Advances Meeting SO ANNALS OF VASCULAR SURGERY LA English DT Article ID PERIPHERAL ARTERIAL-DISEASE; FOOT INFECTION WIFI; LOWER-EXTREMITY; CLASSIFICATION-SYSTEM; CLINICAL-OUTCOMES; REVASCULARIZATION; IMPACT; ANGIOPLASTY; ANGIOGRAPHY; PERFUSION AB Over 500,000 patients each year are diagnosed with critical limb ischemia (CLI), the most severe form of peripheral artery disease. CLI portends a grim prognosis; half the patients die from a cardiovascular cause within 5 years, a rate that is 5 times higher than a matched population without CLI. In 2014, the Centers for Medicare and Medicaid Services paid approximately $ 3.6 billion for claims submitted by hospitals for inpatient and outpatient care delivered to patients with CLI. Although significant advances in diagnosis, treatment, and follow-up of patients with CLI have been made, many challenges remain. In this article, we summarize selected presentations from the 2015 Vascular Interventional Advances Conference related to the modern demographics, diagnosis, and management of patients with CLI. C1 [Rundback, John H.] Holy Name Med Ctr, Intervent Inst, Teaneck, NJ 07666 USA. [Armstrong, Ehrin J.] VA Eastern Colorado Healthcare Syst, Dept Vasc Surg, Denver, CO USA. [Armstrong, Ehrin J.] Univ Colorado, Denver, CO 80202 USA. [Contos, Brian; Tallian, Alexander] Advisory Board Co, Washington, DC USA. [Iida, Osamu; Uematsu, Masaaki] Kansai Rosai Hosp, Ctr Cardiovasc, Amagasaki, Hyogo, Japan. [Jacobs, Donald] St Louis Univ, Sch Med, Dept Surg, St Louis, MO USA. [Jaff, Michael R.] Massachusetts Gen Hosp, Dept Vasc Med, Boston, MA 02114 USA. [Matsumoto, Alan H.; Wilkins, Luke R.] Univ Virginia Hlth Syst, Dept Radiol & Med Imaging, Charlottesville, VA USA. [Mills, Joseph L., Sr.; Montero-Baker, Miguel] Baylor Coll Med, Div Vasc Surg & Endovasc Therapy, Houston, TX 77030 USA. [Pena, Constantino] Baptist Hosp Miami, Miami Cardiac & Vasc Inst, Miami, FL USA. [Shishehbor, Mehdi H.] Cleveland Clin, Inst Heart & Vasc, Dept Cardiovasc Med, Cleveland, OH 44106 USA. RP Rundback, JH (reprint author), Holy Name Med Ctr, Intervent Inst, Teaneck, NJ 07666 USA. EM rundbacks@optonline.net FU Phillips Imaging Systems FX J.H.R. is a paid consultant to Phillips Imaging Systems. NR 49 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 0890-5096 EI 1615-5947 J9 ANN VASC SURG JI Ann. Vasc. Surg. PD JAN PY 2017 VL 38 BP 191 EP 205 DI 10.1016/j.avsg.2016.08.001 PG 15 WC Surgery; Peripheral Vascular Disease SC Surgery; Cardiovascular System & Cardiology GA EO1EL UT WOS:000396441100029 PM 27569717 ER PT J AU Buehrle, DJ Shields, RK Clarke, LG Potoski, BA Clancy, CJ Nguyen, MH AF Buehrle, Deanna J. Shields, Ryan K. Clarke, Lloyd G. Potoski, Brian A. Clancy, Cornelius J. Nguyen, M. Hong TI Carbapenem-Resistant Pseudomonas aeruginosa Bacteremia: Risk Factors for Mortality and Microbiologic Treatment Failure SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article DE Pseudomonas aeruginosa; carbapenem resistance; bacteremia; mortality ID BLOOD-STREAM INFECTIONS; ACINETOBACTER-BAUMANNII; ANTIMICROBIAL THERAPY; KLEBSIELLA-PNEUMONIAE; MECHANISMS; STRAINS; ENTEROBACTERIACEAE; PREVALENCE; IMPACT; EPIDEMIOLOGY AB We reviewed 37 patients treated for bacteremia due to carbapenemresistant (CR) Pseudomonas aeruginosa. Although 65% of isolates were multiple-drug resistant, therapeutic options were available, as all were susceptible to >= 1 antibiotic. A total of 92% of patients received active antimicrobial therapy, but only 57% received early active therapy (within 48 h). Fourteen-day mortality was 19%. Microbiologic failure occurred in 29%. The Pitt bacteremia score (P = 0.046) and delayed active therapy (P = 0.027) were predictive of death and microbiologic failure, respectively. C1 [Buehrle, Deanna J.; Shields, Ryan K.; Clancy, Cornelius J.; Nguyen, M. Hong] Univ Pittsburgh, Dept Med, Pittsburgh, PA 15260 USA. [Shields, Ryan K.; Clancy, Cornelius J.; Nguyen, M. Hong] Univ Pittsburgh, Med Ctr, XDR Pathogen Lab, Pittsburgh, PA 15260 USA. [Clarke, Lloyd G.; Potoski, Brian A.] Univ Pittsburgh, Dept Pharm & Therapeut, Pittsburgh, PA USA. [Clancy, Cornelius J.] VA Pittsburgh Healthcare Syst, Pittsburgh, PA 15240 USA. RP Clancy, CJ (reprint author), Univ Pittsburgh, Dept Med, Pittsburgh, PA 15260 USA.; Clancy, CJ (reprint author), Univ Pittsburgh, Med Ctr, XDR Pathogen Lab, Pittsburgh, PA 15260 USA.; Clancy, CJ (reprint author), VA Pittsburgh Healthcare Syst, Pittsburgh, PA 15240 USA. EM cjc76@pitt.edu FU National Institutes of Health (NIH) [K08AI114883] FX R.K.S. is supported by the National Institutes of Health (NIH) under award K08AI114883. The content of this article is solely our responsibility and does not necessarily represent the official views of the NIH. NR 34 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 EI 1098-6596 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD JAN PY 2017 VL 61 IS 1 AR e01243-16 DI 10.1128/AAC.01243-16 PG 7 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA EK7HC UT WOS:000394095800015 ER PT J AU Davidson, CL Anestis, MD Gutierrez, PM AF Davidson, Collin L. Anestis, Michael D. Gutierrez, Peter M. TI Ecological Momentary Assessment is a Neglected Methodology in Suicidology SO ARCHIVES OF SUICIDE RESEARCH LA English DT Article DE suicide; Ecological Momentary Assessment; Experience Sampling Method ID BORDERLINE PERSONALITY-DISORDER; RANDOMIZED CONTROLLED-TRIAL; EXPERIENCE; BEHAVIOR; IDEATION; RISK; VALIDITY; IMPLICIT; RELAPSE; STATES AB Ecological momentary assessment (EMA) is a group of research methods that collect data frequently, in many contexts, and in real-world settings. EMA has been fairly neglected in suicidology. The current article provides an overview of EMA for suicidologists including definitions, data collection considerations, and different sampling strategies. Next, the benefits of EMA in suicidology (i.e., reduced recall bias, accurate tracking of fluctuating variables, testing assumptions of theories, use in interventions), participant safety considerations, and examples of published research that investigate self-directed violence variables using EMA are discussed. The article concludes with a summary and suggested directions for EMA research in suicidology with the particular aim to spur the increased use of this methodology among suicidologists. C1 [Davidson, Collin L.] Hennepin Cty Med Ctr, 700 Pk Ave S, Minneapolis, MN 55415 USA. [Anestis, Michael D.] Univ Southern Mississippi, Dept Psychol, Oxford, MS USA. [Gutierrez, Peter M.] Univ Colorado, Sch Med, Denver VA Med Ctr, Denver, CO USA. [Gutierrez, Peter M.] Univ Colorado, Sch Med, Dept Psychiat, Denver, CO 80262 USA. RP Davidson, CL (reprint author), Hennepin Cty Med Ctr, 700 Pk Ave S, Minneapolis, MN 55415 USA. EM collin.davidson@hcmed.org NR 37 TC 0 Z9 0 U1 0 U2 0 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1381-1118 EI 1543-6136 J9 ARCH SUICIDE RES JI Arch. Suicide Res. PY 2017 VL 21 IS 1 BP 1 EP 11 DI 10.1080/13811118.2015.1004482 PG 11 WC Psychiatry; Psychology; Psychology, Multidisciplinary SC Psychiatry; Psychology GA EM1GV UT WOS:000395067000001 PM 26821811 ER PT J AU Cha, CB Najmi, S Amir, N Matthews, JD Deming, CA Glenn, JJ Calixte, RM Harris, JA Nock, MK AF Cha, Christine B. Najmi, Sadia Amir, Nader Matthews, John D. Deming, Charlene A. Glenn, Jeffrey J. Calixte, Rachelle M. Harris, Julia A. Nock, Matthew K. TI Testing the Efficacy of Attention Bias Modification for Suicidal Thoughts: Findings From Two Experiments SO ARCHIVES OF SUICIDE RESEARCH LA English DT Article DE attentional bias; cognitive bias modification; suicidal ideation; suicide ID MODIFICATION PROGRAM; SELECTIVE ATTENTION; GENERALIZED ANXIETY; SOCIAL ANXIETY; STROOP; INDIVIDUALS; DISORDER; STIMULI; TASKS; VULNERABILITY AB This study explores whether four sessions of attention bias modification (ABM) decreases suicide-specific attentional bias. We conducted two experiments where suicide ideators completed either a Training or Control version of ABM, a computer-based intervention intended to target attentional bias. Suicide-specific attentional bias was measured using adapted Stroop and probe discrimination tasks. The first experiment with community-based suicide ideators did not show that ABM impacts attentional bias or suicidal ideation. The second experiment with clinically severe suicidal inpatients yielded similar results. Post-hoc findings suggest that the type of attentional bias targeted by the current intervention may differ from the type that marks suicide risk. There remains little to no evidence that the ABM intervention changes suicide-specific attentional bias or suicidal ideation. C1 [Cha, Christine B.] Columbia Univ, Teachers Coll, 525 W 120th St,Box102, New York, NY 10027 USA. [Najmi, Sadia; Amir, Nader] San Diego State Univ, Joint Doctoral Program Clin Psychol, San Diego, CA 92182 USA. [Najmi, Sadia; Amir, Nader] Univ Calif San Diego, San Diego, CA 92103 USA. [Matthews, John D.; Nock, Matthew K.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Deming, Charlene A.; Glenn, Jeffrey J.; Calixte, Rachelle M.; Harris, Julia A.; Nock, Matthew K.] Harvard Univ, Dept Psychol, 33 Kirkland St, Cambridge, MA 02138 USA. RP Cha, CB (reprint author), Columbia Univ, Teachers Coll, 525 W 120th St,Box102, New York, NY 10027 USA. EM cha@tc.columbia.edu FU Harvard University FX Both research studies received internal funding from Harvard University. NR 41 TC 0 Z9 0 U1 0 U2 0 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1381-1118 EI 1543-6136 J9 ARCH SUICIDE RES JI Arch. Suicide Res. PY 2017 VL 21 IS 1 BP 33 EP 51 DI 10.1080/13811118.2016.1162241 PG 19 WC Psychiatry; Psychology; Psychology, Multidisciplinary SC Psychiatry; Psychology GA EM1GV UT WOS:000395067000003 PM 26984769 ER PT J AU Schwartz, DG Bellou, A Garcia-Castrillo, L Muraro, A Papadopoulos, N AF Schwartz, David G. Bellou, Abdelouahab Garcia-Castrillo, Luis Muraro, Antonella Papadopoulos, Nikolaos TI Exploring mHealth Participation for Emergency Response Communities SO AUSTRALASIAN JOURNAL OF INFORMATION SYSTEMS LA English DT Article DE mHealth; participation; smartphones; chronic disease; emergency medical response; social networking; anaphylaxis; EMS; shared identity; diffused responsibility ID AUTOMATED EXTERNAL DEFIBRILLATORS; SOFT-SYSTEMS METHODOLOGY; SOCIAL NETWORKS; HEALTH-CARE; GROUP MEMBERSHIP; CARDIAC-ARREST; ACCESS; ANAPHYLAXIS; INTERVENTION; INFORMATION AB We explore the challenges of participation by members of emergency response communities who share a similar condition and treatment, and are called upon to participate in emergency events experienced by fellow members. Smartphones and location-based social networking technologies present an opportunity to re-engineer certain aspects of emergency medical response. Life-saving prescription medication extended in an emergency by one individual to another occurs on a micro level, anecdotally documented. We illustrate the issues and our approach through the example of an app to support patients prone to anaphylaxis and prescribed to carry epinephrine auto-injectors. We address unique participation challenges in an mHealth environment in which interventions are primarily short-term interactions which require clear and precise decision-making and constant tracking of potential participants in responding to an emergency medical event. The conflicting effects of diffused responsibility and shared identity are identified as key factors in modelling participation. C1 [Schwartz, David G.] Bar Ilan Univ, Grad Sch Business Adm, Ramat Gan, Israel. [Bellou, Abdelouahab] Harvard Med Sch, Beth Israel Deaconness Med Ctr, Boston, MA USA. [Garcia-Castrillo, Luis] Hosp Univ Marques de Valdecilla, Emergency Dept, Serv Cantabro Salud, Cantabria, Spain. [Muraro, Antonella] Padua Gen Univ Hosp, Food Allergy Referral Ctr Veneto Reg, Padua, Italy. [Papadopoulos, Nikolaos] Univ Manchester, Inst Human Dev, Ctr Pediat & Child Hlth, Manchester, Lancs, England. [Papadopoulos, Nikolaos] Univ Athens, Dept Allergy, Athens, Greece. RP Schwartz, DG (reprint author), Bar Ilan Univ, Grad Sch Business Adm, Ramat Gan, Israel. EM david.schwartz@biu.ac.il NR 81 TC 0 Z9 0 U1 0 U2 0 PU UNIV CANBERRA, FAC INFORMATION SCIENCES & ENGINEERING PI BRUCE PA BLDG 11, KIRINARI ST, BRUCE, ACT 2617, AUSTRALIA SN 1449-8618 EI 1326-2238 J9 AUSTRALAS J INF SYST JI Australas. J. Inf. Syst. PY 2017 VL 21 PG 17 WC Computer Science, Information Systems SC Computer Science GA EO5JX UT WOS:000396730300006 ER PT J AU Mao, K Klionsky, DJ AF Mao, Kai Klionsky, Daniel J. TI Xenophagy: A battlefield between host and microbe, and a possible avenue for cancer treatment SO AUTOPHAGY LA English DT Editorial Material DE autophagy; bacteria; cancer; host; xenophagy ID HELICOBACTER-PYLORI; AUTOPHAGY; PATHWAY AB In eukaryotes, xenophagy is defined as a type of selective macroautophagy/autophagy that is used for eliminating invading pathogens. In contrast to other types of selective autophagy, such as mitophagy, pexophagy and ribophagy, xenophagy is used by eukaryotes for targeting microbeshence the prefix xeno meaning other or foreignthat have infected a host cell, leading to their lysosomal degradation. This unique characteristic links xenophagy to antibacterial and antiviral defenses, as well as the immune response. Furthermore, recent studies suggest a complicated role of xenophagy in cancer, through either suppressing tumorigenesis or promoting survival of established tumors. In this issue, Sui etal. summarize previous and current studies of xenophagy and consider them in the context of anticancer treatment. C1 [Mao, Kai; Klionsky, Daniel J.] Univ Michigan, Life Sci Inst, Rm 6036,210 Washtenaw Ave, Ann Arbor, MI 48109 USA. [Mao, Kai; Klionsky, Daniel J.] Univ Michigan, Dept Mol Cellular & Dev Biol, Ann Arbor, MI 48109 USA. [Mao, Kai] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Mao, Kai] Harvard Med Sch, Dept Genet, Boston, MA USA. RP Klionsky, DJ (reprint author), Univ Michigan, Life Sci Inst, Rm 6036,210 Washtenaw Ave, Ann Arbor, MI 48109 USA. EM klionsky@umich.edu FU Damon Runyon postdoctoral fellowship [DRG-2213-15]; NIH [GM053396] FX This work was supported by Damon Runyon postdoctoral fellowship DRG-2213-15 to KM, and NIH grant GM053396 to DJK. The authors thank Dr. Hongming Pan for helpful comments. NR 10 TC 0 Z9 0 U1 3 U2 3 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 1554-8627 EI 1554-8635 J9 AUTOPHAGY JI Autophagy PY 2017 VL 13 IS 2 BP 223 EP 224 DI 10.1080/15548627.2016.1267075 PG 2 WC Cell Biology SC Cell Biology GA EM2CY UT WOS:000395125200001 PM 28026986 ER PT J AU Abt, NB Sethi, RK Lehmann, AE Kozin, ED Justicz, N Naunheim, MR Curtin, HD Emerick, KS AF Abt, N. B. Sethi, R. K. Lehmann, A. E. Kozin, E. D. Justicz, N. Naunheim, M. R. Curtin, H. D. Emerick, K. S. TI Plunging ranula with prestyloid parapharyngeal space, masticator space, and parotid gland extension SO B-ENT LA English DT Article DE Ranula; plunging ranula; parotid; parapharyngeal space; masticator space ID MANAGEMENT AB Plunging ranula with prestyloid parapharyngeal space, masticator space, and parotid gland extension. Introduction: Ranulas develop from mucous extravasation secondary to sublingual gland duct obstruction or trauma. Plunging ranula usually dive into the submandibular space. Methods: This is the first reported case of a plunging ranula with direct extension to the prestyloid parapharyngeal space, masticator space, and parotid gland with avoidance of the submandibular space. Results: The patient presented with a tender parotid mass, of which the differential is broad, including parotitis, parotid malignancy, metastatic malignancy, lymphoma, as well as other infectious etiologies. When an intraoral component is not identified, other differential considerations would be thyroglossal duct cyst, branchial cleft cyst, parathyroid cyst, cervical thymic cyst, dermoid cyst, cystic hygroma, or benign teratoma. Conclusion: The case is unique due to ranula extension into multiple spaces. For optimal treatment, the sublingual gland along with its tract and contents needs to completely removed. C1 [Abt, N. B.; Sethi, R. K.; Lehmann, A. E.; Kozin, E. D.; Justicz, N.; Naunheim, M. R.; Emerick, K. S.] Harvard Med Sch, Massachusetts Eye & Ear Infirm, Dept Otolaryngol Head & Neck Surg, 243 Charles St, Boston, MA 02114 USA. [Curtin, H. D.] Harvard Med Sch, Massachusetts Eye & Ear Infirm, Dept Radiol, Boston, MA USA. RP Abt, NB (reprint author), Harvard Med Sch, Massachusetts Eye & Ear Infirm, Dept Otolaryngol Head & Neck Surg, 243 Charles St, Boston, MA 02114 USA. EM nicholas_abt@meei.harvard.edu NR 10 TC 0 Z9 0 U1 0 U2 0 PU ROYAL BELGIAN SOC EAR, NOSE, THROAT, HEAD & NECK SURGERY PI LEUVEN PA PO BOX 1248, LEUVEN, 00000, BELGIUM SN 0001-6497 J9 B-ENT JI B-ENT PY 2017 VL 13 IS 1 BP 57 EP 60 PG 4 WC Otorhinolaryngology SC Otorhinolaryngology GA EP1GZ UT WOS:000397134700003 ER PT J AU Baker, AW Keshaviah, A Goetter, EM Bui, E Swee, M Rosencrans, PL Simon, NM AF Amanda Keshaviah, Aparna Goetter, Elizabeth M. Bui, Eric Swee, Michaela Rosencrans, Peter L. Simon, Naomi M. TI Examining the Role of Anxiety Sensitivity in Sleep Dysfunction Across Anxiety Disorders SO BEHAVIORAL SLEEP MEDICINE LA English DT Article ID INSOMNIA; COMORBIDITY; PREDICTORS; SYMPTOMS; BELIEFS AB Anxiety Sensitivity (AS) has been associated with sleep difficulties in certain anxiety disorder populations, but no studies have examined cross-diagnostically the role of anxiety sensitivity in sleep dysfunction. Three hundred one participants with generalized anxiety disorder (GAD), social anxiety disorder (SAD), and panic disorder (PD) completed an ancillary questionnaire-based study. Linear regression was used to examine AS and sleep dysfunction, and mediation analyses were used to examine whether AS was a mediator of the effect of primary diagnosis on sleep. AS was associated with increased sleep dysfunction across anxiety disorders, and primary anxiety disorder diagnosis was significantly associated with sleep dysfunction. However, after controlling for AS, primary diagnosis was no longer significant. AS significantly mediated the effects of PD versus SAD and of PD versus GAD on sleep dysfunction, but did not significantly mediate the effect of GAD versus SAD on sleep dysfunction. Taken together, AS appears to be a more important predictor of sleep dysfunction overall, emphasizing the cross-diagnostic nature of AS and bolstering the RDoC initiative approach for treating psychological dysfunction. C1 [Amanda; Keshaviah, Aparna; Goetter, Elizabeth M.; Bui, Eric; Swee, Michaela; Rosencrans, Peter L.; Simon, Naomi M.] Massachusetts Gen Hosp, Ctr Anxiety & Traumat Stress Disorders, Dept Psychiat, 1 Bowdoin Sq, Boston, MA 02114 USA. [Amanda; Keshaviah, Aparna; Goetter, Elizabeth M.; Bui, Eric; Simon, Naomi M.] Harvard Med Sch, Boston, MA USA. RP Baker, AW (reprint author), Massachusetts Gen Hosp, Ctr Anxiety & Traumat Stress Disorders, Dept Psychiat, 1 Bowdoin Sq, Boston, MA 02114 USA. EM awbaker@mgh.harvard.edu NR 29 TC 0 Z9 0 U1 1 U2 1 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1540-2002 EI 1540-2010 J9 BEHAV SLEEP MED JI Behav. Sleep Med. PY 2017 VL 15 IS 3 BP 216 EP 227 DI 10.1080/15402002.2015.1120202 PG 12 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA EO6YX UT WOS:000396839500004 PM 26788969 ER PT J AU Hur, W Rosen, H Gray, NS AF Hur, Wooyoung Rosen, Hugh Gray, Nathanael S. TI A benzo[b]thiophene-based selective type 4 S1P receptor agonist SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE Sphingosine-1-phosphate; S1P receptor; S1PR4; S1P4; Selective agonist ID IMMUNOSUPPRESSANT FTY720; LYMPHOCYTE EGRESS; SPHINGOSINE-1-PHOSPHATE; DISCOVERY; POTENT; ORGANS AB S1P receptors (S1PR1-5) are a group of GPCRs activated by a high affinity binding with S1P that have important roles in the regulation of the immune system. A potent S1PR agonist FTY720 is an immunomodulator used to treat multiple sclerosis and several 'second generation' drugs are under clinical development. Subtype-selective agonists have been reported for each S1PR isotype, some of which are used as pharmacological tools for functional studies. Here we report the discovery and initial characterization of compound 5c, a benzo[b]thiophene amino carboxylate which exhibits potent and selective agonist activity for S1PR4. Compound 5c has an EC50 = 200 nM as an agonist in GTP gamma S-35 binding assay for S1PR4 and exhibits no activity against S1PR1,2,3,5. We confirmed its potent activity and decent S1PR subtype selectivity using biochemical and cellular assays. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Hur, Wooyoung; Gray, Nathanael S.] Harvard Med Sch, Dana Farber Canc Inst, Dept Canc Biol, 360 Longwood Ave, Boston, MA 02215 USA. [Rosen, Hugh] Scripps Res Inst, Dept Physiol Chem, 10550 N Torrey Pines Rd, La Jolla, CA 92037 USA. [Hur, Wooyoung] KIST, Chem Kin Res Ctr, 5 Hwarangro 14 Gil, Seoul 02792, South Korea. RP Gray, NS (reprint author), Harvard Med Sch, Dana Farber Canc Inst, Dept Canc Biol, 360 Longwood Ave, Boston, MA 02215 USA. EM Nathanael_Gray@dfci.harvard.edu NR 29 TC 0 Z9 0 U1 2 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-894X EI 1464-3405 J9 BIOORG MED CHEM LETT JI Bioorg. Med. Chem. Lett. PD JAN 1 PY 2017 VL 27 IS 1 BP 1 EP 5 DI 10.1016/j.bmcl.2016.11.050 PG 5 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA EN1LH UT WOS:000395771100001 PM 27894870 ER PT J AU Hamdy, O Mottalib, A Morsi, A El-Sayed, N Goebel-Fabbri, A Arathuzik, G Shahar, J Kirpitch, A Zrebiec, J AF Hamdy, Osama Mottalib, Adham Morsi, Amr El-Sayed, Nuha Goebel-Fabbri, Ann Arathuzik, Gillian Shahar, Jacqueline Kirpitch, Amanda Zrebiec, John TI Long-term effect of intensive lifestyle intervention on cardiovascular risk factors in patients with diabetes in real-world clinical practice: a 5-year longitudinal study SO BMJ OPEN DIABETES RESEARCH & CARE LA English DT Article ID WEIGHT-LOSS; OBESE SUBJECTS; INSULIN-RESISTANCE; BODY-WEIGHT; MANAGEMENT; DIET; EXERCISE; OUTCOMES; WOMEN; MASS AB sustained weight loss versus weight regain on cardiovascular risk factors in real-world clinical practice. Methods: We evaluated 129 obese patients with diabetes enrolled in Weight Achievement and Intensive Treatment (Why WAIT) program, a 12-week clinical model of intensive lifestyle intervention. After 1 year, we divided participants into group A, who maintained < 7% weight loss (47.3%) and group B (52.7%), who maintained >= 7% weight loss. We continued to follow them for a total of 5 years. Results: The total cohort lost 23.8 lbs (-9.7%) at 12 weeks and maintained -16.2 lbs (-6.4%) at 5 years (p< 0.001). Group A maintained -8.4 lbs (-3.5%) and group B maintained -23.1 lbs (-9.0%) at 5 years. In group A, A1C decreased from 7.5 +/- 1.3% to 6.7 +/- 0.9% at 12 weeks but increased to 7.7 +/- 1.4% at 1 year and 8.0 +/- 1.9% at 5 years. In group B, A1C decreased from 7.4 +/- 1.2% to 6.4 +/- 0.9% at 12 weeks and rose to 6.8 +/- 1.2% at 1 year and 7.3 +/- 1.5% at 5 years. Despite weight regain, group A maintained improvement in low-density lipoprotein-cholesterol and high-density lipoprotein-cholesterol with worsening of serum triglycerides and no change in blood pressure (BP). Group B maintained improvement in lipid profile for 5 years and had significantly lower BP for 18 months. Conclusions: Weight reduction in patients with diabetes can be maintained for 5 years and is predicted by patients' ability to maintain >= 7% weight loss at 1 year. A1C and triglycerides deteriorate with weight regain, while other lipid improvements are maintained. Sustained weight loss is associated with significantly lower A1C for 5 years and lowers BP for 18 months. Trial registration number: NCT01937845. C1 [Hamdy, Osama; Mottalib, Adham; Morsi, Amr; El-Sayed, Nuha; Goebel-Fabbri, Ann; Arathuzik, Gillian; Shahar, Jacqueline; Kirpitch, Amanda; Zrebiec, John] Harvard Med Sch, Joslin Diabet Ctr, Boston, MA 02115 USA. RP Hamdy, O (reprint author), Harvard Med Sch, Joslin Diabet Ctr, Boston, MA 02115 USA. EM osama.hamdy@joslin.harvard.edu FU Novartis Nutrition; LifeScan FX Why WAIT program received unrestricted grant from Novartis Nutrition and LifeScan. Both companies were not involved in design, conduct, data collection, management, analysis, interpretation of results, preparation of manuscript or approval of this study. We are grateful to Cathy Carver, NP, and Jo-Anne Rizzotto, RDN, LDN, CDE, for their substantial administrative support and to Joan Beaton for her efforts in coordinating the Why WAIT program. Martin Abrahamson, MD; Voula Mentzelopoulos, MD; Joanna Mitri, MD; Mohamed Shihab-Eldin, MD; Ahmed Elshebiny, MD; Roberta Capelson, NP; Rebecca Longo, ACNP; Iris Marquis, NP; Elisha Phelan, NP; Cara Kilroy, NP; Jeffrey Richard, RCEP; Michael See, RCEP; Sue-Ellen Anderson-Haynes, RD; Veronica Salsberg, RD; Andrea Penney, RN, CDE; Stacey O'Donnell, RN, CDE; Pamela Needle, RN, CDE; Laura Schwab, RN, CDE; and Erin Kelly, RN, CDE, from the Joslin Diabetes Center in Boston actively contributed to the Why WAIT program at different time periods but were not involved in this study. NR 29 TC 0 Z9 0 U1 0 U2 0 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 2052-4897 J9 BMJ OPEN DIAB RES CA JI BMJ Open Diab. Res. Care PD JAN PY 2017 VL 5 IS 1 DI 10.1136/bmjdrc-2016-000259 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EO9VX UT WOS:000397037300003 ER PT J AU Nakas, E Lauc, T Tiro, A Dzemidzic, V Zukanovic, A Franic, M Ivkovic, V AF Nakas, Enita Lauc, Tomislav Tiro, Alisa Dzemidzic, Vildana Zukanovic, Amila Franic, Miljenko Ivkovic, Vladimir TI Dose- and time-dependent effects of clodronate on orthodontic tooth movement SO BOSNIAN JOURNAL OF BASIC MEDICAL SCIENCES LA English DT Article DE Histology; tooth movement; pharmacology; bone biology; clodronate; bisphosphonate ID BONE-RESORPTION; ROOT RESORPTION; RATS; BISPHOSPHONATES; OSTEONECROSIS; OSTEOCLAST; JAW; DOXYCYCLINE AB Orthodontic tooth movement is the result of bone remodeling that occurs in periodontal ligament and alveolar bone tissue as a response to mechanical loading of the tooth. The aim of this study is to investigate the time- and dose-response effects of locally administered clodronate on tooth movement. Sixty Wistar rats were randomly assigned to 4 groups of 15 specimens: E1-application of 10 mMol of clodronate in 3-day intervals; E2-application of 2.5 mMol of clodronate in 3-day intervals; E3-application of 10 mMol of clodronate in 7-day intervals; E4-application of 2.5 mMol of clodronate in 7-day intervals. A 50 mu L clodronate solution was injected into a subperiosteal area to the right maxillary incisor. The left maxillary incisor served as a control, with an injection of saline solution. In 3-day interval application regime, there was no effect of clodronate dosing on tooth movement. In 7-day interval application regime, decreased tooth movement was observed with 10 mMol compared with 2.5 mMol clodronate concentration. However, decreased tooth movement was also observed when 2.5 mMol of clodronate was applied in 7-versus 3-day intervals. Conversely, no difference was observed when 10 mMol concentration was applied in 3-versus 7-day intervals. When clodronate is applied subperiosteally in the root area, it decreases the tooth movement. Tooth movement is impeded by the higher clodronate dosing, as well as by shorter application interval even with lower dosing. The purpose of future trials should, therefore, be to determine a safe therapeutic dose/interval application of clodronate in humans and their potential side effects. C1 [Nakas, Enita; Tiro, Alisa; Dzemidzic, Vildana] Univ Sarajevo, Sch Dent, Dept Orthodont, Sarajevo, Bosnia & Herceg. [Lauc, Tomislav] Univ Osijek, Fac Med, Dept Dent Med, Osijek, Croatia. [Lauc, Tomislav] Univ Zagreb, Fac Social Studies Humanities, Dept Anthropol, Varsavska 10, HR-10000 Zagreb, Croatia. [Zukanovic, Amila] Univ Sarajevo, Sch Dent, Dept Prevent Dent, Sarajevo, Bosnia & Herceg. [Franic, Miljenko] Univ Osijek, Fac Med, Dept Orthoped & Phys Rehabil, Osijek, Croatia. [Ivkovic, Vladimir] Massachusetts Gen Hosp, Harvard Med Sch, Neural Syst Grp Dept, Lab Neuroimaging & Integrat Physiol, Boston, MA 02114 USA. RP Lauc, T (reprint author), Univ Zagreb, Fac Social Studies Humanities, Dept Anthropol, Varsavska 10, HR-10000 Zagreb, Croatia. EM tomislav.lauc@gmail.com NR 25 TC 0 Z9 0 U1 0 U2 0 PU ASSOC BASIC MEDICAL SCI FEDERATION BOSNIA & HERZEGOVINA SARAJEVO PI CEKALUSA PA UNIV SARAJEVO, MEDICAL FAC, CEKALUSA, SARAJEVO 90, BOSNIA & HERCEG SN 1512-8601 EI 1840-4812 J9 BOSNIAN J BASIC MED JI Bosnian J. Basic Med. Sci. PY 2017 VL 17 IS 1 BP 23 EP 28 DI 10.17305/bjbms.2017.1715 PG 6 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EO2QM UT WOS:000396541000005 PM 28086064 ER PT J AU Bountress, KE Wei, W Sheerin, C Chung, DJ Amstadter, AB Mandel, H Wang, Z AF Bountress, Kaitlin E. Wei, Wei Sheerin, Christina Chung, Dongjun Amstadter, Ananda B. Mandel, Howard Wang, Zhewu TI Relationships between GAT1 and PTSD, Depression, and Substance Use Disorder SO BRAIN SCIENCES LA English DT Article DE GAT1; post-traumatic stress disorder; major depressive disorder; substance use disorder; veterans ID POSTTRAUMATIC-STRESS-DISORDER; ENVIRONMENTAL-INFLUENCES; GABA TRANSPORTER; MOOD DISORDERS; ALCOHOL-USE; MEMORY; COMORBIDITY; SYMPTOMS; GENETICS; ILLNESS AB Post-traumatic stress disorder (PTSD), Major Depressive Disorder (MDD), and Substance Use Disorder (SUD) have large public health impacts. Therefore, researchers have attempted to identify those at greatest risk for these phenotypes. PTSD, MDD, and SUD are in part genetically influenced. Additionally, genes in the glutamate and gamma-aminobutyric acid (GABA) system are implicated in the encoding of emotional and fear memories, and thus may impact these phenotypes. The current study examined the associations of single nucleotide polymorphisms in GAT1 individually, and at the gene level, using a principal components (PC) approach, with PTSD, PTSD comorbid with MDD, and PTSD comorbid with SUD in 486 combat-exposed veterans. Findings indicate that several GAT1 SNPs, as well as one of the GAT1 PCs, was associated with PTSD, with and without MDD and SUD comorbidity. The present study findings provide initial insights into one pathway by which shared genetic risk influences PTSD-MDD and PTSD-SUD comorbidities, and thus identify a high-risk group (based on genotype) on whom prevention and intervention efforts should be focused. C1 [Bountress, Kaitlin E.; Wang, Zhewu] Med Univ South Carolina, Dept Psychiat, Charleston, SC 29425 USA. [Wei, Wei; Chung, Dongjun] Med Univ South Carolina, Dept Publ Hlth Sci, Charleston, SC 29425 USA. [Sheerin, Christina; Amstadter, Ananda B.] Virginia Commonwealth Univ, Virginia Inst Psychiat & Behav Genet, Richmond, VA 23219 USA. [Mandel, Howard; Wang, Zhewu] Ralph H Johnson VA Med Ctr, Charleston, SC 29401 USA. RP Wang, Z (reprint author), Med Univ South Carolina, Dept Psychiat, Charleston, SC 29425 USA.; Wang, Z (reprint author), Ralph H Johnson VA Med Ctr, Charleston, SC 29401 USA. EM bountres@musc.edu; weiwe@musc.edu; Christina.sheerin@gmail.com; chungd@musc.edu; Ananda.Amstadter@vcuhealth.org; mandel@musc.edu; wanzh@musc.edu FU Ralph H. Johnson VA Medical Center; Clinical Sciences Program of the Department of Veterans Affairs Merit Review Grant [1I01CX000487-01A1]; National Institute of General Medical Sciences [GM122078]; National Cancer Institute [CA209848]; National Institute of Mental Health [MH18869, MH020030]; BBRF [20066, R21 MH103686, R01MH101518, P60MD002256]; [R01AA020179]; [K02 AA023239] FX This work was supported by Ralph H. Johnson VA Medical Center and the Clinical Sciences Program of the Department of Veterans Affairs Merit Review Grant (No. 1I01CX000487-01A1). Dongjun Chung is supported by the National Institute of General Medical Sciences R01 grant GM122078 and the National Cancer Institute R21 grant CA209848. Kaitlin E. Bountress and Christina Sheerin are supported by National Institute of Mental Health T32 grants MH18869 (KB) and MH020030 (CS). Ananda B. Amstadter is supported by grants R01AA020179, K02 AA023239, BBRF 20066, R21 MH103686, R01MH101518, and P60MD002256. NR 39 TC 0 Z9 0 U1 0 U2 0 PU MDPI AG PI BASEL PA ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND SN 2076-3425 EI 2976-3425 J9 BRAIN SCI JI Brain Sci. PD JAN PY 2017 VL 7 IS 1 AR 6 DI 10.3390/brainsci7010006 PG 13 WC Neurosciences SC Neurosciences & Neurology GA EM7IC UT WOS:000395483700006 ER PT J AU Merrill, AL Buckley, J Tang, R Brachtel, E Rai, U Michaelson, J Ly, A Specht, MC Yagi, Y Smith, BL AF Merrill, Andrea L. Buckley, Julliette Tang, Rong Brachtel, Elena Rai, Upahvan Michaelson, James Ly, Amy Specht, Michelle C. Yagi, Yukako Smith, Barbara L. TI A Study of the Growth Patterns of Breast Carcinoma Using 3D Reconstruction: A Pilot Study SO BREAST JOURNAL LA English DT Article DE 3D anatomy; breast carcinoma; lumpectomy; margins; microanatomy ID FROZEN-SECTION ANALYSIS; INFILTRATING LOBULAR CARCINOMA; NIPPLE-SPARING MASTECTOMY; MICRO-COMPUTED TOMOGRAPHY; 20-YEAR FOLLOW-UP; CONSERVING SURGERY; DUCTAL CARCINOMA; POSITIVE MARGINS; RE-EXCISION; CONSERVATION SURGERY AB Lumpectomy with microscopically clear margins is a safe and effective approach for surgical management of breast carcinoma. Margins are positive for tumor in 18-50% of lumpectomies, as it is not possible to accurately determine the shape or microscopic borders of a tumor preoperatively or intraoperatively. We examined the 3D microanatomy and growth patterns of common breast carcinoma subtypes to provide guidance for lumpectomy surgery. Prospective consent was obtained for the use of excess tissue from patients undergoing lumpectomy or mastectomy for breast carcinoma. Tissue blocks from nine breast carcinomas were serially sectioned. Hematoxylin and eosin-stained slides at 100 mu m intervals were scanned using a Nanozoomer (Hamamatsu, Japan) microscopic-resolution scanner. Three-dimensional reconstructions of tumors were created from scanned images using Reconstruct, open-access software. Breast carcinoma subtypes demonstrated characteristic growth patterns within breast tissue, which may have implications for lumpectomy surgery. Invasive ductal carcinomas showed a spherical shape, with a spiculated surface representing tumor cells infiltrating into surrounding parenchyma. Ductal carcinoma in situ appeared to spread along the duct system, creating dilated, tortuous, tumor-filled ducts. The invasive lobular carcinomas examined had a haphazard, linear, infiltrative growth pattern, different from the shape seen in ductal carcinomas. Our preliminary work suggests that invasive ductal and invasive lobular carcinomas appear to have distinct growth patterns in three dimensions and ductal carcinoma in situ appears to grow in a linear fashion along the duct network. The microanatomy studies described have the potential to guide refinements in breast lumpectomy technique. C1 [Merrill, Andrea L.; Buckley, Julliette; Tang, Rong; Rai, Upahvan; Specht, Michelle C.; Smith, Barbara L.] Massachusetts Gen Hosp, Ctr Breast Canc, Div Surg Oncol, Boston, MA 02114 USA. [Brachtel, Elena; Michaelson, James; Ly, Amy; Yagi, Yukako] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. RP Smith, BL (reprint author), Massachusetts Gen Hosp, Div Surg Oncol, Gillette Ctr Womens Canc, Boston, MA 02114 USA. EM blsmith1@mgh.harvard.edu NR 44 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1075-122X EI 1524-4741 J9 BREAST J JI Breast J. PD JAN-FEB PY 2017 VL 23 IS 1 BP 83 EP 89 DI 10.1111/tbj.12688 PG 7 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA EO1ML UT WOS:000396462500013 PM 27860134 ER PT J AU Francini, E Taplin, ME AF Francini, Edoardo Taplin, Mary-Ellen TI Prostate Cancer: Developing Novel Approaches to Castration-Sensitive Disease SO CANCER LA English DT Review DE castration-sensitive; chemohormonal therapy; immunotherapy; novel approaches; prostate cancer ID ANDROGEN-DEPRIVATION THERAPY; RANDOMIZED CONTROLLED-TRIAL; DEFINITIVE LOCAL THERAPY; PHASE-II TRIAL; RADICAL PROSTATECTOMY; HIGH-RISK; ZOLEDRONIC ACID; DOUBLE-BLIND; OPEN-LABEL; NEOADJUVANT DOCETAXEL AB Although androgen-deprivation therapy (ADT) remains the mainstay of castration-sensitive prostate cancer (CSPC) therapy, the disease's heterogeneity and the limited duration of the response have chaperoned the introduction of chemotherapy and the investigation of novel hormonal targeted agents in this setting. Combinations of ADT plus chemotherapy or novel hormonal therapies are being tested at various stages of CSPC with promising results. Furthermore, immunotherapy and experimental drugs are also being actively investigated in this setting. Intriguing multimodality strategies, chiefly deployed for early-stage disease with the aim of maximizing the efficacy and duration of the response, are being explored and may become valid therapeutic options in the future. Ultimately, striking a balance between the clinical gains of these combinations and possibly increased toxicity and reduced quality of life will be necessary. The development of precision medicine and accurate biomarkers is fundamental to progress. (C) 2016 American Cancer Society. C1 [Francini, Edoardo; Taplin, Mary-Ellen] Dana Farber Canc Inst, Lank Ctr Genitourinary Oncol, 450 Brookline Ave, Boston, MA 02115 USA. [Francini, Edoardo] Univ Rome, Umberto Hosp 1, Med Oncol Unit, Rome, Italy. RP Taplin, ME (reprint author), Dana Farber Canc Inst, Lank Ctr Genitourinary Oncol, 450 Brookline Ave, Boston, MA 02115 USA. EM mary_taplin@dfci.harvard.edu FU Fairweather Family Fund; Fat Boys/Slim Sisters Pan-Mass Prostate Cancer Research Fund FX This work was supported by the Fairweather Family Fund and the Fat Boys/Slim Sisters Pan-Mass Prostate Cancer Research Fund. NR 79 TC 0 Z9 0 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X EI 1097-0142 J9 CANCER-AM CANCER SOC JI Cancer PD JAN 1 PY 2017 VL 123 IS 1 BP 29 EP 42 DI 10.1002/cncr.30329 PG 14 WC Oncology SC Oncology GA EL6GT UT WOS:000394719100006 PM 27802360 ER PT J AU Schuetze, SM Bolejack, V Choy, E Ganjoo, KN Staddon, AP Chow, WA Tawbi, HA Samuels, BL Patel, SR von Mehren, M D'Amato, G Leu, KM Loeb, DM Forscher, CA Milhem, MM Rushing, DA Lucas, DR Chugh, R Reinke, DK Baker, LH AF Schuetze, Scott M. Bolejack, Vanessa Choy, Edwin Ganjoo, Kristen N. Staddon, Arthur P. Chow, Warren A. Tawbi, Hussein A. Samuels, Brian L. Patel, Shreyaskumar R. von Mehren, Margaret D'Amato, Gina Leu, Kirsten M. Loeb, David M. Forscher, Charles A. Milhem, Mohammed M. Rushing, Daniel A. Lucas, David R. Chugh, Rashmi Reinke, Denise K. Baker, Laurence H. TI Phase 2 Study of Dasatinib in Patients With Alveolar Soft Part Sarcoma, Chondrosarcoma, Chordoma, Epithelioid Sarcoma, or Solitary Fibrous Tumor SO CANCER LA English DT Article DE Bayesian; chemotherapy; Choi; chondrosarcoma; chordoma; dasatinib; phase 2; sarcoma ID SINGLE-INSTITUTION; IMATINIB; HEMANGIOPERICYTOMA; EXPERIENCE; SUNITINIB; PATHWAY; SERIES; EGFR AB BACKGROUND: Alveolar soft part sarcoma (ASPS), chondrosarcoma (CS), chordoma, epithelioid sarcoma, and solitary fibrous tumor (SFT) are malignant tumors that are relatively resistant to chemotherapy and for which more effective drug therapy is needed. METHODS: The 5 listed subtypes were enrolled into a single indolent sarcoma cohort in a phase 2 study of dasatinib using a Bayesian continuous monitoring rule for enrollment. The primary objective was to estimate the 6-month progression-free survival (PFS) rate according to the Choi criteria with a target of >= 50%. Cross-sectional imaging was performed before the start of treatment, every 2 months for 6 months, and then every 3 months during treatment. The 2-and 5-year survival rates were determined. RESULTS: One hundred sixteen patients were enrolled within 45 months, and 109 began treatment with dasatinib. The 6-month PFS rate and the median PFS were 48% and 5.8 months, respectively. The PFS rate at 6 months was highest with ASPS (62%) and lowest with SFT (30%). More than 10% of the patients with ASPS, CS, or chordoma had stable disease for more than 1 year. Collectively, for all 5 subtypes, the 2-and 5-year overall survival rates were 44% and 13%, respectively. An objective response was observed in 18% of the patients with CS or chordoma. CONCLUSIONS: Dasatinib failed to achieve control of sarcoma growth for at least 6 months in more than 50% of the patients in this trial according to the Choi tumor response criteria. An objective tumor response and prolonged stable disease was observed in > 10% of patients with CS or chordoma. (C) 2016 American Cancer Society. C1 [Schuetze, Scott M.; Lucas, David R.; Chugh, Rashmi; Baker, Laurence H.] Univ Michigan, Ann Arbor, MI 48109 USA. [Bolejack, Vanessa] Canc Res & Biostat, Seattle, WA USA. [Choy, Edwin] Massachussetts Gen Hosp, Boston, MA USA. [Ganjoo, Kristen N.] Stanford Univ, Palo Alto, CA 94304 USA. [Staddon, Arthur P.] Univ Penn, Sch Med, Philadelphia, PA 19104 USA. [Chow, Warren A.] City Hope Med Ctr, Duarte, CA USA. [Tawbi, Hussein A.; Patel, Shreyaskumar R.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Samuels, Brian L.] Northwest Oncol, Post Falls, ID USA. [von Mehren, Margaret] Fox Chase Canc Ctr, 7701 Burholme Ave, Philadelphia, PA 19111 USA. [D'Amato, Gina] Georgia Canc Specialists, Sandy Springs, GA USA. [Leu, Kirsten M.] Nebraska Canc Specialists, Omaha, NE USA. [Loeb, David M.] Johns Hopkins Univ, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. [Forscher, Charles A.] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. [Milhem, Mohammed M.] Univ Iowa, Iowa City, IA USA. [Rushing, Daniel A.] Indiana Univ, Indianapolis, IN 46204 USA. [Reinke, Denise K.] Sarcoma Alliance Res & Collaborat, Ann Arbor, MI USA. RP Schuetze, SM (reprint author), Univ Michigan, Div Hematol Oncol, 1500 East Med Ctr Dr,C342 Med Inn,SPC 5848, Ann Arbor, MI 48109 USA. EM scotschu@med.umich.edu FU Sarcoma Alliance Through Research and Collaboration; Bristol-Myers Squibb FX This work was supported by the Sarcoma Alliance Through Research and Collaboration and Bristol-Myers Squibb. Dasatinib was provided by Bristol-Myers Squibb to the participating sites. Funding for the study was provided to the Sarcoma Alliance Through Research and Collaboration by Bristol-Myers Squibb. NR 26 TC 1 Z9 1 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X EI 1097-0142 J9 CANCER-AM CANCER SOC JI Cancer PD JAN 1 PY 2017 VL 123 IS 1 BP 90 EP 97 DI 10.1002/cncr.30379 PG 8 WC Oncology SC Oncology GA EL6GT UT WOS:000394719100012 PM 27696380 ER PT J AU Wood, MJ Drachman, DE AF Wood, Malissa J. Drachman, Douglas E. TI Angiographic and interventional management of spontaneous coronary artery dissections: When less is more, or "When "Better' flow is the enemy of good flow" SO CATHETERIZATION AND CARDIOVASCULAR INTERVENTIONS LA English DT Editorial Material C1 [Wood, Malissa J.; Drachman, Douglas E.] Massachusetts Gen Hosp, Corrigan Minehan Heart Ctr, Boston, MA 02114 USA. RP Wood, MJ (reprint author), 55 Fruit St Blake 256, Boston, MA 02114 USA. EM mjwood@partners.org NR 6 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1522-1946 EI 1522-726X J9 CATHETER CARDIO INTE JI Catheter. Cardiovasc. Interv. PD JAN PY 2017 VL 89 IS 1 BP 68 EP 70 DI 10.1002/ccd.26895 PG 3 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EL6GO UT WOS:000394718600018 PM 28116866 ER PT J AU Xian, Y Xu, HL Lytle, B Blevins, J Peterson, ED Hernandez, AF Smith, EE Saver, JL Messe, SR Paulsen, M Suter, RE Reeves, MJ Jauch, EC Schwamm, LH Fonarow, GC AF Xian, Ying Xu, Haolin Lytle, Barbara Blevins, Jason Peterson, Eric D. Hernandez, Adrian F. Smith, Eric E. Saver, Jeffrey L. Messe, Steven R. Paulsen, Mary Suter, Robert E. Reeves, Mathew J. Jauch, Edward C. Schwamm, Lee H. Fonarow, Gregg C. TI Use of Strategies to Improve Door-to-Needle Times With Tissue-Type Plasminogen Activator in Acute Ischemic Stroke in Clinical Practice: Findings from Target: Stroke SO CIRCULATION-CARDIOVASCULAR QUALITY AND OUTCOMES LA English DT Article DE plasminogen activator; quality improvement; stroke; surveys; tissue ID GUIDELINES-STROKE; THROMBOLYSIS; QUALITY; DELAYS; ASSOCIATION; ALTEPLASE; OUTCOMES; MINUTES; THERAPY; BRAIN AB Background The implementation of Target: Stroke Phase I, the first stage of the American Heart Association's national quality improvement initiative to accelerate door-to-needle (DTN) times, was associated with an average 15-minute reduction in DTN times. Target: Stroke phase II was launched in April 2014 with a goal of promoting further reduction in treatment times for tissue-type plasminogen activator (tPA) administration. Methods and Results We conducted a second survey of Get With The Guidelines-Stroke hospitals regarding strategies used to reduce delays after Target: Stroke and quantify their association with DTN times. A total of 16901 ischemic stroke patients were treated with intravenous tPA within 4.5 hours of symptom onset from 888 surveyed hospitals between June 2014 and April 2015. The patient-level median DTN time was 56 minutes (interquartile range, 42-75), with 59.3% of patients receiving intravenous tPA within 60 minutes and 30.4% within 45 minutes after hospital arrival. Most hospitals reported routinely using a majority of Target: Stroke key practice strategies, although direct transport of patients to computed tomographic/magenetic resonance imaging scanner, premix of tPA ahead of time, initiation of tPA in brain imaging suite, and prompt data feedback to emergency medical services providers were used less frequently. Overall, we identified 16 strategies associated with significant reductions in DTN times. Combined, a total of 20 minutes (95% confidence intervals 15-25 minutes) could be saved if all strategies were implemented. Conclusions Get With The Guidelines-Stroke hospitals have initiated a majority of Target: Stroke-recommended strategies to reduce DTN times in acute ischemic stroke. Nevertheless, certain strategies were infrequently practiced and represent a potential immediate target for further improvements. C1 [Xian, Ying; Xu, Haolin; Lytle, Barbara; Blevins, Jason; Peterson, Eric D.; Hernandez, Adrian F.] Duke Clin Res Inst, Durham, NC USA. [Xian, Ying] Duke Univ, Med Ctr, Dept Neurol, Durham, NC USA. [Smith, Eric E.] Univ Calgary, Dept Clin Neurosci, Calgary, AB T2N 1N4, Canada. [Smith, Eric E.] Univ Calgary, Hotchkiss Brain Inst, Calgary, AB T2N 1N4, Canada. [Saver, Jeffrey L.] Univ Calif Los Angeles, Dept Neurol, Los Angeles, CA 90024 USA. [Fonarow, Gregg C.] Univ Calif Los Angeles, Div Cardiol, Los Angeles, CA USA. [Messe, Steven R.] Univ Penn, Philadelphia, PA 19104 USA. [Paulsen, Mary] Amer Heart Assoc, Dallas, TX USA. [Suter, Robert E.] Univ Texas Southwestern, Dept Emergency Med, Dallas, TX USA. [Reeves, Mathew J.] Michigan State Univ, E Lansing, MI 48824 USA. [Jauch, Edward C.] Med Univ South Carolina, Charleston, SC USA. [Schwamm, Lee H.] Massachusetts Gen Hosp, Stroke Serv, Boston, MA 02114 USA. RP Fonarow, GC (reprint author), Ronald Reagan UCLA Med Ctr, Ahmanson UCLA Cardiomyopathy Ctr, 10833 LeConte Ave,Room 47-123 CHS, Los Angeles, CA 90095 USA. EM gfonarow@mednet.ucla.edu FU Daiichi Sankyo; Janssen Pharmaceutical Companies; Genentech; Lilly; Johnson Johnson; Bristol-Myers Squibb; Sanofi-Aventis; Merck-Schering; Amgen; Bristol Myers Squibb; GlaxoSmithKline; Janssen; Novartis; Portola Pharmaceuticals; Medtronic/Covidien; Stryker; Neuravia; BrainsGate; Pfizer; Squibb; Boehringer-Ingelheim; National Institutes of Health; WL Gore; National Institute of Neurological Disorders and Stroke; Patient Centered Outcome Research Institute; GWTG Steering Committee FX Y. Xian reports receiving a research grant directed to the Duke Clinical Research Institute from Daiichi Sankyo, Janssen Pharmaceutical Companies, and Genentech. Dr Peterson reports receiving research grants from Lilly, Johnson & Johnson, Bristol-Myers Squibb, Sanofi-Aventis, and Merck-Schering Plow partnership and serving as principal investigator of the data analytic center for Get With The Guidelines (GWTG). A.F. Hernandez reports receiving research grants from Amgen, Bristol Myers Squibb, GlaxoSmithKline, Janssen, Novartis, and Portola Pharmaceuticals and receiving honoraria from Amgen, GlaxoSmithKline, Janssen, and Novartis. Dr Saver is an employee of the University of California. The Regents of the University of California receive funding for his services as a scientific consultant regarding trial design and conduct to Medtronic/Covidien, Stryker, Neuravia, BrainsGate, Pfizer, Squibb, Boehringer-Ingelheim (prevention only), ZZ Biotech, and St. Jude Medical. He has served as an unpaid site investigator in multicenter trials run by Lundbeck for which the UC Regents received payments on the basis of clinical trial contracts for the number of subjects enrolled. He serves as an unpaid consultant to Genentech advising on the design and conduct of the Study of the Efficacy and Safety of Activase (Alteplase) in Patients With Mild Stroke (PRISMS) trial; neither the University of California nor Dr Saver received any payments for this voluntary service. The University of California has intellectual property rights in retrieval devices for stroke and certification vignettes for the modified Rankin Scale. Dr Messe has served on the speaker's bureau for Boehringer-Ingelheim and receives research support from the National Institutes of Health and WL Gore. M Paulsen reports employment with the American Heart Association. Dr Suter reports previous employment with the American Heart Association. E.C. Jauch reports research funding from Genentech for the PRISMS study. Dr Schwamm reports being the principal investigator of an investigator-initiated study of extended-window intravenous thrombolysis funded by the National Institute of Neurological Disorders and Stroke (clinicaltrials.gov/show/NCT01282242) for which Genentech provides alteplase free of charge to Massachusetts General Hospital and supplemental per-patient payments to participating sites; serving as chair of the American Heart Association/American Stroke Association GWTG-Stroke Clinical Work Group; serving as a stroke systems consultant to the Massachusetts Department of Public Health; and serving as a scientific consultant for trial design and conduct of Lundbeck (international steering committee, DIAS3, 4 trial) and Penumbra (data and safety monitoring committee, Separator 3D trial). G.C. Fonarow reports receiving research support from the Patient Centered Outcome Research Institute, GWTG Steering Committee, and is an employee of the University of California, which has a patient on an endovascular device. NR 23 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 1941-7705 EI 1941-7713 J9 CIRC-CARDIOVASC QUAL JI Circ.-Cardiovasc. Qual. Outcomes PD JAN PY 2017 VL 10 IS 1 AR UNSP e003227 DI 10.1161/CIRCOUTCOMES.116.003227 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EL1OB UT WOS:000394388600010 ER PT J AU Mayo-Smith, LM Simon, JK Chen, WH Haney, D Lock, M Lyon, CE Calderwood, SB Kirkpatrick, BD Cohen, M Levine, MM Gurwith, M Harris, JB AF Mayo-Smith, Leslie M. Simon, Jakub K. Chen, Wilbur H. Haney, Douglas Lock, Michael Lyon, Caroline E. Calderwood, Stephen B. Kirkpatrick, Beth D. Cohen, Mitchell Levine, Myron M. Gurwith, Marc Harris, Jason B. TI The Live Attenuated Cholera Vaccine CVD 103-HgR Primes Responses to the Toxin-Coregulated Pilus Antigen TcpA in Subjects Challenged with Wild-Type Vibrio cholerae SO CLINICAL AND VACCINE IMMUNOLOGY LA English DT Article DE TcpA; challenge; cholera; priming; vaccines ID B-CELL RESPONSES; O1 EL-TOR; HOUSEHOLD CONTACTS; BANGLADESH; PROTECTION; INFECTION; IMMUNOGENICITY; PILIN; SUSCEPTIBILITY; PATHOGENESIS AB One potential advantage of live attenuated bacterial vaccines is the ability to stimulate responses to antigens which are only expressed during the course of infection. To determine whether the live attenuated cholera vaccine CVD 103-HgR (Vaxchora) results in antibody responses to the in vivo-induced toxin-coregulated pilus antigen TcpA, we measured IgA and IgG responses to Vibrio cholerae O1 El Tor TcpA in a subset of participants in a recently reported experimental challenge study. Participants were challenged with V. cholerae O1 El Tor Inaba N16961 either 10 days or 90 days after receiving the vaccine or a placebo. Neither vaccination nor experimental infection with V. cholerae alone resulted in a robust TcpA IgG or IgA response, but each did elicit a strong response to cholera toxin. However, compared to placebo recipients, vaccinees had a marked increase in IgG TcpA antibodies following the 90-day challenge, suggesting that vaccination with CVD 103-HgR resulted in priming for a subsequent response to TcpA. No such difference between vaccine and placebo recipients was observed for volunteers challenged 10 days after vaccination, indicating that this was insufficient time for vaccine-induced priming of the TcpA response. The priming of the response to TcpA and potentially other antigens expressed in vivo by attenuated V. cholerae may have relevance to the maintenance of immunity in areas where cholera is endemic. C1 [Mayo-Smith, Leslie M.; Kirkpatrick, Beth D.; Harris, Jason B.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Simon, Jakub K.] Merck & Co Inc, Kenilworth, NJ USA. [Chen, Wilbur H.] Univ Maryland, Sch Med, Ctr Vaccine Dev, Baltimore, MD 21201 USA. [Haney, Douglas; Lock, Michael] PaxVax Inc, Redwood City, CA USA. [Lyon, Caroline E.; Kirkpatrick, Beth D.] Univ Vermont, Coll Med, Dept Med, Infect Dis Unit, Burlington, VT 05405 USA. [Lyon, Caroline E.; Kirkpatrick, Beth D.] Univ Vermont, Coll Med, Vaccine Testing Ctr, Burlington, VT USA. [Calderwood, Stephen B.] Harvard Med Sch, Dept Med, Boston, MA USA. [Cohen, Mitchell] Univ Cincinnati, Coll Med, Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH USA. [Cohen, Mitchell] Univ Cincinnati, Coll Med, Dept Pediat, Cincinnati, OH USA. [Cohen, Mitchell] Univ Alabama Birmingham, Dept Pediat, Birmingham, AL USA. [Harris, Jason B.] Harvard Med Sch, Dept Pediat, Boston, MA 02115 USA. RP Harris, JB (reprint author), Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA.; Harris, JB (reprint author), Harvard Med Sch, Dept Pediat, Boston, MA 02115 USA. EM jbharris@mgh.harvard.edu FU Massachusetts General Hospital [R01 AI103055, R01 AI099243]; PaxVax, Inc. FX This research was supported by the Massachusetts General Hospital and the following grants: R01 AI103055 (J.B.H.) and R01 AI099243 (J.B.H.). The original clinical challenge study was funded by PaxVax, Inc. NR 29 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 1556-6811 EI 1556-679X J9 CLIN VACCINE IMMUNOL JI Clin. Vaccine Immunol. PD JAN PY 2017 VL 24 IS 1 AR UNSP e00470-16 DI 10.1128/CVI.00470-16 PG 10 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA EK9DH UT WOS:000394223700012 ER PT J AU Moye, J AF Moye, Jennifer TI Are We Doing a Good Job? In Praise of Program Evaluation SO CLINICAL GERONTOLOGIST LA English DT Editorial Material C1 [Moye, Jennifer] VA Boston Healthcare Syst, Boston, MA 02130 USA. [Moye, Jennifer] Harvard Med Sch, Boston, MA 02115 USA. RP Moye, J (reprint author), VA Boston Healthcare Syst, Boston, MA 02130 USA.; Moye, J (reprint author), Harvard Med Sch, Boston, MA 02115 USA. EM Jennifer.moye@va.gov RI Moye, Jennifer/F-2240-2017 OI Moye, Jennifer/0000-0002-3434-347X NR 7 TC 0 Z9 0 U1 0 U2 0 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 0731-7115 EI 1545-2301 J9 CLIN GERONTOLOGIST JI Clin. Gerontol. PY 2017 VL 40 IS 2 BP 75 EP 76 DI 10.1080/07317115.2016.1268864 PG 2 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA EL6AZ UT WOS:000394704100001 ER PT J AU Barocas, JA Linas, BP AF Barocas, Joshua A. Linas, Benjamin P. TI Decision Science at Work: The Case of Hepatitis C Virus Postexposure Prophylaxis SO CLINICAL INFECTIOUS DISEASES LA English DT Editorial Material DE HCV prevention; prophylaxis; HCV treatment; decision analysis ID COST-EFFECTIVENESS C1 [Barocas, Joshua A.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Linas, Benjamin P.] Boston Univ, Sch Med & Publ Hlth, Boston, MA USA. [Linas, Benjamin P.] Boston Med Ctr, Boston, MA USA. RP Linas, BP (reprint author), Boston Med Ctr, Infect Dis Sect, HIV Epidemiol & Outcomes Res Unit, Crosstown Bldg,Room 2007,801 Massachusetts Ave, Boston, MA 02118 USA. EM benjamin.linas@bmc.org FU NIAID NIH HHS [P30 AI042853]; NIDA NIH HHS [R01 DA031059, P30 DA040500] NR 7 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 1058-4838 EI 1537-6591 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD JAN 1 PY 2017 VL 64 IS 1 BP 100 EP 101 DI 10.1093/cid/ciw680 PG 2 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA EP1CN UT WOS:000397123100026 PM 27815292 ER PT J AU Gonzalez, DA Soble, JR AF Gonzalez, David Andres Soble, Jason R. TI Corticobasal syndrome due to sporadic Creutzfeldt-Jakob disease: a review and neuropsychological case report SO CLINICAL NEUROPSYCHOLOGIST LA English DT Article DE Case report; review; corticobasal syndrome; Creutzfeldt-Jakob disease; CBS; CJD ID DEGENERATION; DIAGNOSIS; VARIANT; DEMENTIAS; ACCURACY; CRITERIA; FLUID; EEG AB Objective: Creutzfeldt-Jakob disease (CJD) is a rare, rapidly progressive, and fatal neurodegenerative disease with neuropsychological sequelae. This study highlighted a rare presentation of CJD (e.g. corticobasal syndrome [CBS]), reviewed updated diagnostic criteria and procedures for CJD (e.g. diffusion weighted imaging [DWI], real-time quaking-induced conversion [RT-QuIC]), and discussed differential diagnoses. Method: Case report methodology focused on a 68-year-old, Hispanic, right-handed man with 11years of education. He presented with a 1-2-month history of gait and motor difficulties (e.g. rigidity, myoclonus). Results: After evaluation, a cortical ribboning' pattern on DWI and positive RT-QuIC was integrated with performance on neurobehavioral exam (i.e. alien limb phenomenon, unilateral ideomotor apraxia) and neuropsychological testing (i.e. frontal-parietal dysfunction pattern) to reach a diagnosis of sCJD-CBS. The patient expired 3months after onset of symptoms. Conclusions: This literature review and case report highlighted the importance of staying abreast of developments in neurological literature and the added value of neuropsychology, when integrated with newer procedures, for confirming and excluding diagnostic considerations. C1 [Gonzalez, David Andres] Univ Texas Hlth Sci Ctr San Antonio, Dept Neurol, San Antonio, TX 78229 USA. [Gonzalez, David Andres; Soble, Jason R.] South Texas Vet Hlth Care Syst, Psychol Serv, San Antonio, TX USA. RP Gonzalez, DA (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Neurol, San Antonio, TX 78229 USA.; Gonzalez, DA (reprint author), South Texas Vet Hlth Care Syst, Psychol Serv, San Antonio, TX USA. EM gonzalezD15@uthscsa.edu NR 55 TC 0 Z9 0 U1 1 U2 1 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 1385-4046 EI 1744-4144 J9 CLIN NEUROPSYCHOL JI Clin. Neuropsychol. PY 2017 VL 31 IS 3 BP 676 EP 689 DI 10.1080/13854046.2016.1259434 PG 14 WC Psychology, Clinical; Clinical Neurology; Psychology SC Psychology; Neurosciences & Neurology GA EM5FX UT WOS:000395338500013 PM 27871202 ER PT J AU Sena, DF Lindsley, K AF Sena, Dayse F. Lindsley, Kristina TI Neuroprotection for treatment of glaucoma in adults SO COCHRANE DATABASE OF SYSTEMATIC REVIEWS LA English DT Review DE Antihypertensive Agents [therapeutic use]; Brimonidine Tartrate; Disease Progression; Glaucoma, Open-Angle [drug therapy]; Neuroprotective Agents [administration & dosage]; Optic Nerve; Optic Nerve Diseases [etiology; prevention & control]; Quinoxalines [therapeutic use]; Randomized Controlled Trials as Topic; Retinal Ganglion Cells [physiology]; Timolol [therapeutic use]; Adult; Humans ID NORMAL-TENSION GLAUCOMA; OPEN-ANGLE GLAUCOMA; LOW-PRESSURE GLAUCOMA; RETINAL GANGLION-CELLS; VISUAL-FIELD DAMAGE; OCULAR PERFUSION-PRESSURE; INTRAOCULAR-PRESSURE; CLINICAL-TRIAL; OPTIC NEUROPATHY; OPEN-LABEL AB Background Glaucoma is a heterogeneous group of conditions involving progressive damage to the optic nerve, deterioration of retinal ganglion cells, and ultimately visual field loss. It is a leading cause of blindness worldwide. Open angle glaucoma (OAG), the most common form of glaucoma, is a chronic condition that may or may not present with increased intraocular pressure (IOP). Neuroprotection for glaucoma refers to any intervention intended to prevent optic nerve damage or cell death. Objectives The objective of this review was to systematically examine the evidence regarding the effectiveness of neuroprotective agents for slowing the progression of OAG in adults compared with no neuroprotective agent, placebo, or other glaucoma treatment. Search methods We searched CENTRAL (which contains the Cochrane Eyes and Vision Trials Register) (2016, Issue 7), Ovid MEDLINE, Epub Ahead of Print, In-Process & Other Non-Indexed Citations, Ovid MEDLINE Daily (January 1946 to August 2016), Embase (January 1980 to August 2016), Latin American and Caribbean Literature on Health Sciences (LILACS) (January 1982 to August 2016), the ISRCTN registry (www.isrctn.com/editAdvancedSearch), ClinicalTrials.gov (www.clinicaltrials.gov), and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 16 August 2016. Selection criteria We included randomised controlled trials (RCTs) in which topical or oral treatments were used for neuroprotection in adults with OAG. Minimum follow-up time was four years. Data collection and analysis Two review authors independently reviewed titles and abstracts from the literature searches. We obtained full-text copies of potentially relevant studies and re-evaluated for inclusion. Two review authors independently extracted data related to study characteristics, risk of bias, and outcomes. We identified one trial for this review, thus we performed no meta-analysis. Two studies comparing memantine to placebo are currently awaiting classification until study investigators provide additional study details. We documented reasons for excluding studies from the review. Main results We included one multicenter RCT of adults with low-pressure glaucoma (Low-pressure Glaucoma Treatment Study, LoGTS) conducted in the USA. The primary outcome was progression of visual field loss after four years of treatment with either brimonidine or timolol. Of the 190 adults enrolled in the study, the investigators excluded 12 (6.3%) after randomization; 77 participants (40.5%) did not complete four years of follow-up. The rate of attrition was unbalanced between groups with more participants dropping out of the brimonidine group (55%) than the timolol group (29%). Of those remaining in the study at four years, participants assigned to brimonidine showed less progression of visual field loss than participants assigned to timolol (risk ratio (RR) 0.35, 95% confidence interval (CI) 0.14 to 0.86; 101 participants). Because of high risk of attrition bias and potential selective outcome reporting, we graded the certainty of evidence for this outcome as very low. At the four-year follow-up, the mean IOP was similar in both groups among those for whom data were available (mean difference 0.20 mmHg, 95% CI -0.73 to 1.13; 91 participants; very low-certainty evidence). The study authors did not report analyzable data for visual acuity or any data related to vertical cup-disc ratio, quality of life, or economic outcomes. The most frequent adverse event was ocular allergy to the study drug, which affected more participants in the brimonidine group than the timolol group (RR 5.32, 95% CI 1.64 to 17.26; 178 participants; very low-certainty evidence). Authors' conclusions Although the only trial we included in this review found less visual field loss in the brimonidine-treated group, the evidence was of such low certainty that we can draw no conclusions from this finding. Further clinical research is needed to determine whether neuroprotective agents may be beneficial for individuals with OAG. Such research should focus on outcomes important to patients, such as preservation of vision, and how these outcomes relate to cell death and optic nerve damage. As OAG is a chronic, progressive disease with variability in symptoms, RCTs designed to measure the effectiveness of neuroprotective agents require a long-term follow-up of five years or longer to detect clinically meaningful effects. C1 [Sena, Dayse F.] Massachusetts Eye & Ear Infirm, 243 Charles St,Connecting Bldg 703, Boston, MA 02114 USA. [Lindsley, Kristina] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. RP Sena, DF (reprint author), Massachusetts Eye & Ear Infirm, 243 Charles St,Connecting Bldg 703, Boston, MA 02114 USA. EM sena.dayse@gmail.com FU National Eye Institute, National Institutes of Health, USA [1 U01 EY020522]; National Institute for Health Research (NIHR), UK; Department of Health by the National Institute for Health Research; NIHR FX External sources; Grant 1 U01 EY020522, National Eye Institute, National Institutes of Health, USA.; National Institute for Health Research (NIHR), UK.; Richard Wormald, Co-ordinating Editor for Cochrane Eyes and Vision (CEV) acknowledges financial support for his CEV research sessions from the Department of Health through the award made by the National Institute for Health Research to Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology for a Specialist Biomedical Research Centre for Ophthalmology.; The NIHR also funds the CEV Editorial Base in London. NR 116 TC 0 Z9 0 U1 0 U2 0 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1469-493X EI 1361-6137 J9 COCHRANE DB SYST REV JI Cochrane Database Syst Rev. PY 2017 IS 1 AR CD006539 DI 10.1002/14651858.CD006539.pub4 PG 37 WC Medicine, General & Internal SC General & Internal Medicine GA EN6DX UT WOS:000396095800022 ER PT J AU Nillni, YI Pineles, SL Rohan, KJ Zvolensky, MJ Rasmusson, AM AF Nillni, Yael I. Pineles, Suzanne L. Rohan, Kelly J. Zvolensky, Michael J. Rasmusson, Ann M. TI The influence of the menstrual cycle on reactivity to a CO2 challenge among women with and without premenstrual symptoms SO COGNITIVE BEHAVIOUR THERAPY LA English DT Article DE CO2 challenge; menstrual cycle; panic; PMS ID CARBON-DIOXIDE INHALATION; DYSPHORIC DISORDER; ANXIETY SENSITIVITY; PANIC DISORDER; ENRICHED AIR; VALIDATION; DEPRESSION; ESTROGEN; HORMONES; STRESS AB Clinically significant premenstrual symptoms (PMS) is conceptualized as a depressive disorder in DSM-5, however, it may share pathophysiological processes with anxiety- and fear-related disorders. Specifically, women with PMS panic at higher rates during biological challenge procedures. It is unclear if this increased interoceptive sensitivity is a general vulnerability or specific to the premenstrual phase. The current study examined the role of menstrual cycle phase on reactivity to a CO2 challenge among women with (n = 11) and without (n = 26) clinically significant PMS (N = 37). During the late follicular phase (days 6-12), women with and without PMS responded similarly to the CO2 challenge, whereas during the premenstrual phase (within 5 days before menses), women with PMS reported significantly more intense panic symptoms in response to the challenge than women without PMS. Vulnerability to panic in women with PMS may be specific to the premenstrual phase. Potential psychological and neurobiological mechanisms underlying this phenomenon are discussed. C1 [Nillni, Yael I.; Pineles, Suzanne L.; Rasmusson, Ann M.] VA Boston Healthcare Syst, Natl Ctr PTSD, Womens Hlth Sci Div, Boston, MA USA. [Nillni, Yael I.; Pineles, Suzanne L.; Rasmusson, Ann M.] Boston Univ Sch Med, Dept Psychiat, Boston, MA 02118 USA. [Rohan, Kelly J.] Univ Vermont, Burlington, VT USA. [Zvolensky, Michael J.] Univ Houston, Houston, TX USA. [Zvolensky, Michael J.] Univ Texas MD Anderson Canc Ctr, Houston, TX USA. RP Nillni, YI (reprint author), Boston Univ Sch Med, Dept Psychiat, Boston, MA 02118 USA. EM yael.nillni@va.gov FU National Institute of Mental Health Dissertation [1R36MH086170] FX This research was supported by a National Institute of Mental Health Dissertation grant awarded to Yael I. Nillni [grant number 1R36MH086170]. NR 37 TC 0 Z9 0 U1 0 U2 0 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1650-6073 EI 1651-2316 J9 COGN BEHAV THERAPY JI Cogn. Behav. Ther. PY 2017 VL 46 IS 3 BP 239 EP 249 DI 10.1080/16506073.2016.1236286 PG 11 WC Behavioral Sciences; Psychology, Clinical SC Behavioral Sciences; Psychology GA EO6ZM UT WOS:000396841000005 PM 27687294 ER PT J AU Farrar, D Budson, AE AF Farrar, Danielle Budson, Andrew E. TI The relationship between functional magnetic resonance imaging activation, diffusion tensor imaging, and training effects SO COGNITIVE NEUROSCIENCE LA English DT Editorial Material DE Diffusion tensor imaging; functional magnetic resonance imaging; training ID WORKING-MEMORY; FMRI AB While the relationship between diffusion tensor imaging (DTI) measurements and training effects is explored by Voelker et al. (this issue), a cursory discussion of functional magnetic resonance imaging (fMRI) measurements categorizes increased activation with findings of greater white matter integrity. Evidence of the relationship between fMRI activation and white matter integrity is conflicting, as is the relationship between fMRI activation and training effects. An examination of the changes in fMRI activation in response to training is helpful, but the relationship between DTI and fMRI activation, particularly in the context of white matter changes, must be examined further before general conclusions can be drawn. C1 [Farrar, Danielle] Boston Univ, Sch Med, Dept Anat & Neurobiol, 72 E Concord St L 1004, Boston, MA 02118 USA. [Budson, Andrew E.] VA Boston Healthcare Syst, Boston, MA USA. RP Farrar, D (reprint author), Boston Univ, Sch Med, Dept Anat & Neurobiol, 72 E Concord St L 1004, Boston, MA 02118 USA. EM dfarrar@bu.edu NR 8 TC 0 Z9 0 U1 0 U2 0 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1758-8928 EI 1758-8936 J9 COGN NEUROSCI-UK JI Cogn. Neurosci PY 2017 VL 8 IS 2 BP 132 EP 133 DI 10.1080/17588928.2016.1208645 PG 2 WC Neurosciences SC Neurosciences & Neurology GA EN0II UT WOS:000395693100014 PM 27457121 ER PT J AU Singh, I Hershman, JM AF Singh, Ishita Hershman, Jerome M. TI Pathogenesis of Hyperthyroidism SO COMPREHENSIVE PHYSIOLOGY LA English DT Article ID HUMAN CHORIONIC-GONADOTROPIN; AMIODARONE-INDUCED THYROTOXICOSIS; MALIGNANT STRUMA OVARII; RECEPTOR CROSS-TALK; GRAVES-DISEASE; TSH RECEPTOR; THYROTROPIN RECEPTOR; SUBACUTE THYROIDITIS; SUPPURATIVE THYROIDITIS; AUTOIMMUNE-THYROIDITIS AB Hyperthyroidism is a form of thyrotoxicosis in which there is excess thyroid hormone synthesis and secretion. Multiple etiologies can lead to a common clinical state of "thyrotoxicosis," which is a consequence of the high thyroid hormone levels and their action on different tissues of the body. The most common cause of thyrotoxicosis is Graves' disease, an autoimmune disorder in which stimulating thyrotropin receptor antibodies bind to thyroid stimulating hormone (TSH) receptors on thyroid cells and cause overproduction of thyroid hormones. Other etiologies include: forms of thyroiditis in which inflammation causes release of preformed hormone, following thyroid gland insult that is autoimmune, infectious, mechanical or medication induced; secretion of human chorionic gonadotropin in the setting of transient gestational thyrotoxicosis and trophoblastic tumors; pituitary thyrotropin release, and exposure to extra-thyroidal sources of thyroid hormone that may be endogenous or exogenous. (C) 2017 American Physiological Society. C1 [Singh, Ishita; Hershman, Jerome M.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Endocrinol Diabet & Hypertens, Los Angeles, CA 90095 USA. [Singh, Ishita; Hershman, Jerome M.] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA 90073 USA. RP Hershman, JM (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Endocrinol Diabet & Hypertens, Los Angeles, CA 90095 USA.; Hershman, JM (reprint author), VA Greater Los Angeles Healthcare Syst, Los Angeles, CA 90073 USA. EM jhershmn@ucla.edu NR 99 TC 0 Z9 0 U1 1 U2 1 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 2040-4603 J9 COMPR PHYSIOL JI Compr. Physiol. PD JAN PY 2017 VL 7 IS 1 BP 67 EP 79 DI 10.1002/cphy.c160001 PG 13 WC Physiology SC Physiology GA EK8PQ UT WOS:000394186300003 ER PT J AU Hsu, D Marshall, GA AF Hsu, David Marshall, Gad A. TI Primary and Secondary Prevention Trials in Alzheimer Disease: Looking Back, Moving Forward SO CURRENT ALZHEIMER RESEARCH LA English DT Review DE Alzheimer disease; neuropsychological; pathophysiology; anxiety; hypertension ID RANDOMIZED CONTROLLED-TRIAL; MILD COGNITIVE IMPAIRMENT; ASSOCIATION/AMERICAN-STROKE-ASSOCIATION; HEALTH INITIATIVE MEMORY; NATIONAL INSTITUTE; DIAGNOSTIC GUIDELINES; OLDER-ADULTS; PHYSICAL-ACTIVITY; POSTMENOPAUSAL WOMEN; CLINICAL-TRIALS AB The field of Alzheimer disease (AD) prevention has been a culmination of basic science, clinical, and translational research. In the past three years since the new 2011 AD diagnostic guidelines, large-scale collaborative efforts have embarked on new clinical trials with the hope of someday preventing AD. This review will shed light on the historical and scientific contexts in which these trials were based on, as well as discuss potential challenges these trials may face in the coming years. Primary preventive measures, such as lifestyle, multidomain, medication, and supplemental interventions, will be analyzed. Secondary prevention as represented by disease-modifying interventions, such as antiamyloid therapy and pioglitazone, will also be reviewed. Finally, hypotheses on future directions for AD prevention trials will be proposed. C1 [Hsu, David] Harvard Med Sch, Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Marshall, Gad A.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Hsu, David; Marshall, Gad A.] Harvard Med Sch, Brigham & Womens Hosp, Ctr Alzheimer Res & Treatment, 60 Fenwood Rd,9016P, Boston, MA 02115 USA. [Hsu, David; Marshall, Gad A.] Harvard Med Sch, Brigham & Womens Hosp, Dept Neurol, Boston, MA 02115 USA. RP Marshall, GA (reprint author), Harvard Med Sch, Brigham & Womens Hosp, Ctr Alzheimer Res & Treatment, 60 Fenwood Rd,9016P, Boston, MA 02115 USA. EM gamarshall@partners.org FU Massachusetts Alzheimer's Disease Research Center [P50 AG005134, K23 AG033634, R01 AG027435, K24 AG035007]; Harvard Aging Brain Study [P01 AGO36694, R01 AG037497] FX The authors would like to thank Reisa Sperling, MD, MMSc for inspiration and Marwan Sabbagh, MD for review of the manuscript. The authors are supported by the following grants: K23 AG033634, R01 AG027435, K24 AG035007, the Massachusetts Alzheimer's Disease Research Center (P50 AG005134), and the Harvard Aging Brain Study (P01 AGO36694, R01 AG037497). NR 82 TC 1 Z9 1 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 1567-2050 EI 1875-5828 J9 CURR ALZHEIMER RES JI Curr. Alzheimer Res. PY 2017 VL 14 IS 4 BP 426 EP 440 DI 10.2174/1567205013666160930112125 PG 15 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA EL0DW UT WOS:000394294100008 PM 27697063 ER PT J AU Ly, KI Wen, PY AF Ly, K. Ina Wen, Patrick Y. TI Clinical Relevance of Steroid Use in Neuro-Oncology SO CURRENT NEUROLOGY AND NEUROSCIENCE REPORTS LA English DT Review DE Brain tumor; Brain metastases; Corticosteroids; Steroids; Cerebral edema; Response assessment ID PRIMARY BRAIN-TUMORS; ENDOTHELIAL GROWTH-FACTOR; DEXAMETHASONE TREATMENT; MALIGNANT GLIOMA; ADVERSE EVENTS; OPPORTUNISTIC INFECTIONS; GLUCOCORTICOID THERAPY; CORTICOSTEROID-THERAPY; GLIOBLASTOMA PATIENTS; RHEUMATOID-ARTHRITIS AB Background Corticosteroids are commonly used in the management of primary central nervous system (CNS) tumors and CNS metastases to treat cancer-and treatment-related cerebral edema and improve neurologic function. However, they are also associated with significant morbidity and mortality, given their wide range of adverse effects. Purpose of Review To review the mechanism of action, pharmacology, and toxicity profile of corticosteroids and to critically appraise the evidence that supports their use in neurooncologic practice based on the latest scientific and clinical data. Recent Findings Recent data suggest that corticosteroids may negatively impact survival in glioma patients. In addition, corticosteroids should be incorporated as a standard criterion to assess a patient's clinical and radiographic response to treatment. Summary Corticosteroids should be used judiciously in neuro-oncologic patients, given the potential deleterious effects on clinical outcome and patient survival. Anti-angiogenic agents, which lack these adverse effects, may be a reasonable alternative to corticosteroids. C1 [Ly, K. Ina; Wen, Patrick Y.] Dana Farber Canc Inst, Ctr Neurooncol, 450 Brookline Ave, Boston, MA 02215 USA. [Ly, K. Ina] Massachusetts Gen Hosp, Stephen E & Catherine Pappas Ctr Neurooncol, 55 Fruit St, Boston, MA 02114 USA. RP Wen, PY (reprint author), Dana Farber Canc Inst, Ctr Neurooncol, 450 Brookline Ave, Boston, MA 02215 USA. EM patrick_wen@dfci.harvard.edu NR 83 TC 0 Z9 0 U1 2 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1528-4042 EI 1534-6293 J9 CURR NEUROL NEUROSCI JI Curr. Neurol. Neurosci. Rep. PD JAN PY 2017 VL 17 IS 1 AR 5 DI 10.1007/s11910-017-0713-6 PG 10 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA EL0UO UT WOS:000394337500004 PM 28138871 ER PT J AU Anderson, LJ Albrecht, ED Garcia, JM AF Anderson, Lindsey J. Albrecht, Eliette D. Garcia, Jose M. TI Update on Management of Cancer-Related Cachexia SO CURRENT ONCOLOGY REPORTS LA English DT Review DE Cancer; Cachexia; Quality of life; Muscle loss; Body weight; Nutrition; Inflammation; Appetite; Ghrelin; Exercise; Therapy; Multimodal; Clinical management ID CELL LUNG-CANCER; QUALITY-OF-LIFE; III CLINICAL-TRIAL; DOUBLE-BLIND; MEGESTROL-ACETATE; PHASE-III; EICOSAPENTAENOIC ACID; ANDROGEN RECEPTOR; ESOPHAGEAL CANCER; GHRELIN AB Cachexia is a metabolic syndrome driven by inflammation and characterized by loss of muscle with or without loss of fat mass. In cancer cachexia, the tumor burden and host response induce increased inflammation, decreased anabolic tone, and suppressed appetite leading to the clinical presentation of reduced body weight and quality of life (QOL). There is no approved treatment for cancer cachexia, and commonly used nutritional and anti-inflammatory strategies alone have proven ineffective for management of symptoms. Several other pharmacological agents are currently in development and have shown promise as a clinical strategy in early-phase trials. Recently, it has been proposed that multimodal strategies, with an anabolic focus, initiated early in the disease/treatment progression may provide the most therapeutic potential for symptom management. Here we review the data from recent clinical trials in cancer cachexia including pharmacological, exercise, and nutritional interventions. C1 [Anderson, Lindsey J.; Albrecht, Eliette D.; Garcia, Jose M.] VA Puget Sound Hlth Care Syst, GRECC, Seattle, WA 98108 USA. [Albrecht, Eliette D.] Yale Univ, New Haven, CT 06520 USA. [Garcia, Jose M.] Univ Washington, Sch Med, Dept Med, Div Gerontol & Geriatr Med, Seattle, WA 98195 USA. RP Garcia, JM (reprint author), VA Puget Sound Hlth Care Syst, GRECC, Seattle, WA 98108 USA.; Garcia, JM (reprint author), Univ Washington, Sch Med, Dept Med, Div Gerontol & Geriatr Med, Seattle, WA 98195 USA. EM lindsey.anderson5@va.gov; eliette.albrecht@yale.edu; Jg77@uw.edu FU U.S. Dept. of Veterans Affairs (MERIT) [I01BX002807, I01 CX000174]; NIH [AG040583, AR067319, CA185349] FX This work was funded by the U.S. Dept. of Veterans Affairs (MERIT grants I01BX002807 and I01 CX000174, VA seed fund) and NIH Grants AG040583, AR067319, and CA185349 to JMG. We thank the University of Washington DERC (P30 DK017047) and NORC (P30 DK035816) for their help. NR 69 TC 1 Z9 1 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1523-3790 EI 1534-6269 J9 CURR ONCOL REP JI Curr. Oncol. Rep. PD JAN PY 2017 VL 19 IS 1 AR 3 DI 10.1007/s11912-017-0562-0 PG 11 WC Oncology SC Oncology GA EM2SF UT WOS:000395165200003 PM 28138933 ER PT J AU Morone, NE Greco, CM Moore, CG Rollman, BL Lane, B Morrow, LA Glynn, NW Weiner, DK AF Morone, N. E. Greco, C. M. Moore, C. G. Rollman, B. L. Lane, B. Morrow, L. A. Glynn, N. W. Weiner, D. K. TI A Mind-Body Program for Older Adults With Chronic Low Back Pain: A Randomized Clinical Trial SO DEUTSCHE ZEITSCHRIFT FUR AKUPUNKTUR LA English DT Editorial Material ID MEDITATION; YOGA C1 [Morone, N. E.] Univ Pittsburgh, Sch Med, Pittsburgh, PA USA. Carolinas Hlth Care Syst, Dickson Adv Analyt, Charlotte, NC USA. Vet Affairs Pittsburgh Healthcare Syst, Penn Geriatr Res Educ & Clin Ctr, Pittsburgh, PA USA. RP Morone, NE (reprint author), Univ Pittsburgh, Sch Med, Pittsburgh, PA USA. NR 6 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER GMBH, URBAN & FISCHER VERLAG PI JENA PA OFFICE JENA, P O BOX 100537, 07705 JENA, GERMANY SN 0415-6412 EI 1439-4359 J9 DTSCH Z AKUPUNKT JI Dtsch. Z. Akupunkt. PY 2017 VL 60 IS 1 BP 30 EP 31 PG 2 WC Integrative & Complementary Medicine SC Integrative & Complementary Medicine GA EO4NO UT WOS:000396671800008 ER PT J AU Posner, LS Camargo, CA AF Posner, Larry S. Camargo, Carlos A., Jr. TI Update on the usage and safety of epinephrine auto-injectors, 2017 SO DRUG HEALTHCARE AND PATIENT SAFETY LA English DT Review DE allergy; anaphylaxis; asthma; pediatrics ID FOOD-INDUCED ANAPHYLAXIS; MEDICAL EMERGENCIES; ALLERGIC REACTIONS; EMBEDDED NEEDLES; AUTOINJECTOR USE; NATIONAL-SURVEY; UNITED-STATES; CHILDREN; ADRENALINE; EPIPEN AB Anaphylaxis is a serious, potentially fatal allergic reaction. Guidelines recommend prompt intramuscular injections of epinephrine as the first-line therapy for anaphylaxis. Delayed epinephrine treatment may cause undesirable clinical outcomes, including death. In the community, epinephrine auto-injectors (EAIs) are commonly used to treat anaphylaxis. This literature review examines several recent concerns regarding the safety of EAIs that may prevent the timely administration of epinephrine. Reports of cardiovascular complications are linked with epinephrine administration, although recent studies suggest that these events are much more commonly associated with intravenous epinephrine rather than with EAIs. Recent studies have also highlighted accidental injections of EAIs in patients' or caregivers' fingers and lacerations associated with the use of EAI in children. However, the data suggest that both accidental injections and lacerations are rare and require limited medical intervention. In addition, patients may receive conflicting information on the safety and efficacy of using expired EAIs. Overall, it is believed that the benefits of using EAIs far outweigh the potential risks of not administering an EAI. Although legitimate safety concerns are associated with EAIs, adverse events are rare. Continued training of medical providers, caregivers, and patients may be beneficial to address these concerns and reduce EAI-associated injuries while ensuring that patients receive necessary medical care. C1 [Posner, Larry S.] North Bay Allergy & Asthma Associates Inc, 1100 Pear Tree Lane, Napa, CA 94558 USA. [Camargo, Carlos A., Jr.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA USA. RP Posner, LS (reprint author), North Bay Allergy & Asthma Associates Inc, 1100 Pear Tree Lane, Napa, CA 94558 USA. EM LPosnerMD@NorthBayAllergy.com FU Mylan Specialty L.P. FX Editorial assistance was provided under the direction of the authors by Scott Houck, PhD, and Jennifer Rossi, MA, ELS, MedThink SciCom, and funded by Mylan Specialty L.P. NR 73 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 1179-1365 J9 DRUG HEALTHC PATIENT JI DRUG HEALTHC. PATIENT SAF. PY 2017 VL 9 BP 9 EP 18 DI 10.2147/DHPS.S121733 PG 10 WC Health Care Sciences & Services SC Health Care Sciences & Services GA EO6NS UT WOS:000396810400001 PM 28356773 ER PT J AU Clarke, BL Vokes, TJ Bilezikian, JP Shoback, DM Lagast, H Mannstadt, M AF Clarke, Bart L. Vokes, Tamara J. Bilezikian, John P. Shoback, Dolores M. Lagast, Hjalmar Mannstadt, Michael TI Effects of parathyroid hormone rhPTH(1-84) on phosphate homeostasis and vitamin D metabolism in hypoparathyroidism: REPLACE phase 3 study SO ENDOCRINE LA English DT Article DE Hypoparathyroidism; Phosphate; rhPTH(1-84); Parathyroid hormone; Vitamin D ID IDIOPATHIC HYPOPARATHYROIDISM; PTH(1-84); THERAPY; CALCIFICATION; EFFICACY; SAFETY; MANAGEMENT; MECHANISM; FUTURE; ADULTS AB In hypoparathyroidism, inappropriately low levels of parathyroid hormone lead to unbalanced mineral homeostasis. The objective of this study was to determine the effect of recombinant human parathyroid hormone, rhPTH (1-84), on phosphate and vitamin D metabolite levels in patients with hypoparathyroidism. Following pretreatment optimization of calcium and vitamin D doses, 124 patients in a phase III, 24-week, randomized, double-blind, placebo-controlled study of adults with hypoparathyroidism received subcutaneous injections of placebo or rhPTH(1-84) (50 mu g/day, titrated to 75 and then 100 mu g/day, to permit reductions in oral calcium and active vitamin D doses while maintaining serum calcium within 2.0-2.2 mmol/L). Predefined endpoints related to phosphate homeostasis and vitamin D metabolism were analyzed. Serum phosphate levels decreased rapidly from the upper normal range and remained lower with rhPTH(1-84) (P < 0.001 vs. placebo). At week 24, serum calcium-phosphate product was lower with rhPTH(1-84) vs. placebo (P < 0.001). rhPTH(1-84) treatment resulted in significant reductions in oral calcium dose compared with placebo (P < 0.001) while maintaining serum calcium. After pretreatment optimization, baseline serum 25-hydroxyvitamin D (25[OH]D) and 1,25-dihydroxyvitamin D (1,25[OH](2)D) levels were within the normal range in both groups. After 24 weeks, 1,25(OH)(2)D levels were unchanged in both treatment groups, despite significantly greater reductions in active vitamin D dose in the rhPTH(1-84) group. In hypoparathyroidism, rhPTH (1-84) reduces serum phosphate levels, improves calcium-phosphate product, and maintains 1,25(OH)(2)D and serum calcium in the normal range while allowing significant reductions in active vitamin D and oral calcium doses. C1 [Clarke, Bart L.] Mayo Clin, Div Endocrinol Diabet Metab & Nutr, E18-A,200 1st St SW, Rochester, MN 55905 USA. [Vokes, Tamara J.] Univ Chicago Med, Endocrinol Sect, 5841 South Maryland Ave,MC1027, Chicago, IL 60637 USA. [Bilezikian, John P.] Columbia Univ, Coll Phys & Surg, Div Endocrinol, 630 W 168th St,Room 864, New York, NY 10032 USA. [Shoback, Dolores M.] Univ Calif San Francisco, San Francisco Dept Vet Affairs Med Ctr, Endocrine Res Unit, 1700 Owens St, San Francisco, CA 94158 USA. [Lagast, Hjalmar] NPS Pharmaceut Inc, 300 Shire Way, Lexington, MA 02421 USA. [Mannstadt, Michael] Massachusetts Gen Hosp, Endocrine Unit, 50 Blossom St,Thier 1123, Boston, MA 02114 USA. [Mannstadt, Michael] Harvard Med Sch, 50 Blossom St,Thier 1123, Boston, MA 02114 USA. RP Clarke, BL (reprint author), Mayo Clin, Div Endocrinol Diabet Metab & Nutr, E18-A,200 1st St SW, Rochester, MN 55905 USA. EM clarke.bart@mayo.edu FU NPS Pharmaceuticals, Inc. FX This study was funded by NPS Pharmaceuticals, Inc., a wholly owned indirect subsidiary of Shire. NR 29 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1355-008X EI 1559-0100 J9 ENDOCRINE JI Endocrine PD JAN PY 2017 VL 55 IS 1 BP 282 EP 291 DI 10.1007/s12020-016-1141-0 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EK9PY UT WOS:000394257600035 PM 27734257 ER PT J AU Zhang, JM Liu, ZH Umukoro, PE Cavallari, JM Fang, SC Weisskopf, MG Lin, XH Mittleman, MA Christiani, DC AF Zhang, Jinming Liu, Zhonghua Umukoro, Peter E. Cavallari, Jennifer M. Fang, Shona C. Weisskopf, Marc G. Lin, Xihong Mittleman, Murray A. Christiani, David C. TI An epigenome-wide association analysis of cardiac autonomic responses among a population of welders SO EPIGENETICS LA English DT Article DE Acceleration; deceleration; epigenetics; EWAS; GPR133; heart rate ID HEART-RATE-VARIABILITY; PROTEIN-COUPLED RECEPTORS; REPEATED-MEASURES PANEL; BETA-BLOCKER USE; DECELERATION CAPACITIES; UROTHELIAL CARCINOMA; URINARY-BLADDER; GLOBAL BURDEN; RISK-FACTORS; PERIPLAKIN AB DNA methylation is one of the potential epigenetic mechanisms associated with various adverse cardiovascular effects; however, its association with cardiac autonomic dysfunction, in particular, is unknown. In the current study, we aimed to identify epigenetic variants associated with alterations in cardiac autonomic responses. Cardiac autonomic responses were measured with two novel markers: acceleration capacity (AC) and deceleration capacity (DC). We examined DNA methylation levels at more than 472,506 CpG probes through the Illumina Infinium HumanMethylation450 BeadChip assay. We conducted separate linear mixed models to examine associations of DNA methylation levels at each CpG with AC and DC. One CpG (cg26829071) located in the GPR133 gene was negatively associated with DC values after multiple testing corrections through false discovery rate. Our study suggests the potential functional importance of methylation in cardiac autonomic responses. Findings from the current study need to be replicated in future studies in a larger population. C1 [Zhang, Jinming; Umukoro, Peter E.; Weisskopf, Marc G.; Christiani, David C.] Harvard TH Chan Sch Publ Hlth, Dept Environm Hlth, Boston, MA 02115 USA. [Liu, Zhonghua; Lin, Xihong] Harvard TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Cavallari, Jennifer M.] Univ Connecticut, Ctr Hlth, Dept Community Med & Hlth Care, Farmington, CT USA. [Fang, Shona C.] New England Res Inst, Dept Epidemiol, Watertown, NY USA. [Weisskopf, Marc G.; Mittleman, Murray A.; Christiani, David C.] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Mittleman, Murray A.] Harvard Med Sch, Cardiovasc Epidemiol Res Unit, Beth Israel Deaconess Med Ctr, Boston, MA USA. [Christiani, David C.] Harvard Med Sch, Massachusetts Gen Hosp, Div Pulm & Crit Care, Boston, MA 02115 USA. RP Christiani, DC (reprint author), Harvard TH Chan Sch Publ Hlth, Dept Environm Hlth, Boston, MA 02115 USA.; Christiani, DC (reprint author), Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA.; Christiani, DC (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Div Pulm & Crit Care, Boston, MA 02115 USA. EM dchris@hsph.harvard.edu FU NIEHS [ES009860, ES000002, T32 ES 07069]; Harvard Education and Research Center [ERC -T42OH008416]; American Heart Association Scientist Development award FX The current research was supported by NIEHS ES009860 (to DC), ES000002 (to DC), T32 ES 07069 (to DC), Harvard Education and Research Center (ERC -T42OH008416 to DC), an American Heart Association Scientist Development award to S Fang. NR 47 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 1559-2294 EI 1559-2308 J9 EPIGENETICS-US JI Epigenetics PY 2017 VL 12 IS 2 BP 71 EP 76 DI 10.1080/15592294.2016.1270486 PG 6 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA EM2WZ UT WOS:000395177800001 PM 28075199 ER PT J AU Wang, S Meigs, JB Dupuis, J AF Wang, Shuai Meigs, James B. Dupuis, Josee TI Joint association analysis of a binary and a quantitative trait in family samples SO EUROPEAN JOURNAL OF HUMAN GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; GENERALIZED ESTIMATING EQUATIONS; BODY-MASS INDEX; EXTENDED QUASI-LIKELIHOOD; SUSCEPTIBILITY LOCI; GENETIC ASSOCIATION; CLUSTERED DATA; METAANALYSIS; MODELS; RISK AB In recent years, improved genotyping and sequencing technologies have enabled the discovery of new loci associated with various diseases or traits. For instance, by testing the association with each single-nucleotide variant (SNV) separately, genome-wide association studies (GWAS) have achieved tremendous success in identifying SNVs associated with specific traits. However, little is known about the common genetic basis of multiple traits owing to lack of efficient methods. With the use of extended quasi-likelihood, a Wald test has been proposed to perform a bivariate analysis of a continuous and a binary trait in unrelated samples. However, owing to its low computational efficiency, it has not been implemented in real applications to large-scale genetic studies. In this paper, we propose an efficient bivariate robust score test for two traits, one continuous and one binary, based on extended generalized estimating equations. Our approach is applicable to both family-based and unrelated study designs and can be extended to test the association of multiple traits. Our simulation studies demonstrate the type-I error rate of our approach is well controlled in all minor allele frequency (MAF) scenarios, with MAF ranging from 1 to 30%, and the method is more powerful in certain MAF scenarios than univariate testing with correction for multiple testing. Because of the computational advantage of score tests, our approach is readily applicable to GWAS or sequencing studies. Finally, we present a real application to uncover genetic variants associated with body mass index and type-2 diabetes in the Framingham Heart Study. C1 [Wang, Shuai; Dupuis, Josee] Boston Univ, Sch Publ Hlth, Dept Biostat, 801 Mass Ave,3rd Floor, Boston, MA 02118 USA. [Meigs, James B.] Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. [Meigs, James B.] Harvard Med Sch, Dept Med, Boston, MA USA. [Dupuis, Josee] NHLBI, Framingham Heart Study, Framingham, MA USA. RP Wang, S (reprint author), Boston Univ, Sch Publ Hlth, Dept Biostat, 801 Mass Ave,3rd Floor, Boston, MA 02118 USA. EM tutuwang@bu.edu FU National Heart, Lung and Blood Institute's Framingham Heart Study [N01-HC-25195, HHSN268201500001I]; Affymetrix Inc [N02-HL-6-4278]; National Institute of National Institute for Diabetes and Digestive and Kidney Diseases (NIDDK) [R01 DK078616, DK080140]; American Diabetes Association Mentor-Based Postdoctoral Fellowship [7-09-MN-32]; NIDDK [K24 DK080140] FX This work was supported by the National Heart, Lung and Blood Institute's Framingham Heart Study (Contract No. N01-HC-25195 & HHSN268201500001I) and its contract with Affymetrix, Inc for genotyping services (Contract No. N02-HL-6-4278), and by grants from the National Institute of National Institute for Diabetes and Digestive and Kidney Diseases (NIDDK) R01 DK078616, NIDDK K24 DK080140 and American Diabetes Association Mentor-Based Postdoctoral Fellowship Award # 7-09-MN-32. NR 35 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 1018-4813 EI 1476-5438 J9 EUR J HUM GENET JI Eur. J. Hum. Genet. PD JAN PY 2017 VL 25 IS 1 BP 130 EP 136 DI 10.1038/ejhg.2016.134 PG 7 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA EK7OW UT WOS:000394116100020 PM 27782109 ER PT J AU Kokkinidis, DG Waldo, SW Armstrong, EJ AF Kokkinidis, Damianos G. Waldo, Stephen W. Armstrong, Ehrin J. TI Treatment of coronary artery in-stent restenosis SO EXPERT REVIEW OF CARDIOVASCULAR THERAPY LA English DT Review DE Coronary artery disease; in-stent restenosis; percutaneous coronary intervention; drug-eluting stents; drug-coated balloons ID DRUG-ELUTING STENT; BIORESORBABLE VASCULAR SCAFFOLD; PACLITAXEL-COATED BALLOON; OPTICAL COHERENCE TOMOGRAPHY; BARE-METAL STENTS; RANDOMIZED CONTROLLED-TRIAL; DUAL ANTIPLATELET THERAPY; INTRAVASCULAR ULTRASOUND ANALYSIS; GAMMA-RADIATION THERAPY; TERM-FOLLOW-UP AB Introduction: Although drug-eluting stents (DES) have significantly reduced the incidence and prevalence of coronary in-stent restenosis (ISR), ISR still occurs in approximately 10% of patients in real-world practice. Areas covered: The development of newer generations of DES, drug-coated balloons (DCB) and increased use of intracoronary imaging have improved our treatment options for and pathophysiologic understanding of ISR. These technological advancements have also largely supplanted older modalities for treatment of ISR, such as brachytherapy, bare metal stents, conventional and cutting balloon angioplasty, and atherectomy devices. This article reviews the presentation, pathophysiology, and treatment of coronary artery ISR, with a focus on recent clinical data and emerging therapies for this difficult to treat clinical problem. Expert commentary: DCB and second-generation DES are the most effective treatment options for ISR. Most trials support a slight superiority of second-generation DES, while DCB have the advantage of not adding another metal layer. The role of bioresorbable vascular scaffolds will be determined in the near future. C1 [Kokkinidis, Damianos G.; Waldo, Stephen W.; Armstrong, Ehrin J.] Univ Colorado, Sch Med, Cardiol Sect, Aurora, CO USA. [Kokkinidis, Damianos G.; Waldo, Stephen W.; Armstrong, Ehrin J.] Denver VA Med Ctr, 1055 Clermont St, Denver, CO 80220 USA. RP Armstrong, EJ (reprint author), Denver VA Med Ctr, 1055 Clermont St, Denver, CO 80220 USA. EM ehrin.armstrong@ucdenver.edu NR 115 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 1477-9072 EI 1744-8344 J9 EXPERT REV CARDIOVAS JI Expert Rev. Cardiovasc. Ther. PY 2017 VL 15 IS 3 BP 191 EP 202 DI 10.1080/14779072.2017.1284588 PG 12 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EO7KW UT WOS:000396870600005 PM 28116914 ER PT J AU Khan, F Owens, MB Restrepo, M Povoa, P Martin-Loeches, I AF Khan, Faheem Owens, Mark B. Restrepo, Marcos Povoa, Pedro Martin-Loeches, Ignacio TI Tools for outcome prediction in patients with community acquired pneumonia SO EXPERT REVIEW OF CLINICAL PHARMACOLOGY LA English DT Review DE Pneumonia; community acquired pneumonia; scores; APACHE; CURB; sepsis; treatment failure ID C-REACTIVE PROTEIN; RESPIRATORY-TRACT INFECTIONS; INTENSIVE-CARE-UNIT; RANDOMIZED-CONTROLLED-TRIAL; GERMAN COMPETENCE NETWORK; LOW-RISK PATIENTS; ANTIBIOTIC-THERAPY; TREATMENT FAILURE; CLINICAL STABILITY; PROCALCITONIN-GUIDANCE AB Introduction: Community-acquired pneumonia (CAP) is one of the most common causes of mortality world-wide. The mortality rate of patients with CAP is influenced by the severity of the disease, treatment failure and the requirement for hospitalization and/or intensive care unit (ICU) management, all of which may be predicted by biomarkers and clinical scoring systems. Areas covered: We review the recent literature examining the efficacy of established and newly-developed clinical scores, biological and inflammatory markers such as C-Reactive protein (CRP), procalcitonin (PCT) and Interleukin-6 (IL-6), whether used alone or in conjunction with clinical severity scores to assess the severity of CAP, predict treatment failure, guide acute in-hospital or ICU admission and predict mortality. Expert commentary: The early prediction of treatment failure using clinical scores and biomarkers plays a developing role in improving survival of patients with CAP by identifying high-risk patients requiring hospitalization or ICU admission; and may enable more efficient allocation of resources. However, it is likely that combinations of scoring systems and biomarkers will be of greater use than individual markers. Further larger studies are needed to corroborate the additive value of these markers to clinical prediction scores to provide a safer and more effective assessment tool for clinicians. C1 [Khan, Faheem; Owens, Mark B.; Martin-Loeches, Ignacio] St James Univ Hosp, Intens Care Med, POB 8, Dublin, Ireland. [Restrepo, Marcos] South Texas Vet Hlth Care Syst, Dept Resp Med, San Antonio, TX USA. [Restrepo, Marcos] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX USA. [Povoa, Pedro] Sao Francisco Xavier Hosp, Ctr Hosp Lisboa Ocident, Dept Intens Care Med, Polyvalent Intens Care Unit, Lisbon, Portugal. [Povoa, Pedro] Univ Nova Lisboa, Nova Med Sch, CEDOC, Lisbon, Portugal. St James Hosp, Trin Coll, Welcome Trust HRB Clin Res Facil, Dept Clin Med, Dublin, Ireland. RP Martin-Loeches, I (reprint author), St James Univ Hosp, Intens Care Med, POB 8, Dublin, Ireland. EM drmartinloeches@gmail.com NR 101 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 1751-2433 EI 1751-2441 J9 EXPERT REV CLIN PHAR JI Expert Rev. Clin. Pharmacol. PY 2017 VL 10 IS 2 BP 201 EP 211 DI 10.1080/17512433.2017.1268051 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EO7DM UT WOS:000396851400007 PM 27911103 ER PT J AU Laubach, JP San-Miguel, JF Hungria, V Hou, J Moreau, P Lonial, S Lee, JH Einsele, H Alsina, M Richardson, PG AF Laubach, Jacob P. San-Miguel, Jesus F. Hungria, Vania Hou, Jian Moreau, Philippe Lonial, Sagar Lee, Jae Hoon Einsele, Hermann Alsina, Melissa Richardson, Paul G. TI Deacetylase inhibitors: an advance in myeloma therapy? SO EXPERT REVIEW OF HEMATOLOGY LA English DT Review DE Histone deacetylase inhibitor; multiple myeloma; panobinostat; relapsed or relapsed and refractory; ricolinostat ID REFRACTORY MULTIPLE-MYELOMA; PANOBINOSTAT PLUS BORTEZOMIB; UNFOLDED PROTEIN RESPONSE; PROTEASOME INHIBITORS; HISTONE DEACETYLASES; DEXAMETHASONE; CELLS; COMBINATION; LBH589; TRIAL AB Introduction: A significant unmet need exists in patients with relapsed or refractory multiple myeloma ( MM), which remains an incurable disease despite recent advances in the field. One such development was the use of deacetylase inhibitors ( DACi), which exert unique antimyeloma effects through targeting of epigenetic and protein metabolism pathways. The pan-DACi panobinostat was recently approved in combination with bortezomib and dexamethasone for use in patients with relapsed or relapsed and refractory MM. Results of a phase 3 trial showed that the panobinostat-containing regimen improved the overall response rate and progression-free survival. Panobinostat-associated adverse events included thrombocytopenia, diarrhea, fatigue, and peripheral neuropathy. Research into how to maintain the benefits of DACi while improving tolerability is ongoing. Areas covered: This review focuses on the efficacy and safety of panobinostat and panobinostat-based combinations for MM. Early data from clinical trials investigating the HDAC6 inhibitor ricolinostat are also discussed. Expert commentary: DACi are a unique and effective new class of agents for the treatment of MM, with panobinostat being the first to have clinically meaningful benefit for patients with relapsed or refractory MM. Optimization of dose and schedule, novel combination strategies, and introduction of selective DACi may improve the risk-benefit profile of DACi-based regimens. C1 [Laubach, Jacob P.; Richardson, Paul G.] Dana Farber Canc Inst, Dept Hematol Malignancies, Boston, MA USA. [San-Miguel, Jesus F.] Clin Univ Navarra, CIMA, IDISNA, Dept Hematol, Pamplona, Spain. [Hungria, Vania] Irmandade Santa Casa Misericordia Sao Paulo, Dept Hematol, Dept Oncol, Sao Paulo, Brazil. [Hou, Jian] Shanghai Changzheng Hosp, Dept Hematol, Shanghai, Peoples R China. [Moreau, Philippe] Univ Hosp Nantes, Dept Hematol, Nantes, France. [Lonial, Sagar] Emory Univ, Winship Canc Inst, Dept Hematol & Med Oncol, Atlanta, GA USA. [Lee, Jae Hoon] Gachon Univ, Gil Med Ctr, Div Hematol, Div Oncol, Incheon, South Korea. [Einsele, Hermann] Univ Hosp Wurzburg, Dept Internal Med 2, Wurzburg, Germany. [Alsina, Melissa] H Lee Moffitt Canc Ctr & Res Inst, Blood & Marrow Transplant Program, Tampa, FL USA. RP Laubach, JP (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. EM JacobP_Laubach@DFCI.HARVARD.EDU FU Novartis Pharmaceuticals Corporation FX This paper was funded by Novartis Pharmaceuticals Corporation. NR 50 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 1747-4086 EI 1747-4094 J9 EXPERT REV HEMATOL JI Expert Rev. Hematol. PY 2017 VL 10 IS 3 BP 229 EP 237 DI 10.1080/17474086.2017.1280388 PG 9 WC Hematology SC Hematology GA EM0GP UT WOS:000394997100006 PM 28076695 ER PT J AU Shi, Y Wang, H Yin, J Zhang, X Li, M Xin, C Chen, X Wang, N AF Shi, Y. Wang, H. Yin, J. Zhang, X. Li, M. Xin, C. Chen, X. Wang, N. TI Outcomes of microcatheter-assisted trabeculotomy following failed angle surgeries in primary congenital glaucoma SO EYE LA English DT Article ID 360-DEGREES SUTURE TRABECULOTOMY; DEVELOPMENTAL GLAUCOMA; ILLUMINATED MICROCATHETER; CHILDHOOD GLAUCOMA; OUTFLOW FACILITY; MESHWORK; GONIOTOMY; FLOW; EYES AB Purpose To report surgical outcomes of microcatheter-assisted trabeculotomy following failed angle surgeries, and compare those with no previous angle surgery, in primary congenital glaucoma (PCG). Methods The early postoperative (12 months) results of 42 eyes of 36 patients who underwent microcatheter-assisted trabeculotomy by single surgeon for PCG were retrospectively analyzed. Group 1, 20 eyes of 16 patients, had no previous angle surgery. Group 2, 22 eyes of 20 patients, had one or two previous failed angle surgeries. Success was defined as an intraocular pressure (IOP) < 21mm Hg with at least a 30% reduction from preoperative IOP with (qualified success) or without (complete success) the use of antiglaucoma medication. Results Mean IOP decreased from 31.5 +/- 7.2 mm Hg on 3 (median, range: 1-5) medications in Group 1 and 34.6 +/- 7.3 mm Hg on 3 (median, range: 1-4) medications in Group 2 preoperatively to 15.6 +/- 3.1 mm Hg on 0 (median, range: 0-4) medications in Group 1 and 16.0 +/- 4.6 mm Hg on 0 (median, range: 0-2) medications in Group 2 postoperatively at 12 months (both P<0.001), respectively. The mean percentage of IOP reduction from preoperative to last postoperative visit was 46.0 +/- 20.1% in Group 1 and 45.5 +/- 25.0% in Group 2, P= 0.947. Qualified and complete successes were comparable between Group 1 and Group 2 (qualified success: 90.0% vs 77.3%, P= 0.294; complete success: 78.9% vs 77.3%, P= 0.853). Complications were minimal. Conclusions Microcatheter-assisted trabeculotomy achieved significant pressurelowering effects with a reduction in medication use in PCG, and it represents a reasonable choice of initial and repeat surgical treatment for PCG. C1 [Shi, Y.; Wang, H.; Zhang, X.; Li, M.; Wang, N.] Capital Med Univ, Beijing Tongren Hosp, Dept Ophthalmol, Beijing Tongren Eye Ctr, 1 Dongjiaominxiang St, Beijing 100730, Peoples R China. [Yin, J.] Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Boston, MA 02114 USA. [Xin, C.] Beijing Anzhen Hosp, Dept Ophthalmol, Beijing, Peoples R China. [Chen, X.] First Peoples Hosp Xuzhou, Dept Ophthalmol, Xuzhou, Peoples R China. RP Wang, N (reprint author), Capital Med Univ, Beijing Tongren Hosp, Dept Ophthalmol, Beijing Tongren Eye Ctr, 1 Dongjiaominxiang St, Beijing 100730, Peoples R China. EM wningli@vip.163.com NR 29 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 0950-222X EI 1476-5454 J9 EYE JI Eye PD JAN PY 2017 VL 31 IS 1 BP 132 EP 139 DI 10.1038/eye.2016.212 PG 8 WC Ophthalmology SC Ophthalmology GA EL1AU UT WOS:000394353700016 PM 27740616 ER PT J AU Lee, T Bian, ZG Zhao, B Hogdal, LJ Sensintaffar, JL Goodwin, CM Belmar, J Shaw, S Tarr, JC Veerasamy, N Matulis, SM Koss, B Fischer, MA Arnold, AL Camper, DV Browning, CF Rossanese, OW Budhraja, A Opferman, J Boise, LH Savona, MR Letai, A Olejniczak, ET Fesik, SW AF Lee, Taekyu Bian, Zhiguo Zhao, Bin Hogdal, Leah J. Sensintaffar, John L. Goodwin, Craig M. Belmar, Johannes Shaw, Subrata Tarr, James C. Veerasamy, Nagarathanam Matulis, Shannon M. Koss, Brian Fischer, Melissa A. Arnold, Allison L. Camper, DeMarco V. Browning, Carrie F. Rossanese, Olivia W. Budhraja, Amit Opferman, Joseph Boise, Lawrence H. Savona, Michael R. Letai, Anthony Olejniczak, Edward T. Fesik, Stephen W. TI Discovery and biological characterization of potent myeloid cell leukemia-1 inhibitors SO FEBS LETTERS LA English DT Article DE apoptosis; cancer; drug discovery; myeloid cell leukemia 1; structure-based drug design ID FRAGMENT-BASED METHODS; STRUCTURE-BASED DESIGN; MCL-1 INHIBITORS; CANCER-THERAPY; STRUCTURAL-ANALYSIS; TARGETING MCL-1; HIGH-AFFINITY; BCL-2; PROTEIN; SPECIFICITY AB Myeloid cell leukemia 1 (Mcl-1) is an antiapoptotic member of the Bcl-2 family of proteins that when overexpressed is associated with high tumor grade, poor survival, and resistance to chemotherapy. Mcl-1 is amplified in many human cancers, and knockdown of Mcl-1 using RNAi can lead to apoptosis. Thus, Mcl-1 is a promising cancer target. Here, we describe the discovery of picomolar Mcl-1 inhibitors that cause caspase activation, mitochondrial depolarization, and selective growth inhibition. These compounds represent valuable tools to study the role of Mcl-1 in cancer and serve as useful starting points for the discovery of clinically useful Mcl-1 inhibitors. C1 [Lee, Taekyu; Bian, Zhiguo; Zhao, Bin; Hogdal, Leah J.; Sensintaffar, John L.; Goodwin, Craig M.; Belmar, Johannes; Shaw, Subrata; Tarr, James C.; Veerasamy, Nagarathanam; Arnold, Allison L.; Camper, DeMarco V.; Browning, Carrie F.; Rossanese, Olivia W.; Olejniczak, Edward T.; Fesik, Stephen W.] Vanderbilt Univ, Sch Med, Dept Biochem, 2215 Garland Ave,607 Light Hall, Nashville, TN 37232 USA. [Matulis, Shannon M.; Boise, Lawrence H.] Emory Univ, Dept Hematol & Med Oncol, Atlanta, GA 30322 USA. [Matulis, Shannon M.; Boise, Lawrence H.] Emory Univ, Winship Canc Inst, Atlanta, GA 30322 USA. [Koss, Brian; Budhraja, Amit; Opferman, Joseph] St Jude Childrens Res Hosp, Dept Cell & Mol Biol, 332 N Lauderdale St, Memphis, TN 38105 USA. [Fischer, Melissa A.; Savona, Michael R.] Vanderbilt Univ, Med Ctr, Nashville, TN USA. [Letai, Anthony] Harvard Med Sch, Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA USA. RP Fesik, SW (reprint author), Vanderbilt Univ, Sch Med, Dept Biochem, 2215 Garland Ave,607 Light Hall, Nashville, TN 37232 USA. EM stephen.fesik@vanderbilt.edu FU U.S. National Institutes of Health, NIH Director's Pioneer Award [DP1OD006933/DP1CA174419]; NCI Experimental Therapeutics (NExT) Program under the Leidos Biomed Prime [BOA29XS129TO22, HHSN261200800001E]; NCI SPORE grant in breast cancer [P50CA098131]; NIH SIG Grant [1S-10RR025677-01]; Vanderbilt University matching funds; U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences [DEAC02-06CH11357] FX The authors thank coworkers at the High-Through-put Screening Core facility of Vanderbilt University, TN, for compound management and Nicolas Pelz for useful discussions. This research was supported by the U.S. National Institutes of Health, NIH Director's Pioneer Award DP1OD006933/DP1CA174419 to SWF. The NCI Experimental Therapeutics (NExT) Program BOA29XS129TO22 under the Leidos Biomed Prime Contract No. HHSN261200800001E, and a career development award to SWF from a NCI SPORE grant in breast cancer (Grant P50CA098131) to CL Arteaga. The Biomolecular NMR Facility at Vanderbilt University is supported in part by a NIH SIG Grant 1S-10RR025677-01 and Vanderbilt University matching funds. Use of the Advanced Photon Source was supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences, under Contract No. DEAC02-06CH11357. NR 44 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0014-5793 EI 1873-3468 J9 FEBS LETT JI FEBS Lett. PD JAN PY 2017 VL 591 IS 1 BP 240 EP 251 DI 10.1002/1873-3468.12497 PG 12 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA EK5HL UT WOS:000393957400026 PM 27878989 ER PT J AU Bahrami, T Soltani, S Moazzami, K Yekaninejad, MS Salmaninejad, A Soltaninejad, E Ziaee, V Rezaei, N AF Bahrami, Tayyeb Soltani, Samaneh Moazzami, Kasra Yekaninejad, Mir Saeed Salmaninejad, Arash Soltaninejad, Ehsan Ziaee, Vahid Rezaei, Nima TI Association of PTPN22 Gene Polymorphisms with Susceptibility to Juvenile Idiopathic Arthritis in Iranian Population SO FETAL AND PEDIATRIC PATHOLOGY LA English DT Article DE Iranian population; juvenile idiopathic arthritis; PTPN22 gene; SNPs; real-time PCR ID PROTEIN-TYROSINE-PHOSPHATASE; SINGLE NUCLEOTIDE POLYMORPHISMS; SYSTEMIC-LUPUS-ERYTHEMATOSUS; RHEUMATOID-ARTHRITIS; AUTOIMMUNE-DISEASES; JAPANESE POPULATION; R620W POLYMORPHISM; VARIANTS; HAPLOTYPES; C1858T AB Juvenile idiopathic arthritis (JIA), the most common cause of chronic arthritis in children, is a complex immune-mediated disease with considerable long-term morbidity and mortality. According to previous studies, PTPN22 gene has been associated with JIA in several populations. In the present study, we attempted to determine the association of PTPN22 single nucleotide polymorphisms (SNPs) with susceptibility to JIA in Iranian population. Using the Real-time PCR allelic discrimination method, samples consisting of 55 unrelated patients and 93 healthy controls were genotyped. Using Fisher exact test or Chi-square test, genotypic and allelic frequencies were estimated. The results of our study indicated a significantly decreased association of rs1310182 (OR = 0.59, 95% CI = 0.36 -0.97, p = 0.037) with JIA. This association may indicate a protective role for rs1310182 SNP against JIA. More research would be needed to elucidate the mechanistic role of this association. C1 [Bahrami, Tayyeb] Univ Social Welf & Rehabil Sci, Dept Med Genet, GRC, Tehran, Iran. [Soltani, Samaneh] Univ Tehran Med Sci, Sch Med, Mol Immunol Res Ctr, Tehran, Iran. [Moazzami, Kasra] Harvard Med Sch, Massachusetts Gen Hosp, Boston, MA 02114 USA. [Moazzami, Kasra] USERN, NIIMA, Boston, MA USA. [Yekaninejad, Mir Saeed] Univ Tehran Med Sci, Sch Med, Dept Epidemiol & Biostat, Tehran, Iran. [Salmaninejad, Arash] Mashhad Univ Med Sci, Dept Med Genet, Mashhad, Iran. [Soltaninejad, Ehsan] Birjand Univ Med Sci, Dept Immunol, Birjand, Iran. [Ziaee, Vahid] Univ Tehran Med Sci, Rheumatol Res Ctr, Pediat Rheumatol Res Grp, Tehran, Iran. [Ziaee, Vahid] Univ Tehran Med Sci, Childrens Med Ctr, Pediat Ctr Excellence, Div Pediat Rheumatol, Tehran, Iran. [Rezaei, Nima] Univ Tehran Med Sci, Childrens Med Ctr, Res Ctr Immunodeficiencies, Tehran, Iran. [Rezaei, Nima] Univ Tehran Med Sci, Sch Med, Dept Immunol, Tehran, Iran. [Rezaei, Nima] USERN, NIIMA, Sheffield, S Yorkshire, England. RP Rezaei, N (reprint author), Childrens Med Ctr Hosp, Res Ctr Immunodeficiencies, Dr Qarib St,Keshavarz Blvd, Tehran 14194, Iran. EM rezaei_nima@tums.ac.ir FU Tehran University of Medical Sciences [22389] FX This work was supported by a research grant (22389) from Tehran University of Medical Sciences. NR 39 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 1551-3815 EI 1551-3823 J9 FETAL PEDIATR PATHOL JI Fetal Pediatr. Pathol. PY 2017 VL 36 IS 1 BP 42 EP 48 DI 10.1080/15513815.2016.1231249 PG 7 WC Pathology; Pediatrics SC Pathology; Pediatrics GA EM2YA UT WOS:000395180500006 PM 27732119 ER PT J AU Deo, R Khodneva, YA Shlipak, MG Soliman, EZ Judd, SE McClellan, WM Brown, TM Rhodes, JD Gutierrez, OM Shah, SJ Albert, CM Safford, MM AF Deo, Rajat Khodneva, Yulia A. Shlipak, Michael G. Soliman, Elsayed Z. Judd, Suzanne E. McClellan, William M. Brown, Todd M. Rhodes, J. David Gutierrez, Orlando M. Shah, Sanjiv J. Albert, Christine M. Safford, Monika M. TI Albuminuria, kidney function, and sudden cardiac death: Findings from The Reasons for Geographic and Racial Differences in Stroke (REGARDS) study SO HEART RHYTHM LA English DT Article DE Albuminuria; Kidney function; Sudden cardiac death; Risk factor; Population health ID CORONARY-HEART-DISEASE; STAGE RENAL-DISEASE; UNEXPECTED DEATH; CYSTATIN C; RISK; ASSOCIATION; DEFIBRILLATOR; EPIDEMIOLOGY; DYSFUNCTION; ARREST AB BACKGROUND Moderate-to-severe kidney disease increases risk for sudden cardiac death (SCD). Limited studies have evaluated how mild degrees of kidney dysfunction impact SCD risk. OBJECTIVE The purpose of this study was to evaluate the association of albuminuria, which is one of the earliest biomarkers of kidney injury, and SCD. METHODS The Reasons for Geographic and Racial Differences in Stroke (REGARDS) study is a prospective, population-based cohort of U.S. adults. Associations between albuminuria, which is categorized using urinary albumin-to-creatinine ratio (ACR), estimated glomerular filtration rate (eGFR), and SCD were assessed independently and in combination. RESULTS After median follow-up of 6.1 years, we identified 335 SCD events. Compared to participants with ACR <15 mg/g, those with higher levels had an elevated adjusted risk of SCD (ACR 15-30 mg/g, hazard ratio [HR] 1.53, 95% confidence interval [CI] 1.11-2.11; ACR >30 mg/g, HR 1.56, 95% CI 1.17-2.11). In contrast, compared to the group with eGFR >90 mL/min/1.73 m(2), the adjusted risk of SCD was significantly elevated only among those with eGFR <45 mL/min/1.73 m(2) (HR 1.66, 95% CI 1.06-2.58). The subgroup with eGFR <45 mL/min/1.73 m(2) (n = 1003) comprised 3.7% of REGARDS, whereas ACR 15-30 mg/g (n = 3089 [11.3%]) and ACR >30 mg/g (n = 4040 [14.8%] were far more common. In the analysis that combined ACR and eGFR categories, albuminuria consistently identified individuals with eGFR >60 mLmin/1.73 m(2) who were at significantly increased SCD risk. CONCLUSION Low levels of kidney injury as measured by ACR predict an increase in SCD risk. C1 [Deo, Rajat] Univ Penn, Perelman Sch Med, Div Cardiovasc Med, Electrophysiol Sect, Philadelphia, PA 19104 USA. [Khodneva, Yulia A.; Brown, Todd M.; Gutierrez, Orlando M.] Univ Alabama Birmingham, Dept Med, Birmingham, AL 35487 USA. [Shlipak, Michael G.] Univ Calif San Francisco, Dept Epidemiol Biostat & Med, San Francisco, CA 94143 USA. [Shlipak, Michael G.] San Francisco VA Med Ctr, Dept Gen Internal Med, San Francisco, CA USA. [Soliman, Elsayed Z.] Epidemiol Cardiol Res Ctr EPICARE, Dept Epidemiol & Prevent, Winston Salem, NC 27109 USA. [Soliman, Elsayed Z.] Wake Forest Univ, Sch Med, Dept Internal Med, Cardiol Sect, Winston Salem, NC 27109 USA. [Judd, Suzanne E.] Univ Alabama Birmingham, Dept Biostat, Birmingham, AL 35294 USA. [McClellan, William M.] Emory Univ, Rollins Sch Publ Hlth, Dept Med & Epidemiol, Atlanta, GA 30322 USA. [Rhodes, J. David] Univ Alabama Birmingham, Dept Epidemiol, Birmingham, AL 35233 USA. [Shah, Sanjiv J.] Northwestern Univ, Div Cardiovasc Med, Chicago, IL 60611 USA. [Albert, Christine M.] Ctr Arrhythmia Prevent, Div Prevent Med, Boston, MA USA. [Albert, Christine M.] Brigham & Womens Hosp, Dept Med, Div Cardiovasc Med, Boston, MA 02115 USA. [Albert, Christine M.] Harvard Med Sch, Boston, MA USA. [Safford, Monika M.] Weill Cornell Med Coll, Dept Med, Div Gen Internal Med, New York, NY USA. RP Deo, R (reprint author), Univ Penn, Div Cardiovasc Med, Electrophysiol Sect, 3400 Spruce St,9 Founders Cardiol, Philadelphia, PA 19104 USA. EM Rajat.Deo@uphs.upenn.edu FU National Institutes of Health [K23DK089118, R01 HL080477, K24 HL111154]; National Institute of Neurological Disorders and Stroke, National Institutes of Health, Department of Health and Human Service [U01 NS041588] FX Dr. Deo was supported by Grant K23DK089118 from the National Institutes of Health. This research project is supported by cooperative agreement U01 NS041588 from the National Institute of Neurological Disorders and Stroke, National Institutes of Health, Department of Health and Human Service. The REGARDS-MI study was supported by National Institutes of Health Grants R01 HL080477 and K24 HL111154. NR 31 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 1547-5271 EI 1556-3871 J9 HEART RHYTHM JI Heart Rhythm PD JAN PY 2017 VL 14 IS 1 BP 65 EP 71 DI 10.1016/j.hrthm.2016.08.004 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EO1BQ UT WOS:000396433000020 PM 27523775 ER PT S AU Fitch, KV Feldpausch, MN Looby, SED AF Fitch, Kathleen V. Feldpausch, Meghan Noonan Looby, Sara E. Dolan BE BrennanIng, M DeMarco, RF TI Biomarkers and Clinical Indices of Aging with HIV SO HIV AND AGING SE Interdisciplinary Topics in Gerontology and Geriatrics LA English DT Article; Book Chapter ID IMMUNODEFICIENCY-VIRUS DISEASE; ACTIVE ANTIRETROVIRAL THERAPY; RISK-FACTORS; MICROBIAL TRANSLOCATION; INFECTED ADULTS; VACS INDEX; SUBCLINICAL ATHEROSCLEROSIS; COLLABORATIVE ANALYSIS; CHRONIC INFLAMMATION; MONOCYTE ACTIVATION AB HIV infection may potentiate specific biomarkers that influence the development of premature clinical indices commonly associated with aging. Therefore, predicting mortality outcomes in people living with HIV is extremely important as this population ages. This chapter describes biomarkers associated with inflammation, coagulation, and immune activation in HIV, and reviews the association between specific biomarkers and the development of co-morbid conditions in individuals with HIV. Measures that incorporate specific biomarkers related to HIV infection, designed to predict mortality outcomes in individuals with HIV, are also discussed. (C) 2017 S. Karger AG, Basel C1 [Fitch, Kathleen V.; Feldpausch, Meghan Noonan; Looby, Sara E. Dolan] Massachusetts Gen Hosp, Program Nutr Metab, 55 Fruit St,5 LON 207, Boston, MA 02114 USA. [Looby, Sara E. Dolan] Yvonne L Munn Ctr Nursing Res, Boston, MA USA. [Looby, Sara E. Dolan] Harvard Med Sch, Boston, MA USA. RP Fitch, KV (reprint author), Massachusetts Gen Hosp, Program Nutr Metab, 55 Fruit St,5 LON 207, Boston, MA 02114 USA. EM kfitch@partners.org NR 65 TC 0 Z9 0 U1 0 U2 0 PU KARGER PI BASEL PA POSTFACH, CH-4009 BASEL, SWITZERLAND SN 2297-3508 BN 978-3-318-05946-5; 978-3-318-05945-8 J9 INTERD T GERONT GERI JI Interdiscipl.Top.Gerontol. PY 2017 VL 42 BP 47 EP 58 DI 10.1159/000448543 PG 12 WC Geriatrics & Gerontology; Infectious Diseases SC Geriatrics & Gerontology; Infectious Diseases GA BG5LA UT WOS:000389524100005 PM 27875823 ER PT J AU Murray, HW Luster, AD Zheng, H Ma, XJ AF Murray, Henry W. Luster, Andrew D. Zheng, Hua Ma, Xiaojing TI Gamma Interferon-Regulated Chemokines in Leishmania donovani Infection in the Liver SO INFECTION AND IMMUNITY LA English DT Article DE chemokines; visceral leishmaniasis; Leishmania donovani; granuloma pentavalent antimony ID EXPERIMENTAL VISCERAL LEISHMANIASIS; MACROPHAGE MICROBICIDAL MECHANISMS; PROTECTIVE IMMUNE-RESPONSE; MICE DEFICIENT; IFN-GAMMA; MYCOBACTERIUM-TUBERCULOSIS; ANTILEISHMANIAL ACTIVITY; INTRACELLULAR INFECTION; ENHANCED RESISTANCE; RECEPTOR BLOCKADE AB In the livers of C57BL/6 mice, gamma interferon (IFN-gamma) controls intracellular Leishmania donovani infection and the efficacy of antimony (Sb) chemotherapy. Since both responses usually correlate with granulomatous inflammation, we tested six prominently expressed, IFN-gamma -regulated chemokines-CXCL9, CXCL10, CXCL13, CXCL16, CCL2, and CCL5-for their roles in (i) mononuclear cell recruitment and granuloma assembly and maturation, (ii) initial control of infection and self-cure, and (iii) responsiveness to Sb treatment. Together, the results for the L. donovani-infected livers of chemokine-deficient mice (CXCR6(-/-) mice were used as CXCL16-deficient surrogates) indicated that individual IFN-gamma-induced chemokines have diverse affects and (i) may be entirely dispensable (CXCL13, CXCL16), (ii) may promote (CXCL10, CCL2, CCL5) or downregulate (CXCL9) initial granuloma assembly, (iii) may enhance (CCL2, CCL5) or hinder (CXCL10) early parasite control, (iv) may promote granuloma maturation (CCL2, CCL5), (v) may exert a granuloma-independent action that enables self-cure (CCL5), and (vi) may have no role in responsiveness to chemotherapy. Despite the near absence of tissue inflammation in early-stage infection, parasite replication could be controlled (in CXCL10(-/-) mice) and Sb was fully active (in CXCL10(-/-), CCL2(-/-), and CCL5(-/-) mice). These results characterize chemokine action in the response to L. donovani and also reemphasize that (i) recruited mononuclear cells and granulomas are not required to control infection or respond to Sb chemotherapy, (ii) granuloma assembly, control of infection, and Sb's efficacy are not invariably linked expressions of the same T cell-dependent, cytokine-mediated antileishmanial mechanism, and (iii) granulomas are not necessarily hallmarks of protective antileishmanial immunity. C1 [Murray, Henry W.] Weill Cornell Med Coll, Dept Med, New York, NY USA. [Ma, Xiaojing] Weill Cornell Med Coll, Dept Microbiol & Immunol, New York, NY USA. [Luster, Andrew D.] Harvard Med Sch, Massachusetts Gen Hosp, Ctr Immunol & Inflammatory Dis, Div Rheumatol & Immunol,Dept Med, Boston, MA USA. [Zheng, Hua; Ma, Xiaojing] Shanghai Jiao Tong Univ, Sch Life Sci & Biotechnol, Shanghai, Peoples R China. RP Murray, HW (reprint author), Weill Cornell Med Coll, Dept Med, New York, NY USA. EM hwmurray@med.cornell.edu FU NIH [5R01AI083219, CA069212]; Sheng Yushou Foundation FX This study was supported by NIH grants 5R01AI083219 (to H.W.M. and X.M.) and CA069212 (to A.D.L.) and a grant from the Sheng Yushou Foundation to Shanghai Jiaotong University (to H.Z.). NR 73 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 EI 1098-5522 J9 INFECT IMMUN JI Infect. Immun. PD JAN PY 2017 VL 85 IS 1 AR UNSP e00824-16 DI 10.1128/IAI.00824-16 PG 14 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA EL4RD UT WOS:000394607700017 ER PT J AU Yu, P Hu, Y Liu, ZQ Kawai, T Taubman, MA Li, W Han, XZ AF Yu, Pei Hu, Yang Liu, Zhiqiang Kawai, Toshihisa Taubman, Martin A. Li, Wei Han, Xiaozhe TI Local Induction of B Cell Interleukin-10 Competency Alleviates Inflammation and Bone Loss in Ligature-Induced Experimental Periodontitis in Mice SO INFECTION AND IMMUNITY LA English DT Article DE B cells; bone resorption; IL-10; periodontitis; RANKL; bone resorption ID B10 CELLS; CD40-CD40 LIGAND; RESPONSES; AUTOIMMUNITY; ARTHRITIS; DISEASE; SUBSET; CANCER; PATHOGENESIS; STIMULATION AB Interleukin-10 (IL-10)-producing B cells (B10 cells) play a critical role in the immune system balance by negatively regulating inflammatory responses. This study was conducted to determine the effect of local B10 cell induction on periodontal inflammation and bone loss in ligature-induced experimental periodontitis in vivo. Purified spleen B cells from C57BL/6J mice (8 to 10 weeks old) were cultured with CD40 ligand (CD40L) and the Toll-like receptor 9 (TLR9) agonist cytidinephosphate- guanosine oligodeoxynucleotide (CpG) to determine effective IL-10 induction in vitro. Silk ligatures (size 7-0) were tied around the mouse maxillary second molars on day 0, followed by the injection of CD40L and CpG into the palatal gingiva on days 3, 6, and 9. All the mice were sacrificed, and samples were collected on day 14. CD40L and CpG significantly increased the level of IL-10 production by B cells in vitro, although the frequencies of CD1(dhi) CD5 (+) and IL-10-producing (IL-10 (+)) CD45 (+) cells were decreased. IL-10 was predominantly produced by the CD1(dhi) CD5 (+) subpopulation of B cells. In vivo, both IL-10 mRNA expression and the number of IL-10 (+) CD45 (+) cells were significantly increased after gingival injection of CD40L and CpG. Periodontal bone loss was significantly decreased and the gingival expression of IL-1 (+), tumor necrosis factor alpha, and RANKL was significantly reduced. The number of multinucleated tartrate-resistant acid phosphatase-positive cells along the alveolar bone surface was significantly decreased after gingival injection of CD40L and CpG. This study indicates for the first time that the local induction of B10 cell activity could inhibit periodontal inflammation and bone loss. C1 [Yu, Pei; Li, Wei] Sichuan Univ, West China Hosp Stomatol, State Key Lab Oral Dis, Chengdu, Sichuan, Peoples R China. [Yu, Pei; Hu, Yang; Liu, Zhiqiang; Kawai, Toshihisa; Taubman, Martin A.; Han, Xiaozhe] Forsyth Inst, Dept Immunol & Infect Dis, Cambridge, MA 02142 USA. [Liu, Zhiqiang] Capital Med Univ, Beijing ChaoYang Hosp, Dept Stomatol, Beijing, Peoples R China. RP Han, XZ (reprint author), Forsyth Inst, Dept Immunol & Infect Dis, Cambridge, MA 02142 USA. EM xhan@forsyth.org FU NIH, NIDCR [R56DE023807, R01DE025255] FX This study was supported by NIH, NIDCR, grants R56DE023807 and R01DE025255 to X. Han. NR 41 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 EI 1098-5522 J9 INFECT IMMUN JI Infect. Immun. PD JAN PY 2017 VL 85 IS 1 AR UNSP e00645 DI 10.1128/IAI.00645-16 PG 14 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA EL4RD UT WOS:000394607700030 ER PT J AU Fava, M Okame, T Matsushima, Y Perry, P Weiller, E Baker, RA AF Fava, Maurizio Okame, Takao Matsushima, Yuki Perry, Pamela Weiller, Emmanuelle Baker, Ross A. TI Switching from Inadequate Adjunctive or Combination Treatment Options to Brexpiprazole Adjunctive to Antidepressant: An Open-Label Study on the Effects on Depressive Symptoms and Cognitive and Physical Functioning SO INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY LA English DT Article DE major depressive disorder; brexpiprazole; adjunctive; switching; antidepressant ID TREATMENT-RESISTANT DEPRESSION; STAR-ASTERISK-D; BIPOLAR DEPRESSION; CONTROLLED-TRIAL; TERM OUTCOMES; RATING-SCALE; DISORDER; AUGMENTATION; STRATEGIES; EFFICACY AB Background: Approximately 50% of patients with major depressive disorder do not respond adequately to their antidepressant treatment, underscoring the need for more effective treatment options. The objective of this study was to investigate the effect of adjunctive brexpiprazole on depressive symptoms in patients with major depressive disorder who were not responding to adjunctive or combination therapy of their current antidepressant treatments with several different classes of agents (NCT02012218). Methods: In this 6-week, open-label, phase 3b study, patients with major depressive disorder who had an inadequate response to >= 1 adjunctive or combination therapy, in addition to history of >= 1 failure to monotherapy antidepressant treatment, were switched to adjunctive brexpiprazole. Efficacy was assessed by change from baseline to week 6 in Montgomery-Asberg Depression Rating Scale total score. Patient functioning was assessed using the Sheehan Disability Scale and the Cognitive and Physical Functioning Questionnaire. Safety and tolerability were also assessed. Results: A total of 51/61 (83.6%) patients completed 6 weeks of treatment with adjunctive brexpiprazole. Improvements in depressive symptoms were observed (least squares mean change from baseline to week 6 in Montgomery-Asberg Depression Rating Scale total score, -17.3 [ P <.0001]) as well as improvements in general and cognitive functioning (mean changes from baseline to week 6: Sheehan Disability Scale, -3.1 [ P <.0001]; Massachusetts General Hospital-Cognitive and Physical Functioning Questionnaire, -9.2 [ P <.0001]). The most common adverse event was fatigue (14.8%); akathisia was reported by 8.2% of patients. Conclusions: In patients with major depressive disorder who had switched to open-label adjunctive brexpiprazole following inadequate response to previous adjunctive or combination therapy, improvements were observed in depressive symptoms, general functioning, cognitive function, and energy/alertness. C1 [Fava, Maurizio] Massachusetts Gen Hosp, 55 Fruit St, Boston, MA 02114 USA. [Okame, Takao; Matsushima, Yuki] Otsuka Pharmaceut Co Ltd, Tokyo, Japan. [Perry, Pamela; Baker, Ross A.] Otsuka Pharmaceut Dev & Commercializat Inc, Princeton, NJ USA. [Weiller, Emmanuelle] H Lundbeck & Co AS, Valby, Denmark. RP Fava, M (reprint author), Massachusetts Gen Hosp, 55 Fruit St, Boston, MA 02114 USA. EM MFAVA@mgh.harvard.edu FU Otsuka Pharmaceutical Co., Ltd. (Tokyo, Japan); H. Lundbeck A/S (Valby, Denmark) FX This work was supported by Otsuka Pharmaceutical Co., Ltd. (Tokyo, Japan) and H. Lundbeck A/S (Valby, Denmark). NR 41 TC 0 Z9 0 U1 1 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1461-1457 EI 1469-5111 J9 INT J NEUROPSYCHOPH JI Int. J. Neuropsychopharmacol. PD JAN PY 2017 VL 20 IS 1 DI 10.1093/ijnp/pyw087 PG 9 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA EP0TB UT WOS:000397098500003 ER PT J AU Aryan, Z Rezaei, N Camargo, CA AF Aryan, Zahra Rezaei, Nima Camargo, Carlos A., Jr. TI Vitamin D status, aeroallergen sensitization, and allergic rhinitis: A systematic review and meta-analysis SO INTERNATIONAL REVIEWS OF IMMUNOLOGY LA English DT Review DE Aeroallergen; allergic rhinitis; atopy; diet; vitamin D ID SERUM 25-HYDROXYVITAMIN D; ATOPIC-DERMATITIS; D SUPPLEMENTATION; CHILDHOOD ASTHMA; D INSUFFICIENCY; BIRTH COHORT; COSTA-RICA; PREGNANCY; CHILDREN; ADULTS AB Purpose: The role of vitamin D status in the etiology of allergic diseases is uncertain. The aim of this study was to investigate the association of vitamin D status with risk of two main outcomes: aeroallergen sensitization and allergic rhinitis (AR).Methods: We performed a systematic review of Medline, Scopus, Science Citation Index, and Google Scholar databases. Studies were included if they reported on prevalent or incident cases of aeroallergen sensitization or AR according to vitamin D status. Quality assessment, data extraction and meta-analysis were performed.Results: A total of 21 observational studies were included. Children with serum 25(OH)D 75 nmol/L had significantly reduced odds of aeroallergen sensitization, but neither vitamin D intake in pregnancy nor vitamin D supplementation in infancy were associated with risk of AR. Individuals with serum 25(OH)D 75 nmol/L had lower prevalence of AR compared to those with serum 25(OH)D <50 nmol/L (OR; 0.71, 95%CI; (0.56-0.89), p = 0.04). This association was mainly observed in adult men; prevalence of AR was lower in men with serum 25(OH)D 75 nmol/L compared to men with serum 25(OH)D <50 nmol/L, while this association was not observed in women.Conclusions: The current literature suggests significant age- and sex-specific relations of vitamin D status to risk of aeroallergen sensitization and AR. C1 [Aryan, Zahra] Univ Tehran Med Sci, Students Sci Res Ctr, Tehran, Iran. [Aryan, Zahra] Univ Tehran Med Sci, Dept Publ Hlth, Tehran, Iran. [Aryan, Zahra] USERN, PRDERN, Tehran, Iran. [Aryan, Zahra; Rezaei, Nima] Univ Tehran Med Sci, Res Ctr Immunodeficiencies, Childrens Med Ctr, Tehran, Iran. [Rezaei, Nima] USERN, NIIMA, Tehran, Iran. [Rezaei, Nima] USERN, Tehran, Iran. [Camargo, Carlos A., Jr.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA USA. [Camargo, Carlos A., Jr.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Med, Div Rheumatol Allergy & Immunol, Boston, MA USA. RP Camargo, CA (reprint author), Massachusetts Gen Hosp, 125 Nashua St,Suite 920, Boston, MA 02114 USA. EM ccamargo@partners.org OI Aryan, Zahra/0000-0002-6908-0016 NR 49 TC 1 Z9 1 U1 0 U2 0 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 0883-0185 EI 1563-5244 J9 INT REV IMMUNOL JI Int. Rev. Immunol. PY 2017 VL 36 IS 1 BP 41 EP 53 DI 10.1080/08830185.2016.1272600 PG 13 WC Immunology SC Immunology GA EM3GQ UT WOS:000395202900005 PM 28102718 ER PT J AU Jowett, N Malka, R Hadlock, TA AF Jowett, Nate Malka, Ronit Hadlock, Tessa A. TI Effect of Weakening of Ipsilateral Depressor Anguli Oris on Smile Symmetry in Postparalysis Facial Palsy SO JAMA FACIAL PLASTIC SURGERY LA English DT Article AB IMPORTANCE Aberrant depressor anguli oris (DAO) activitymay arise after recovery from acute facial paralysis and restrict movement of the oral commissure. OBJECTIVE To quantify the degree to which DAO inhibition affects smile dynamics and perceived emotional state. DESIGN, SETTING, AND PARTICIPANTS In this prospective, pretest-posttest study performed at an academic tertiary referral hospital, patients with unilateral postparalysis facial palsy were studied from January 16 through April 30, 2016. INTERVENTIONS Local anesthetic injection into the ipsilateral DAO. MAIN OUTCOMES AND MEASURES Healthy-and paretic-side commissure displacements from the midline lower vermillion border referenced to the horizontal plane were calculated from random-ordered photographs of full-effort smile before and after injection, and random-ordered hemifacial photographs of the paretic side were assessed as expressing positive, negative, or indiscernible emotion. RESULTS Twenty patients were identified as having unilateral postparalysis facial palsy with marked synkinesis of the ipsilateral DAO. Patient mean age was 46 years (range, 24-67 years), with a male to female ratio of 1: 3. Mean paretic-side commissure displacement increased from 27.45mmat 21.65 degrees above the horizontal plane to 29.35mm at 23.58 degrees after DAO weakening (mean difference, 1.90 mm; 95% CI, 1.26-2.54 mm; and 1.93 degrees; 95% CI, 0.34 degrees-3.51 degrees; P < .001 and P = .20, respectively). Symmetry of excursion between sides improved by 2.00mm(95% CI, 1.16-2.83 mm; P <.001) and 2.71 degrees (95% CI, 1.38 degrees-4.03 degrees; P < .001). At baseline, observers assessed 7 of 20 paretic hemifaces (35%) as expressing positive emotion; this proportion increased to 13 of 20 (65%) after DAO weakening (P = .03). CONCLUSIONS AND RELEVANCE Ipsilateral DAO weakening results in significant improvements in smile dynamics and perceived expression of positive emotion on the paretic hemiface in postparalysis facial palsy. A trial of DAO weakening should be offered to patients with this disfiguring complication of Bell palsy and similar facial nerve insults. C1 [Jowett, Nate; Hadlock, Tessa A.] Massachusetts Eye & Ear Infirm, Dept Otolaryngol, Div Facial Plast & Reconstruct Surg, 243 Charles St, Boston, MA 02114 USA. [Jowett, Nate; Hadlock, Tessa A.] Harvard Med Sch, 243 Charles St, Boston, MA 02114 USA. [Malka, Ronit] Harvard Med Sch, Hlth Sci & Technol Program, Boston, MA USA. [Malka, Ronit] MIT, Boston, MA USA. RP Jowett, N (reprint author), Massachusetts Eye & Ear Infirm, Dept Otolaryngol, Div Facial Plast & Reconstruct Surg, 243 Charles St, Boston, MA 02114 USA.; Jowett, N (reprint author), Harvard Med Sch, 243 Charles St, Boston, MA 02114 USA. EM nate_jowett@meei.harvard.edu 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 2168-6076 EI 2168-6092 J9 JAMA FACIAL PLAST SU JI JAMA Facial Plast. Surg. PD JAN-FEB PY 2017 VL 19 IS 1 BP 29 EP 33 DI 10.1001/jamafacial.2016.1115 PG 5 WC Surgery SC Surgery GA EL2GT UT WOS:000394438800005 PM 27658020 ER PT J AU Colaianni, CA Naunheim, M Tan, OT Deschler, DG AF Colaianni, C. Alessandra Naunheim, Matthew Tan, Oon Tian Deschler, Daniel G. TI Preoperative Laser Depilation Therapy to Address the Hairy Intraoral Flap SO JAMA FACIAL PLASTIC SURGERY LA English DT Letter ID RECONSTRUCTION C1 [Colaianni, C. Alessandra; Naunheim, Matthew; Tan, Oon Tian; Deschler, Daniel G.] Harvard Med Sch, Massachusetts Eye & Ear Infirm, 243 Charles St, Boston, MA 02114 USA. RP Colaianni, CA (reprint author), Harvard Med Sch, Massachusetts Eye & Ear Infirm, 243 Charles St, Boston, MA 02114 USA. EM alessa_colaianni@meei.harvard.edu 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 2168-6076 EI 2168-6092 J9 JAMA FACIAL PLAST SU JI JAMA Facial Plast. Surg. PD JAN-FEB PY 2017 VL 19 IS 1 BP 76 EP + DI 10.1001/jamafacial.2016.1302 PG 2 WC Surgery SC Surgery GA EL2GT UT WOS:000394438800014 PM 27812681 ER PT J AU Munshi, NC Avet-Loiseau, H Rawstron, AC Owen, RG Child, JA Thakurta, A Sherrington, P Samur, MK Georgieva, A Anderson, KC Gregory, WM AF Munshi, Nikhil C. Avet-Loiseau, Herve Rawstron, Andy C. Owen, Roger G. Child, J. Anthony Thakurta, Anjan Sherrington, Paul Samur, Mehmet Kemal Georgieva, Anna Anderson, Kenneth C. Gregory, Walter M. TI Association of Minimal Residual Disease With Superior Survival Outcomes in Patients With Multiple Myeloma A Meta-analysis SO JAMA ONCOLOGY LA English DT Article ID STEM-CELL TRANSPLANTATION; MULTIPARAMETER FLOW-CYTOMETRY; POLYMERASE-CHAIN-REACTION; BONE-MARROW; RESPONSE EVALUATION; MOLECULAR RESPONSE; PROGNOSTIC IMPACT; PHASE-II; DEXAMETHASONE; BORTEZOMIB AB IMPORTANCE Numerous studies have evaluated the prognostic value of minimal residual disease (MRD) in patients with multiplemyeloma (MM). Most studies were small and varied in terms of patient population, treatment, and MRD assessment methods. OBJECTIVE To evaluate the utility of MRD detection in patients with newly diagnosed MM. DATA SOURCES A Medline search was conducted for articles published in English between January 1990 and January 2016. STUDY SELECTION Eligible studies reported MRD status and progression-free survival (PFS) or overall survival (OS) in 20 or more patients following treatment. Among 405 articles identified, 21 met the initial eligibility criteria and were included in the analysis. DATA EXTRACTION AND SYNTHESIS Information on patient characteristics, treatment, MRD assessment, and outcomes were extracted using a standard form. MAIN OUTCOMES AND MEASURES The impact of MRD status on PFS and OS was assessed by pooling data from relevant trials. Data were adjusted to allow for different proportions of patients with MRD in different studies, and analyzed using the Peto method. Forest plots were created based on Cox model analysis. Other prespecified research questions were addressed qualitatively. RESULTS Fourteen studies (n = 1273) provided data on the impact of MRD on PFS, and 12 studies (n = 1100) on OS. Results were reported specifically in patients who had achieved conventional complete response (CR) in 5 studies for PFS (n = 574) and 6 studies for OS (n = 616). An MRD-negative status was associated with significantly better PFS overall (hazard ratio [HR], 0.41; 95% CI, 0.36-0.48; P <. 001) and in studies specifically looking at CR patients (HR, 0.44; 95% CI, 0.34-0.56; P <. 001). Overall survival was also favorable in MRD-negative patients overall (HR, 0.57; 95% CI, 0.46-0.71; P <. 001) and in CR patients (HR, 0.47; 95% CI, 0.33-0.67; P <. 001). Tests of heterogeneity found no significant differences among the studies for PFS and OS. CONCLUSIONS AND RELEVANCE Minimal residual disease-negative status after treatment for newly diagnosed MM is associated with long-term survival. These findings provide quantitative evidence to support the integration of MRD assessment as an end point in clinical trials of MM. C1 [Munshi, Nikhil C.; Samur, Mehmet Kemal; Anderson, Kenneth C.] Harvard Med Sch, Dana Farber Canc Inst, Boston, MA USA. [Avet-Loiseau, Herve] Inst Univ Canc, Unit Genom Myeloma, Toulouse, France. [Rawstron, Andy C.; Owen, Roger G.] St James Univ Hosp, Leeds, W Yorkshire, England. [Child, J. Anthony; Gregory, Walter M.] Univ Leeds, Leeds, W Yorkshire, England. [Thakurta, Anjan] Celgene Corp, Summit, NJ USA. [Sherrington, Paul] Celgene Int, Boudry, Switzerland. [Georgieva, Anna] Excerpta Medica, Amsterdam, Netherlands. RP Munshi, NC (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. EM nikhil_munshi@dfci.harvard.edu FU NIH [PO1-155258, P50-100707]; MRC UK [G0100132]; Celgene FX The work was partly supported by NIH grants PO1-155258, and P50-100707 (NCM, HAL and KCA). and an MRC UK grant G0100132 (JAC) and partly funded by Celgene. Celgene provided financial support for statistical analysis and editorial assistance for this study. NR 42 TC 1 Z9 1 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2374-2445 J9 JAMA ONCOL JI JAMA Oncol. PD JAN PY 2017 VL 3 IS 1 BP 28 EP 35 DI 10.1001/jamaoncol.2016.3160 PG 8 WC Oncology SC Oncology GA EK9PV UT WOS:000394257300008 PM 27632282 ER PT J AU de Morree, ES Vogelzang, NJ Petrylak, DP Budnik, N Wiechno, PJ Sternberg, CN Doner, K Bellmunt, J Burke, JM de Olza, MO Choudhury, A Gschwend, JE Kopyltsov, E Flechon, A van As, N Houede, N Barton, D Fandi, A Jungnelius, U Li, SY Li, JS Li, SS de Wit, R AF de Morree, Ellen S. Vogelzang, Nicholas J. Petrylak, Daniel P. Budnik, Nikolay Wiechno, Pawel J. Sternberg, Cora N. Doner, Kevin Bellmunt, Joaquim Burke, John M. de Olza, Maria Ochoa Choudhury, Ananya Gschwend, Juergen E. Kopyltsov, Evgeny Flechon, Aude van As, Nicolas Houede, Nadine Barton, Debora Fandi, Abderrahim Jungnelius, Ulf Li, Shaoyi Li, Jack Shiansong Li, Shiansong de Wit, Ronald TI Association of Survival Benefit With Docetaxel in Prostate Cancer and Total Number of Cycles Administered A Post Hoc Analysis of the Mainsail Study SO JAMA ONCOLOGY LA English DT Article ID PHASE-3 TRIAL; OPEN-LABEL; CHEMOTHERAPY; PREDNISONE; MITOXANTRONE; ABIRATERONE; ENZALUTAMIDE; CABAZITAXEL; THERAPY AB IMPORTANCE The optimal total number of docetaxel cycles in patients with metastatic castration resistant prostate cancer (mCPRC) has not been investigated yet. It is unknown whether it is beneficial for patients to continue treatment upon 6 cycles. OBJECTIVE To investigate whether the number of docetaxel cycles administered to patients deriving clinical benefit was an independent prognostic factor for overall survival (OS) in a post hoc analysis of the Mainsail trial. DESIGN, SETTING, AND PARTICIPANTS The Mainsail trial was a multinational randomized phase 3 study of 1059 patients with mCRPC receiving docetaxel, prednisone, and lenalidomide (DPL) or docetaxel, prednisone, and a placebo (DP). Study patients were treated until progressive disease or unacceptable adverse effects occurred. Median OS was found to be inferior in the DPL arm compared with the DP arm. As a result of increased toxic effects with the DPL combination, patients on DPL received fewer docetaxel cycles (median, 6) vs 8 cycles in the control group. As the dose intensity was comparable in both treatment arms, we investigated whether the number of docetaxel cycles administered to patients deriving clinical benefit on Mainsail was an independent prognostic factor for OS. We conducted primary univariate and multivariate analyses for the intention-to-treat population. Additional sensitivity analyses were done, excluding patients who stopped treatment for reasons of disease progression and those who received 4 or fewer cycles of docetaxel for other reasons, minimizing the effect of confounding factors. MAIN OUTCOMES AND MEASURES Total number of docetaxel cycles delivered as an independent factor for OS. RESULTS Overall, all 1059 patients from the Mainsail trial were included (mean [SD] age, 68.7 [7.89] years). Treatment with 8 or more cycles of docetaxel was associated with superior OS (hazard ratio [HR], 1.909; 95% CI, 1.660-2.194; P <. 001), irrespective of lenalidomide treatment (HR, 1.060; 95% CI, 0.924-1.215; P =. 41). Likewise, in the sensitivity analysis, patients who received a greater number of docetaxel cycles had superior OS; patients who received more than 10 cycles had a median OS of 33.0 months compared with 26.9 months in patients treated with 8 to 10 cycles; and patients who received 5 to 7 cycles had a median OS of 22.8 months (P <. 001). CONCLUSIONS AND RELEVANCE These findings suggest that continuation of docetaxel chemotherapy contributes to the survival benefit. Prospective validation is warranted. C1 [de Morree, Ellen S.; de Wit, Ronald] Erasmus MC Canc Inst, Dept Med Oncol, Groene Hilledijk 301, NL-3075 EA Rotterdam, Netherlands. [Vogelzang, Nicholas J.; Burke, John M.] US Oncol Res, Houston, TX USA. [Vogelzang, Nicholas J.] Comprehens Canc Ctr Nevada, Las Vegas, NV USA. [Petrylak, Daniel P.] Yale Canc Ctr, Div Oncol, Dept Med, New Haven, CT USA. [Budnik, Nikolay] NSHI Dorozhnaya Clin Hosp OAO Russian Railways, Rostov Na Donu, Russia. [Wiechno, Pawel J.] Inst Marii Sklodowskiej Curie, Dept Urooncol, Ctr Oncol, Warsaw, Poland. [Sternberg, Cora N.] San Camillo & Forlanini Hosp, Dept Med Oncol, Rome, Italy. [Doner, Kevin] Texas Oncol, Austin, TX USA. [Bellmunt, Joaquim] Univ Hosp del Mar IMIM, Barcelona, Spain. [Bellmunt, Joaquim] Harvard Med Sch, Dana Farber Canc Inst, Boston, MA USA. [Burke, John M.] Rocky Mt Canc Ctr, Aurora, CO USA. [de Olza, Maria Ochoa] Catalan Inst Oncol, Dept Med Oncol, Barcelona, Spain. [Choudhury, Ananya] Univ Manchester, Dept Clin Oncol, Christie NHS Fdn Trust & Inst Canc Sci, Manchester, Lancs, England. [Gschwend, Juergen E.] Tech Univ Munich, Dept Urol, Rechts del Isar Med Ctr, Munich, Germany. [Kopyltsov, Evgeny] State Inst Healthcare Reg Clin Oncol Dispensary, Omsk, Russia. [Flechon, Aude] Ctr Leon Berard, Dept Med Oncol, Lyon, France. [van As, Nicolas] Royal Marsden Hosp, Dept Clin Oncol, London, England. [Houede, Nadine] Grp Hosp Univ Caremeau, Dept Med Oncol, Pl Prof Robert Debre, Nimes, France. [Barton, Debora; Fandi, Abderrahim; Jungnelius, Ulf; Li, Shaoyi; Li, Jack Shiansong; Li, Shiansong] Celgene Corp, Summit, NJ USA. RP de Wit, R (reprint author), Erasmus MC Canc Inst, Dept Med Oncol, Groene Hilledijk 301, NL-3075 EA Rotterdam, Netherlands. EM r.dewit@erasmusmc.nl FU Celgene Corporation FX This study was supported by the Celgene Corporation. NR 14 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 2374-2445 J9 JAMA ONCOL JI JAMA Oncol. PD JAN PY 2017 VL 3 IS 1 BP 68 EP 75 DI 10.1001/jamaoncol.2016.3000 PG 8 WC Oncology SC Oncology GA EK9PV UT WOS:000394257300015 PM 27560549 ER PT J AU Rauh-Hain, JA Melamed, A Wright, A Gockley, A Clemmer, JT Schorge, JO del Carmen, MG Keating, NL AF Rauh-Hain, J. Alejandro Melamed, Alexander Wright, Alexi Gockley, Allison Clemmer, Joel T. Schorge, John O. del Carmen, Marcela G. Keating, Nancy L. TI Overall Survival Following Neoadjuvant Chemotherapy vs Primary Cytoreductive Surgery in Women With Epithelial Ovarian Cancer Analysis of the National Cancer Database SO JAMA ONCOLOGY LA English DT Article ID SURGICAL EFFORT; SENSITIVITY; MANAGEMENT; INTERVAL; SOCIETY; MEMBERS; TRIAL; INDEX AB IMPORTANCE Uncertainty remains about the relative benefits of primary cytoreductive surgery (PCS) vs neoadjuvant chemotherapy (NACT) for advanced-stage epithelial ovarian cancer (EOC). OBJECTIVE To compare overall survival of PCS vs NACT in a large national population of women with advanced-stage EOC. DESIGN, SETTING, AND PARTICIPANTS Retrospective cohort study of women with stage IIIC and IV EOC diagnosed between 2003 and 2011 treated at hospitals across the United States reporting to the National Cancer Data Base. We focused on patients 70 years or younger with a Charlson comorbidity index of 0 who were likely candidates for either treatment. EXPOSURES Initial treatment approach of PCS vs NACT, examined using an intent-to-treat analysis. MAIN OUTCOMES AND MEASURES Overall survival, defined as months from cancer diagnosis to death or date of the last contact. We used propensity score matching to compare similar women who underwent PCS and NACT. The association of treatment approach with overall survival was assessed using the Kaplan-Meier method and the log-rank test. We assessed whether the findings were influenced by differences in the prevalence of an unobserved confounder, such as limited performance status (Eastern Cooperative Oncology Group 1-2), preoperative disease burden, and BRCA status. RESULTS Among 22 962 patients (mean [SD] age, 56.12 [9.38] years), 19 836 (86.4%) received PCS and 3126 (13.6%) underwent NACT. We matched 2935 patients treated with NACT with similar patients who received PCS. The median follow-up was 56.5 (95% CI, 54.5-59.2) months in the PCS group and 56.3 (95% CI, 54.5-59.8) months in the NACT group in the propensity-matched cohort. Among propensity score-matched groups, the median overall survival was 37.3 (95% CI, 35.2-38.7) months in the PCS group and 32.1 (95% CI, 30.8-34.1) months in the NACT group (P <. 001). However, if the NACT group had a higher proportion of women with performance statuses of 1 to 2 compared with those who underwent PCS (60% vs 50%), the association of PCS and improved survival would not be statistically significant. CONCLUSIONS AND RELEVANCE Primary cytoreductive surgery was associated with improved survival compared with NACT in otherwise healthy women with advanced-stage epithelial ovarian cancer aged 70 years or younger. The lower survival in women who received NACT could be explained by a higher prevalence of limited performance status in women undergoing NACT. C1 [Rauh-Hain, J. Alejandro; Melamed, Alexander; Gockley, Allison; Clemmer, Joel T.; Schorge, John O.; del Carmen, Marcela G.] Harvard Med Sch, Massachusetts Gen Hosp, Div Gynecol Oncol Vincent Obstet & Gynecol, Boston, MA USA. [Wright, Alexi] Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA USA. [Wright, Alexi] Harvard Med Sch, Dana Farber Canc Inst, Div Populat Sci, Boston, MA USA. [Keating, Nancy L.] Harvard Med Sch, Dept Hlth Care Policy, Boston, MA USA. [Keating, Nancy L.] Brigham & Womens Hosp, Div Gen Internal Med, 75 Francis St, Boston, MA 02115 USA. RP Rauh-Hain, JA (reprint author), Massachusetts Gen Hosp, Div Gynecol Oncol Vincent Obstet & Gynecol, 55 Fruit St,Yawkey 9 E, Boston, MA 02114 USA. EM jrauh-hain@partners.org FU Deborah Kelly Center for Outcomes Research, Massachusetts General Hospital; National Cancer Institute at the National Institutes of Health [R25CA092203]; National Cancer Institute [K07 CA166210, K24CA181510] FX This work was supported by the Deborah Kelly Center for Outcomes Research, Massachusetts General Hospital. This work is supported by grant R25CA092203 from the National Cancer Institute at the National Institutes of Health. Dr Wright is supported by grant K07 CA166210, and Dr Keating, by grant K24CA181510 from the National Cancer Institute. NR 32 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 2374-2445 J9 JAMA ONCOL JI JAMA Oncol. PD JAN PY 2017 VL 3 IS 1 BP 76 EP 82 DI 10.1001/jamaoncol.2016.4411 PG 7 WC Oncology SC Oncology GA EK9PV UT WOS:000394257300016 PM 27892998 ER PT J AU Punglia, RS Cronin, AM Uno, H Stout, NK Ozanne, EM Greenberg, CC Frank, ES Schrag, D AF Punglia, Rinaa S. Cronin, Angel M. Uno, Hajime Stout, Natasha K. Ozanne, Elissa M. Greenberg, Caprice C. Frank, Elizabeth S. Schrag, Deborah TI Association of Regional Intensity of Ductal Carcinoma In Situ Treatment With Likelihood of Breast Preservation SO JAMA ONCOLOGY LA English DT Article ID SURGICAL ADJUVANT BREAST; RADIOTHERAPY; CANCER AB IMPORTANCE Large regional variation exists in the use of radiotherapy after breast-conserving surgery (BCS) for ductal carcinoma in situ (DCIS). Although patients who do not receive initial radiotherapy for DCIS are candidates for subsequent BCS if they experience a second breast event, many undergo mastectomy instead. OBJECTIVE To examine whether regional practice patterns of radiotherapy for DCIS affect the use of mastectomy in these patients. DESIGN, SETTING, AND PARTICIPANTS A retrospective analysis of population-based databases (Surveillance, Epidemiology, and End Results [SEER] and SEER-Medicare). Data were obtained for 2679 women in SEER with a diagnosis of DCIS between 1990 and 2011 and for 757 women in SEER-Medicare with a DCIS diagnosis between 1991 and 2009 who had not undergone radiotherapy for DCIS and experienced a subsequent breast cancer or DCIS diagnosis. EXPOSURES Treatment intensity for primary DCIS (high, medium, low), as defined by separating health service areas (HSAs) into 3 clusters based on radiotherapy use. MAIN OUTCOMES AND MEASURES Mastectomy vs BCS at a second breast event defined as DCIS recurrence or new invasive cancer. RESULTS The median (SD) ages of the participants was 64 (13) years for the 2679 SEER population and 79 (6) years for the SEER-Medicare cohort. Residence in an HSA characterized by greater radiotherapy use for DCIS increased the likelihood of receiving mastectomy vs BCS at a subsequent breast event, even among women who had not previously received radiotherapy for DCIS. Adjusted odds ratios for receiving mastectomy were 1.43 (95% CI, 1.10-1.85) and 1.90 (95% CI, 1.27-2.84) in SEER and SEER-Medicare databases, respectively, among women residing in an HSA with the greatest radiotherapy use vs the least, corresponding to an adjusted increase from 40.8% to 49.6%, and from 38.6% to 54.5%. CONCLUSIONS AND RELEVANCE Areas with more radiotherapy use for DCIS had increased use of mastectomy at the time of a second breast event even among patients eligible for breast conservation. This association suggests that physician-related factors are affecting the likelihood of breast preservation. C1 [Punglia, Rinaa S.] Harvard Med Sch, Dana Farber Canc Inst, Dept Radiat Therapy, 450 Brookline Ave,Dana 1115C, Boston, MA 02115 USA. [Cronin, Angel M.; Uno, Hajime; Schrag, Deborah] Harvard Med Sch, Dana Farber Canc Inst, Div Populat Sci, Boston, MA USA. [Stout, Natasha K.] Harvard Med Sch, Dept Populat Med, Boston, MA USA. [Stout, Natasha K.] Harvard Pilgrim Hlth Care Inst, Boston, MA USA. [Ozanne, Elissa M.] Dartmouth Inst, Geisel Sch Med, Hanover, NH USA. [Greenberg, Caprice C.] Univ Wisconsin, Sch Med, Dept Surg, Wisconsin Surg Outcomes Res Program, Madison, WI 53706 USA. [Frank, Elizabeth S.] Dana Farber Harvard Ctr, Breast Canc Advocacy Grp, Dana Farber Canc Inst, Boston, MA USA. RP Punglia, RS (reprint author), Harvard Med Sch, Dana Farber Canc Inst, Dept Radiat Therapy, 450 Brookline Ave,Dana 1115C, Boston, MA 02115 USA. EM rpunglia@partners.org FU Patient-Centered Outcomes Research Institute FX The Patient-Centered Outcomes Research Institute provided funding for this study. NR 13 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 2374-2445 J9 JAMA ONCOL JI JAMA Oncol. PD JAN PY 2017 VL 3 IS 1 BP 101 EP 104 DI 10.1001/jamaoncol.2016.2164 PG 4 WC Oncology SC Oncology GA EK9PV UT WOS:000394257300019 PM 27442038 ER PT J AU Harris, JR AF Harris, Jay R. TI Unanswered Questions Concerning Locoregional Irradiation in Breast Cancer Reply SO JAMA ONCOLOGY LA English DT Letter C1 [Harris, Jay R.] Harvard Med Sch, Dept Radiat Oncol, Dana Farber Canc Inst, Brigham & Womens Hosp, 450 Brookline Ave,YC 1473, Boston, MA 02215 USA. RP Harris, JR (reprint author), Harvard Med Sch, Dept Radiat Oncol, Dana Farber Canc Inst, Brigham & Womens Hosp, 450 Brookline Ave,YC 1473, Boston, MA 02215 USA. EM jharris@lroc.harvard.edu NR 0 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 2374-2445 J9 JAMA ONCOL JI JAMA Oncol. PD JAN PY 2017 VL 3 IS 1 BP 127 EP 127 DI 10.1001/jamaoncol.2016.3383 PG 1 WC Oncology SC Oncology GA EK9PV UT WOS:000394257300031 PM 27768181 ER PT J AU Wakeman, SE AF Wakeman, Sarah E. TI Medications For Addiction Treatment: Changing Language to Improve Care SO JOURNAL OF ADDICTION MEDICINE LA English DT Editorial Material DE language; medication-assisted treatment; opioid agonist therapy; stigma ID WORDS AB The term medication-assisted treatment has been widely adopted in reference to the use of opioid agonist therapy. Although it is arguably better than the older terms of replacement or substitution therapy, medication-assisted treatment implies that medications are a corollary to whatever the main part of treatment is. No other medication for other health conditions is referred to this way. It has finally been recognized that to improve care and reduce stigma, we must use medically accurate and person-first language, describing those with the disease of addiction as people with substance use disorder. However, to truly change outcomes, we must also alter the language of treatment. C1 [Wakeman, Sarah E.] Harvard Med Sch, Dept Med, Massachusetts Gen Hosp, 55 Fruit St,Founders 880, Boston, MA 02114 USA. RP Wakeman, SE (reprint author), Harvard Med Sch, Dept Med, Massachusetts Gen Hosp, 55 Fruit St,Founders 880, Boston, MA 02114 USA. EM swakeman@partners.org 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 1932-0620 EI 1935-3227 J9 J ADDICT MED JI J. Addict. Med. PD JAN-FEB PY 2017 VL 11 IS 1 BP 1 EP 2 DI 10.1097/ADM.0000000000000275 PG 2 WC Substance Abuse SC Substance Abuse GA EL0JG UT WOS:000394308100001 PM 27898497 ER PT J AU Hser, YI Huang, D Saxon, AJ Woody, G Moskowitz, AL Matthews, AG Ling, W AF Hser, Yih-Ing Huang, David Saxon, Andrew J. Woody, George Moskowitz, Andrew L. Matthews, Abigail G. Ling, Walter TI Distinctive Trajectories of Opioid Use Over an Extended Follow-up of Patients in a Multisite Trial on Buprenorphine plus Naloxone and Methadone SO JOURNAL OF ADDICTION MEDICINE LA English DT Article DE buprenorphine; growth mixture model; methadone maintenance; opioid use trajectory ID ADDICTION SEVERITY INDEX; HEALTH AB Objectives: Uncovering heterogeneities in longitudinal patterns (trajectories) of opioid use among individuals with opioid use disorder can increase our understanding of disease progression and treatment responses to improve care. The present study aims to identify distinctive opioid use trajectories and factors associated with these patterns among participants randomized to treatment with methadone (MET) or buprenorphine+naloxone (BUP). Methods: Growth mixture modeling was applied to identify distinctive opioid use trajectories among 795 opioid users after their enrollment in a multisite trial during 2006 to 2009, with follow-up interviews conducted during 2011 to 2014. Results: Four distinctive trajectories were identified based on opioid use over the follow-up period: low use (42.0%), high use (22.3%), increasing use (17.1%), and decreasing use (18.6%). Greater odds of being in the high use group (relative to low use) was associated with Hispanics (relative to African American, odds ratio [OR] 3.21), injection drug use (OR 2.12), higher mental health functioning at baseline (OR 1.23), location on the West Coast (vs East Coast, OR 2.15), and randomization to BUP (relative to MET, OR 1.53). High use and increasing use groups had greater severity in problems related to drug, employment, legal, and social/family relationships, and worsened mental health functioning at follow-up. Participation in treatment significantly accounted for both within and betweengroup differences in opioid use. Conclusions: Continued treatment is necessary to reduce risk for opioid use and related adverse consequences, particularly among individuals (eg, injecting drug) at risk for consistently high level of opioid use. C1 [Hser, Yih-Ing; Huang, David; Moskowitz, Andrew L.; Ling, Walter] Univ Calif Los Angeles, 11075 Santa Monica Blvd,Suite 200, Los Angeles, CA 90025 USA. [Saxon, Andrew J.] Vet Affairs Puget Sound Hlth Care Syst, Seattle, WA USA. [Woody, George] Univ Penn, Dept Psychiat, Perelman Sch Med, Philadelphia, PA 19104 USA. [Matthews, Abigail G.] EMMES Corp, Rockville, MD USA. RP Hser, YI (reprint author), Univ Calif Los Angeles, Integrated Subst Abuse Programs, 11075 Santa Monica Blvd,Suite 200, Los Angeles, CA 90025 USA. EM yhser@ucla.edu FU National Institute on Drug Abuse (NIDA) through the Clinical Trials Network (CTN) [U10 DA01714, U10 DA 015815, U10 DA13038, U10 DA13045, UG1 DA013035, U10 DA13043]; NIDA [P30DA016383] FX The main study funding was provided by the National Institute on Drug Abuse (NIDA) through the Clinical Trials Network (CTN) through a series of grants provided to each participating node: The Pacific Northwest Node (U10 DA01714); The Western States Node (U10 DA 015815); The New England Node (U10 DA13038); The Delaware Valley Node (U10 DA13043); The Pacific Region Node (U10 DA13045); The Greater New York Node (UG1 DA013035). Funding was also provided by NIDA through grant number P30DA016383. NR 17 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 1932-0620 EI 1935-3227 J9 J ADDICT MED JI J. Addict. Med. PD JAN-FEB PY 2017 VL 11 IS 1 BP 63 EP 69 DI 10.1097/ADM.0000000000000274 PG 7 WC Substance Abuse SC Substance Abuse GA EL0JG UT WOS:000394308100010 PM 27898496 ER PT J AU Stein, BD Mendelsohn, J Gordon, AJ Dick, AW Burns, RM Sorbero, M Shih, RA Pacula, RL AF Stein, Bradley D. Mendelsohn, Joshua Gordon, Adam J. Dick, Andrew W. Burns, Rachel M. Sorbero, Mark Shih, Regina A. Pacula, Rosalie Liccardo TI Opioid analgesic and benzodiazepine prescribing among Medicaid-enrollees with opioid use disorders: The influence of provider communities SO JOURNAL OF ADDICTIVE DISEASES LA English DT Article DE Opioid use disorders; benzodiazepines; opioids; social network analysis; prescribing behavior; Medicaid ID PRESCRIPTION DRUG OVERDOSES; SUBSTANCE USE; DEPENDENCE; RELAPSE; IMPACT; DOCTOR; BUPRENORPHINE; MAINTENANCE; BEHAVIOR; VIOLENCE AB Opioid analgesic and benzodiazepine use in individuals with opioid use disorders can increase the risk for medical consequences and relapse. Little is known about rates of use of these medications or prescribing patterns among communities of prescribers. The goal of this study was to examine rates of prescribing to Medicaid-enrollees in the calendar year after an opioid use disorder diagnosis, and to examine individual, county, and provider community factors associated with such prescribing. 2008 Medicaid claims data were used from 12 states to identify enrollees diagnosed with opioid use disorders, and 2009 claims data were used to identify rates of prescribing of each drug. Social network analysis was used to identify provider communities, and multivariate regression analyses was used to to identify patient, county, and provider community level factors associated with prescribing these drugs. The authors also examined variation in rates of prescribing across provider communities. Among Medicaid-enrollees identified with an opioid use disorder, 45% filled a prescription for an opioid analgesic, 37% filled a prescription for a benzodiazepine, and 21% filled a prescription for both in the year following their diagnosis. Females, older individuals, individuals with pain syndromes, and individuals residing in counties with higher rates of poverty were more likely to fill prescriptions. Prescribing rates varied substantially across provider communities, with rates in the highest quartile of prescribing communities over 2.5times the rates in the lowest prescribing communities. Prescribing opioid analgesics and benzodiazepines to individuals diagnosed with opioid use disorders may increase risk of relapse and overdose. Interventions should be considered that target provider communities with the highest rates of prescribing and individuals at the highest risk. C1 [Stein, Bradley D.; Burns, Rachel M.; Sorbero, Mark] RAND Corp, 4570 Fifth Ave, Pittsburgh, PA 15213 USA. [Stein, Bradley D.; Gordon, Adam J.] Univ Pittsburgh, Sch Med, Pittsburgh, PA USA. [Mendelsohn, Joshua; Pacula, Rosalie Liccardo] RAND Corp, Santa Monica, CA USA. [Gordon, Adam J.] VA Pittsburgh Healthcare Syst, Ctr Hlth Equ Res & Promot, Pittsburgh, PA USA. [Dick, Andrew W.] RAND Corp, Boston, MA USA. [Shih, Regina A.] RAND Corp, Arlington, VA USA. RP Stein, BD (reprint author), RAND Corp, 4570 Fifth Ave, Pittsburgh, PA 15213 USA. EM stein@rand.org FU National Institute on Drug Abuse of the National Institutes of Health (NIH) [1R01DA032881-01A1, RO1AG043960-01] FX The National Institute on Drug Abuse of the National Institutes of Health (NIH) provided support (award 1R01DA032881-01A1, PI: Stein and RO1AG043960-01, PI: Shih) for this study. NR 45 TC 0 Z9 0 U1 2 U2 2 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1055-0887 EI 1545-0848 J9 J ADDICT DIS JI J. Addict. Dis. PY 2017 VL 36 IS 1 BP 14 EP 22 DI 10.1080/10550887.2016.1211784 PG 9 WC Substance Abuse SC Substance Abuse GA EL2PR UT WOS:000394462400003 PM 27449904 ER PT J AU Kalapatapu, RK Ventura, MI Barnes, DE AF Kalapatapu, Raj K. Ventura, Maria I. Barnes, Deborah E. TI Lifetime alcohol use and cognitive performance in older adults SO JOURNAL OF ADDICTIVE DISEASES LA English DT Article DE Alcohol; substance use; cognition; cognitive; older adult ID SUBSTANCE USE DISORDERS; RANDOMIZED-CONTROLLED-TRIAL; CAUSAL-DIAGRAMS; DRUG-USE; CONSUMPTION; AGE; IMPAIRMENT; PREVALENCE; COMMUNITY; AMERICANS AB Substance use is an important clinical issue in the older adult population. As older adults are susceptible to cognitive disorders, the intersection of the fields of substance use and cognitive neuroscience is an active area of research. Prior studies of alcohol use and cognitive performance are mixed, and inconsistencies may be due to under- or over-adjustment for confounders. This article adds to this literature by conducting a secondary analysis of self-reported lifetime history of alcohol use and cognitive performance in older adults (n = 133). It was hypothesized that current alcohol users would have poorer cognitive performance compared to never/minimal and former alcohol users. Older adult participants were classified into never/minimal alcohol users, former alcohol users, and current alcohol users. A neurocognitive battery included a global cognitive measure and individual measures of attention, memory, fluency, and executive function. A directed acyclic graph-based approach was used to select variables to be included in the multiple linear regression models. Though unadjusted analyses showed some significant associations between alcohol use and cognitive performance, all associations between alcohol use and cognitive performance were eliminated after adjusting for age, education, sex, race, and smoking pack years. Alcohol drink years were not significantly associated with cognitive performance among current and former alcohol users. These results suggest that lifetime alcohol use is not significantly associated with cognitive performance in older adults after adjustment for key confounders. Inconsistencies in prior studies may be due to uncontrolled confounding and/or unnecessary adjustment of mediators and/or colliders. C1 [Kalapatapu, Raj K.; Barnes, Deborah E.] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA. [Kalapatapu, Raj K.; Ventura, Maria I.; Barnes, Deborah E.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Kalapatapu, Raj K.; Barnes, Deborah E.] San Francisco VA Med Ctr, San Francisco, CA USA. RP Kalapatapu, RK (reprint author), Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA.; Kalapatapu, RK (reprint author), Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA.; Kalapatapu, RK (reprint author), San Francisco VA Med Ctr, Opioid Treatment Program, Bldg 1,Ground Floor,Room 24,Mailstop 116F, San Francisco, CA 94121 USA. EM kalapatapu.raj.k@gmail.com FU National Institutes of Health [K01AG024069]; Alzheimer's Association [IIRG-06-27306]; National Center for Advancing Translational Sciences, National Institutes of Health, through UCSF-CTSI Grant [UL1 TR001872]; [K23DA034883] FX Dr. Kalapatapu is currently funded by K23DA034883. The MAX trial was funded by the National Institutes of Health (K01AG024069) and the Alzheimer's Association (IIRG-06-27306). This publication was also supported by the National Center for Advancing Translational Sciences, National Institutes of Health, through UCSF-CTSI Grant Number UL1 TR001872. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. NR 51 TC 0 Z9 0 U1 0 U2 0 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1055-0887 EI 1545-0848 J9 J ADDICT DIS JI J. Addict. Dis. PY 2017 VL 36 IS 1 BP 38 EP 47 DI 10.1080/10550887.2016.1245029 PG 10 WC Substance Abuse SC Substance Abuse GA EL2PR UT WOS:000394462400006 PM 27719514 ER PT J AU Sellal, F Wallon, D Martinez-Almoyna, L Marelli, C Dhar, A Oesterle, H Rovelet-Lecruxe, A Rousseaud, S Kourkoulis, CE Rosand, J DiPucchio, ZY Frosch, M Gombert, C Audoin, B Mine, M Riant, F Frebourg, T Hannequin, D Campion, D Greenberg, SM Tournier-Lasserve, E Nicolas, G AF Sellal, Francois Wallon, David Martinez-Almoyna, Laurent Marelli, Cecilia Dhar, Abhinav Oesterle, Helene Rovelet-Lecruxe, Anne Rousseaud, Stephane Kourkoulis, Christina E. Rosand, Jon DiPucchio, Zora Y. Frosch, Matthew Gombert, Claudine Audoin, Bertrand Mine, Manuele Riant, Florence Frebourg, Thierry Hannequin, Didier Campion, Dominique Greenberg, Steven M. Tournier-Lasserve, Elisabeth Nicolas, Gael TI APP Mutations in Cerebral Amyloid Angiopathy with or without Cortical Calcifications: Report of Three Families and a Literature Review SO JOURNAL OF ALZHEIMERS DISEASE LA English DT Review DE Alzheimer's disease; amyloid-beta; APP; calcification; cerebral amyloid angiopathy; mutation ID PRECURSOR PROTEIN MUTATION; ALZHEIMERS-DISEASE; SENILE PLAQUES; HEMORRHAGE; DEMENTIA; PHENOTYPES; SPECTRUM; CARRIERS; VARIANT; ONSET AB Background: Specific APP mutations cause cerebral amyloid angiopathy (CAA) with or without Alzheimer's disease (AD). Objective: We aimed at reporting APP mutations associated with CAA, describe the clinical, cerebrospinal fluid AD biomarkers, and neuroimaging features, and compare them with the data from the literature. Methods: We performed a retrospective study in two French genetics laboratories by gathering all clinical and neuroimaging data from patients referred for a genetic diagnosis of CAA with an age of onset before 66 years and fulfilling the other Boston revised criteria. We studied the segregation of mutations in families and performed a comprehensive literature review of all cases reported with the same APP mutation. Results: We screened APP in 61 unrelated French patients. Three mutations, located in the A beta coding region, were detected in five patients from three families: p.Ala692Gly (Flemish), p.Glu693Lys (Italian), and p.Asp694Asn (Iowa). Patients exhibited CAA and progressive cognitive impairment associated with cortical calcifications in the Iowa and Italian mutation carriers, but not the patient carrying the Flemish mutation. Conclusions: This is the first evidence of cortical calcification in patients with an APP mutation other than the Iowa mutation. We discuss the radiological, cerebrospinal fluid, and clinical phenotype of patients carrying these mutations in the literature. C1 [Sellal, Francois] Hop Civils Colmar, Dept Neurol & Consultat Memoire Ressource & Rech, Colmar, France. [Sellal, Francois] Univ Strasbourg, INSERM, Fac Med, U 1118, F-67070 Strasbourg, France. [Wallon, David] Rouen Univ Hosp, Dept Neurol, Rouen, France. [Wallon, David; Rousseaud, Stephane; Hannequin, Didier; Campion, Dominique; Nicolas, Gael] Rouen Univ Hosp, CNR MAJ, Rouen, France. [Wallon, David; Rovelet-Lecruxe, Anne; Frebourg, Thierry; Hannequin, Didier; Campion, Dominique; Nicolas, Gael] Univ Rouen, Normandy Univ, Inserm U1079, IRIB, Rouen, France. [Wallon, David; Rovelet-Lecruxe, Anne; Rousseaud, Stephane; Frebourg, Thierry; Hannequin, Didier; Campion, Dominique; Nicolas, Gael] Normandy Ctr Genom & Personalized Med, Rouen, France. [Martinez-Almoyna, Laurent; Gombert, Claudine] Ctr Hosp, Dept Neurol, Aix En Provence, France. [Marelli, Cecilia] CMRR, CHRU Gui Chauliac, Serv Neurol, Montpellier, France. [Dhar, Abhinav; Oesterle, Helene] Hosp Moenchsberg, Serv Radiol, Mulhouse, France. [Kourkoulis, Christina E.; Rosand, Jon; DiPucchio, Zora Y.; Greenberg, Steven M.] Massachusetts Gen Hosp, J Philip Kistler Stroke Res Ctr, Boston, MA 02114 USA. [DiPucchio, Zora Y.] Massachusetts Gen Hosp, Dept Neurol, Div Neurocrit Care & Emergency Neurol, Boston, MA 02114 USA. [Frosch, Matthew] Massachusetts Gen Hosp, CS Kubik Lab Neuropathol, Neuropathol Serv, Boston, MA 02114 USA. [Frosch, Matthew] Harvard Med Sch, Boston, MA USA. [Audoin, Bertrand] Aix Marseille Univ, CNRS, CRMBM UMR 7339, Marseille, France. [Audoin, Bertrand] Hop La Timone, APHM, Pole Neurosci Clin, Serv Neurol, Marseille, France. [Mine, Manuele; Riant, Florence; Tournier-Lasserve, Elisabeth] Hop Lariboisiere, AP HP, Serv Genet Mol Neurovasc, Paris, France. [Mine, Manuele; Riant, Florence; Tournier-Lasserve, Elisabeth] Univ Paris 07, INSERM, U1161, Paris, France. [Frebourg, Thierry; Hannequin, Didier; Nicolas, Gael] Rouen Univ Hosp, Dept Genet, 1Rue Germont, F-76031 Rouen, France. [Campion, Dominique] Rouvray Psychiat Hosp, Dept Res, Rouen, France. RP Nicolas, G (reprint author), Rouen Univ Hosp, Dept Genet, 1Rue Germont, F-76031 Rouen, France. EM gaelnicolas@hotmail.com FU Clinical Research Hospital Program from the French Ministry of Health (GMAJ) [PHRC 2008/067]; CNR-MAJ FX This study was funded by grants from the Clinical Research Hospital Program from the French Ministry of Health (GMAJ, PHRC 2008/067) and the CNR-MAJ. The funding sources had no specific roles. NR 31 TC 1 Z9 1 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 1 BP 37 EP 46 DI 10.3233/JAD-160709 PG 10 WC Neurosciences SC Neurosciences & Neurology GA EK4GW UT WOS:000393886100003 PM 27858710 ER PT J AU Ho, L Legere, M Li, TB Levine, S Hao, K Valcarcel, B Pasinetti, GM AF Ho, Lap Legere, Marc Li, Tongbin Levine, Samara Hao, Ke Valcarcel, Breanna Pasinetti, Giulio M. TI Autonomic Nervous System Dysfunctions as a Basis for a Predictive Model of Risk of Neurological Disorders in Subjects with Prior History of Traumatic Brain Injury: Implications in Alzheimer's Disease SO JOURNAL OF ALZHEIMERS DISEASE LA English DT Article DE Alzheimer's disease; autonomic nervous system; biomarker; neurodegenerative disorders; risk factor; traumatic brain injury ID SYMPATHETIC HYPERACTIVITY; SELECTION AB Autonomic dysfunction is very common in patients with dementia, and its presence might also help in differential diagnosis among dementia subtypes. Various central nervous system structures affected in Alzheimer's disease (AD) are also implicated in the central autonomic nervous system (ANS) regulation. For example, deficits in central cholinergic function in AD could likely lead to autonomic dysfunction. We recently developed a simple, readily applicable evaluation for monitoring ANS disturbances in response to traumatic brain injury (TBI). This ability to monitor TBI allows for the possible detection and targeted prevention of long-term, detrimental brain responses caused by TBI that lead to neurodegenerative diseases such as AD. We randomly selected and extracted de-identified medical record information from subjects who have been assessed using the ANS evaluation protocol. Using machine learning strategies in the analysis of information from individual as well as a combination of ANS evaluation protocol components, we identified a novel prediction model that is effective in correctly segregating between cases with or without a documented history of TBI exposure. Results from our study support the hypothesis that trauma-induced ANS dysfunctions may contribute to clinical TBI features. Because autonomic dysfunction is very common in AD patients it is possible that TBI may also contribute to AD and/or other forms of dementia through these novel mechanisms. This study provides a novel prediction model to physiologically assess the likelihood of subjects with prior history of TBI to develop clinical TBI complications, such as AD. C1 [Ho, Lap; Levine, Samara; Valcarcel, Breanna; Pasinetti, Giulio M.] Icahn Sch Med Mt Sinai, Dept Neurol, New York, NY 10029 USA. [Ho, Lap; Pasinetti, Giulio M.] James J Peters Vet Affairs Med Ctr, Geriatr Res Educ & Clin Ctr, Bronx, NY USA. [Legere, Marc] PATCH Chiropract, Philadelphia, PA USA. [Li, Tongbin] AccuraSci, Johnston, IA USA. [Hao, Ke] Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA. RP Pasinetti, GM (reprint author), 1468 Madison Ave,Annenberg Bldg,Room 20-02, New York, NY 10029 USA. EM giulio.pasinetti@mssm.edu FU Icahn School of Medicine at Mount Sinai; Geriatric Research Education and Clinical Centers (GRECC) of the James J. Peters Veterans Affairs Medical Center; Career Scientist Award in the Research and Development unit; Altschul Foundation; VA Grant [1I01BX000870-01A2]; National Natural Science Foundation of China [21477087]; Ministry of Science and Technology of the People's Republic of China [2016YFC0206507] FX This study was supported by discretionary funding from the Icahn School of Medicine at Mount Sinai to Dr. Giulio Maria Pasinetti and by the Geriatric Research Education and Clinical Centers (GRECC) of the James J. Peters Veterans Affairs Medical Center. In addition, Dr. Pasinetti holds a Career Scientist Award in the Research and Development unit and is the Director of the Basic and Biomedical Research and Training Program, GRECC, James J. Peters Veterans Affairs Medical Center. We acknowledge that the contents of this manuscript do not represent the views of the U.S. Department of Veterans Affairs or the United States Government. The current study was supported, in part, by the Altschul Foundation and VA Grant 1I01BX000870-01A2 to Dr. Giulio Maria Pasinetti. Dr. Ke Hao is partially supported by the National Natural Science Foundation of China (Grant No. 21477087) and by the Ministry of Science and Technology of the People's Republic of China (Grant No. 2016YFC0206507). NR 33 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 1 BP 305 EP 315 DI 10.3233/JAD-160948 PG 11 WC Neurosciences SC Neurosciences & Neurology GA EK4GW UT WOS:000393886100025 PM 27911325 ER PT J AU Law, LL Schultz, SA Boots, EA Einerson, JA Dougherty, RJ Oh, JM Korcarz, CE Edwards, DF Koscik, RL Dowling, NM Gallagher, CL Bendlin, BB Carlsson, CM Asthana, S Hermann, BP Sager, MA Johnson, SC Cook, DB Stein, JH Okonkwo, OC AF Law, Lena L. Schultz, Stephanie A. Boots, Elizabeth A. Einerson, Jean A. Dougherty, Ryan J. Oh, Jennifer M. Korcarz, Claudia E. Edwards, Dorothy F. Koscik, Rebecca L. Dowling, N. Maritza Gallagher, Catherine L. Bendlin, Barbara B. Carlsson, Cynthia M. Asthana, Sanjay Hermann, Bruce P. Sager, Mark A. Johnson, Sterling C. Cook, Dane B. Stein, James H. Okonkwo, Ozioma C. TI Chronotropic Response and Cognitive Function in a Cohort at Risk for Alzheimer's Disease SO JOURNAL OF ALZHEIMERS DISEASE LA English DT Article DE Alzheimer disease; cardiopulmonary exercise test; cardiovascular health; cognition; heart rate ID HEART-RATE RECOVERY; WHITE-MATTER HYPERINTENSITIES; CARDIORESPIRATORY FITNESS; WISCONSIN-REGISTRY; APOLIPOPROTEIN-E; CARDIAC-OUTPUT; BLOOD-PRESSURE; EXERCISE; MORTALITY; PREDICTOR AB The objective of this study was to examine the association of chronotropic response (CR) and heart rate (HR) recovery-two indices of cardiovascular function within the context of a graded exercise test-with cognitive performance in a cognitively healthy, late-middle-aged cohort at risk for Alzheimer's disease (AD). Ninety participants (age = 63.52 +/- 5.86 years; 65.6% female) from the Wisconsin Registry for Alzheimer's Prevention participated in this study. They underwent graded exercise testing and a comprehensive neuropsychological assessment that assessed the following four cognitive domains: Immediate Memory, Verbal & Learning Memory, Working Memory, and Speed & Flexibility. Regression analyses, adjusted for age, sex, and education, were used to examine the association between CR, HR recovery, and cognition. We found significant associations between CR and cognitive performance in the domains of Immediate Memory, Verbal Learning & Memory, and Speed & Flexibility. In contrast, HR recovery was not significantly associated with cognitive function. The association between CR and cognition persisted even after controlling for HR recovery. Together, these findings indicate that, in a cognitively normal, late-middle-aged cohort, CR is a stronger correlate of cognitive performance than HR recovery. Overall, this study reinforces the idea that cardiovascular health plays an important role in cognitive function, specifically in a cohort at risk for AD; and that interventions that promote vascular health may be a viable pathway to preventing or slowing cognitive decline due to AD. C1 [Law, Lena L.; Schultz, Stephanie A.; Boots, Elizabeth A.; Oh, Jennifer M.; Gallagher, Catherine L.; Bendlin, Barbara B.; Carlsson, Cynthia M.; Asthana, Sanjay; Johnson, Sterling C.; Okonkwo, Ozioma C.] William S Middleton Mem Vet Adm Med Ctr, Geriatr Res Educ & Clin Ctr, Madison, WI 53705 USA. [Law, Lena L.; Schultz, Stephanie A.; Boots, Elizabeth A.; Oh, Jennifer M.; Edwards, Dorothy F.; Gallagher, Catherine L.; Bendlin, Barbara B.; Carlsson, Cynthia M.; Asthana, Sanjay; Hermann, Bruce P.; Sager, Mark A.; Johnson, Sterling C.; Okonkwo, Ozioma C.] Univ Wisconsin, Wisconsin Alzheimers Dis Res Ctr, Sch Med & Publ Hlth, Madison, WI 53792 USA. [Law, Lena L.; Schultz, Stephanie A.; Boots, Elizabeth A.; Oh, Jennifer M.; Edwards, Dorothy F.; Koscik, Rebecca L.; Bendlin, Barbara B.; Hermann, Bruce P.; Sager, Mark A.; Johnson, Sterling C.; Okonkwo, Ozioma C.] Univ Wisconsin, Sch Med & Publ Hlth, Wisconsin Alzheimers Inst, Madison, WI 53792 USA. [Dougherty, Ryan J.; Edwards, Dorothy F.; Cook, Dane B.] Univ Wisconsin, Sch Educ, Dept Kinesiol, Madison, WI 53792 USA. [Einerson, Jean A.; Korcarz, Claudia E.; Stein, James H.] Univ Wisconsin, Sch Med & Publ Hlth, Div Cardiol, Madison, WI 53792 USA. [Dowling, N. Maritza] Univ Wisconsin, Sch Med & Publ Hlth, Dept Biostat & Med Informat, Madison, WI 53792 USA. [Gallagher, Catherine L.] Univ Wisconsin, Sch Med & Publ Hlth, Dept Neurol, Madison, WI 53792 USA. [Cook, Dane B.] William S Middleton Mem Vet Adm Med Ctr, Res Serv, Madison, WI 53705 USA. RP Okonkwo, OC (reprint author), Univ Wisconsin, Dept Med, Madison, WI 53792 USA.; Okonkwo, OC (reprint author), Univ Wisconsin, Alzheimers Dis Res Ctr, Sch Med & Publ Hlth, Madison, WI 53792 USA. EM ozioma@medicine.wisc.edu FU National Institute on Aging [K23 AG045957, R01 AG027161, R01 AG021155, P50 AG033514]; Clinical and Translational Science Award [UL1RR025011]; Alzheimer's Association; Extendicare Foundation; Wisconsin Alumni Research Foundation; Helen Bader Foundation; Northwestern Mutual Foundation; Veterans Administration FX This work was supported by the National Institute on Aging grants K23 AG045957 (OCO), R01 AG027161 (SCJ), R01 AG021155 (SCJ), and P50 AG033514 (SA); and by a Clinical and Translational Science Award (UL1RR025011) to the University of Wisconsin, Madison. Portions of this research were supported by the Alzheimer's Association, the Extendicare Foundation, the Wisconsin Alumni Research Foundation, the Helen Bader Foundation, Northwestern Mutual Foundation, and from the Veterans Administration, including facilities and resources at the Geriatric Research Education and Clinical Center of the William S. Middleton Memorial Veterans Hospital, Madison, WI. We thank the staff and study participants of the Wisconsin Registry for Alzheimer's Prevention without whom this work would not be possible. 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 56 IS 1 BP 351 EP 359 DI 10.3233/JAD-160642 PG 9 WC Neurosciences SC Neurosciences & Neurology GA EK4GW UT WOS:000393886100029 PM 27911299 ER PT J AU Liu, ZQ Hu, Y Yu, P Lin, M Huang, G Kawai, T Taubman, M Wang, ZM Han, XZ AF Liu, Zhiqiang Hu, Yang Yu, Pei Lin, Mei Huang, Grace Kawai, Toshihisa Taubman, Martin Wang, Zuomin Han, Xiaozhe TI Toll-like receptor agonists Porphyromonas gingivalis LPS and CpG differentially regulate IL-10 competency and frequencies of mouse B10 cells SO JOURNAL OF APPLIED ORAL SCIENCE LA English DT Article DE IL-10; Porphyromonas gingivalis LPS ID ESCHERICHIA-COLI; B-CELLS; LIGAND; LIPOPOLYSACCHARIDE; IMMUNITY; ACTIVATION; PATHWAY AB IL-10 expressing regulatory B cells (B10) play a key role in immune system balance by limiting excessive inflammatory responses. Effects of toll-like receptor signaling and co-stimulatory molecules on B10 activity during innate and adaptive immune responses are not fully understood. Objective This study is to determine the effects of P. gingivalis LPS and CpG on B10 cell expansion and IL-10 competency in vitro. Material and Methods Spleen B cells were isolated from C57BL/6J mice with or without formalin-fixed P. gingivalis immunization. B cells were cultured for 48 hours under the following conditions: CD40L, CD40L+LPS, CD40L+CpG, and CD40L+LPS+CpG in the presence or absence of fixed P. gingivalis. Percentages of CD1dhiCD5? B cells were measured by flow cytometry. IL-10 mRNA expression and secreted IL-10 were measured by real-time quantitative PCR and by ELISA respectively. Results P. gingivalis LPS plus CD40L significantly increased CD1dhiCD5+ B cell percentages and secreted IL-10 levels in both immunized and non-immunized mice B cells in the presence or absence of P. gingivalis, compared with control group. Secreted IL-10 levels were significantly increased in CD40L+LPS treated group compared with CD40L treatment group in the absence of P. gingivalis. CpG plus CD40L significantly decreased CD1dhiCD5? B cell percentages, but greatly elevated secreted IL-10 levels in immunized and non-immunized mice B cells in the absence of P. gingivalis, compared with CD40L treatment group. Conclusions P. gingivalis LPS and CpG differentially enhance IL-10 secretion and expansion of mouse B10 cells during innate and adaptive immune responses. C1 [Liu, Zhiqiang; Hu, Yang; Yu, Pei; Huang, Grace; Kawai, Toshihisa; Taubman, Martin; Han, Xiaozhe] Forsyth Inst, Dept Immunol & Infect Dis, Cambridge, MA USA. [Liu, Zhiqiang; Lin, Mei; Wang, Zuomin] Capital Med Univ, Beijing ChaoYang Hosp, Dept Stomatol, Beijing, Peoples R China. [Yu, Pei] Sichuan Univ, West China Sch Stomatol, State Key Lab Oral Dis, Chengdu, Sichuan, Peoples R China. RP Han, XZ (reprint author), 245 First St, Cambridge, MA 02142 USA. EM Xhan@forsyth.org FU NIH NIDCR grant [R21DE021837, R56DE023807] FX This study was supported by NIH NIDCR grant R21DE021837 and R56DE023807. NR 26 TC 0 Z9 0 U1 1 U2 1 PU UNIV SAO PAULO FAC ODONTOLOGIA BAURU PI BAURU-SP PA AL DR OCTAVIO PINHEIRO BRISOLLA, 9-75, BAURU-SP, 17012-901, BRAZIL SN 1678-7757 EI 1678-7765 J9 J APPL ORAL SCI JI J. Appl. Oral Sci. PD JAN-FEB PY 2017 VL 25 IS 1 BP 90 EP 100 DI 10.1590/1678-77572016-0277 PG 11 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA EK8HV UT WOS:000394165400013 PM 28198981 ER PT J AU Wormwood, JB Neumann, AE Barrett, LF Quigley, KS AF Wormwood, Jolie Baumann Neumann, Anna E. Barrett, Lisa Feldman Quigley, Karen S. TI Understanding emotion in context: how the Boston marathon bombings altered the impact of anger on threat perception SO JOURNAL OF APPLIED SOCIAL PSYCHOLOGY LA English DT Article ID NEW-YORK-CITY; INDIVIDUAL-DIFFERENCES; TERRORIST ATTACKS; DISCRETE EMOTIONS; SEPTEMBER 11; EXPERIENCE; RESPONSES; DECISIONS; EXPOSURE; SHOOT AB Three studies examine the impact of an anger manipulation on threat perception among Northeastern University students after the Boston Marathon bombings. Data collection for one experiment began within 24 hours of the bombings. Results suggest that the impact of anger on threat perception differed during the week of the bombings compared to 1 and 5 months later. During the week of the bombings only, participants experiencing anger were less sensitive to the distinction between threats and nonthreats, and more biased toward perceiving all stimuli as threatening relative to control participants. We discuss potential mechanisms for these effects and the need for more rapid response research in the wake of incidents of mass violence. C1 [Wormwood, Jolie Baumann; Neumann, Anna E.; Barrett, Lisa Feldman; Quigley, Karen S.] Northeastern Univ, Dept Psychol, Boston, MA 02115 USA. [Barrett, Lisa Feldman] Harvard Med Sch, Massachusetts Gen Hosp, Dept Psychiat, Boston, MA USA. [Barrett, Lisa Feldman] Harvard Med Sch, Massachusetts Gen Hosp, Martinos Ctr Biomed Imaging, Boston, MA USA. [Quigley, Karen S.] Edith Nourse Rogers Mem VA Hosp, Ctr Healthcare Org & Implementat Res, Bedford, MA USA. RP Wormwood, JB (reprint author), Northeastern Univ, Dept Psychol, Psychol NI 125, 360 Huntington Ave, Boston, MA 02115 USA. EM jbwormwood@gmail.com FU U.S. Army Research Institute for the Behavioral and Social Sciences [W5J9CQ-12-C-0049]; National Science Foundation [BCS-1422327, BCS-1426171] FX This research was supported by the U.S. Army Research Institute for the Behavioral and Social Sciences (W5J9CQ-12-C-0049) and the National Science Foundation (BCS-1422327 and BCS-1426171). 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 55 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0021-9029 EI 1559-1816 J9 J APPL SOC PSYCHOL JI J. Appl. Soc. Psychol. PD JAN PY 2017 VL 47 IS 1 BP 13 EP 22 DI 10.1111/jasp.12412 PG 10 WC Psychology, Social SC Psychology GA EL9XZ UT WOS:000394974700002 ER PT J AU Lee, A Kiessling, AA AF Lee, Amy Kiessling, Ann A. TI Early human embryos are naturally aneuploid-can that be corrected? SO JOURNAL OF ASSISTED REPRODUCTION AND GENETICS LA English DT Review DE Human embryo; Chromosome; Euploid; Aneuploid; In vitro fertilization; Preimplantation genetic screening; Egg donor ID IN-VITRO FERTILIZATION; RANDOMIZED CONTROLLED-TRIAL; CELL-CYCLE NETWORK; X-CHROMOSOME; PREIMPLANTATION EMBRYOS; INSITU HYBRIDIZATION; TUMOR-SUPPRESSOR; PARENTAL ORIGIN; TURNER-SYNDROME; BIOPSY AB Aneuploidy is common and may be a natural occurrence in early human embryos. Selecting against embryos containing aneuploid cells for embryo transfer has been reported to increase clinical pregnancies per transfer in some studies, but not others. Some aneuploidy is due to misallocation of chromosomes during meiosis, in either the egg or sperm, but most aneuploidy is due to misallocation of chromosomes during mitoses after fertilization. Big questions are as follows: Why does this happen? How much aneuploidy in a preimplantation embryo is compatible with normal fetal development? Is aneuploidy increased by in vitro culture, and/or could it be prevented or corrected in the IVF lab? C1 [Lee, Amy] Massachusetts Gen Hosp, Dept Obstet & Gynecol, Div Reprod Endocrinol, Boston, MA 02114 USA. [Kiessling, Ann A.] Bedford Res Fdn, Bedford, MA 01730 USA. RP Kiessling, AA (reprint author), Bedford Res Fdn, Bedford, MA 01730 USA. EM kiessling@bedfordresearch.org NR 51 TC 0 Z9 0 U1 1 U2 1 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1058-0468 EI 1573-7330 J9 J ASSIST REPROD GEN JI J. Assist. Reprod. Genet. PD JAN PY 2017 VL 34 IS 1 BP 15 EP 21 DI 10.1007/s10815-016-0845-7 PG 7 WC Genetics & Heredity; Obstetrics & Gynecology; Reproductive Biology SC Genetics & Heredity; Obstetrics & Gynecology; Reproductive Biology GA EM1HU UT WOS:000395069500005 PM 27900612 ER PT J AU Lo, WCY Uribe-Patarroyo, N Nam, AS Villiger, M Vakoc, BJ Bouma, BE AF Lo, William C. Y. Uribe-Patarroyo, Nestor Nam, Ahhyun S. Villiger, Martin Vakoc, Benjamin J. Bouma, Brett E. TI Laser thermal therapy monitoring using complex differential variance in optical coherence tomography SO JOURNAL OF BIOPHOTONICS LA English DT Article DE laser thermal therapy; optical coherence tomography; retina; skin; esophagus ID IN-VIVO; BARRETTS-ESOPHAGUS; MR THERMOMETRY; ABLATION; BIREFRINGENCE; COLLAGEN; TISSUE; DAMAGE; PHASE; SCARS AB Conventional thermal therapy monitoring techniques based on temperature are often invasive, limited by point sampling, and are indirect measures of tissue injury, while techniques such as magnetic resonance and ultrasound thermometry are limited by their spatial resolution. The visualization of the thermal coagulation zone at high spatial resolution is particularly critical to the precise delivery of thermal energy to epithelial lesions. In this work, an integrated thulium laser thermal therapy monitoring system was developed based on complex differential variance (CDV), which enables the 2D visualization of the dynamics of the thermal coagulation process at high spatial and temporal resolution with an optical frequency domain imaging system. With proper calibration to correct for noise, the CDV-based technique was shown to accurately delineate the thermal coagulation zone, which is marked by the transition from high CDV upon heating to a significantly reduced CDV once the tissue is coagulated, in 3 different tissue types ex vivo: skin, retina, and esophagus. The ability to delineate thermal lesions in multiple tissue types at high resolution opens up the possibility of performing microscopic image-guided procedures in a vast array of epithelial applications ranging from dermatology, ophthalmology, to gastroenterology and beyond. [GRAPHICS] . C1 [Lo, William C. Y.; Uribe-Patarroyo, Nestor; Nam, Ahhyun S.; Villiger, Martin; Vakoc, Benjamin J.; Bouma, Brett E.] Massachusetts Gen Hosp, Wellman Ctr Photomed, 40 Blossom St, Boston, MA 02114 USA. [Lo, William C. Y.; Uribe-Patarroyo, Nestor; Nam, Ahhyun S.; Villiger, Martin; Vakoc, Benjamin J.; Bouma, Brett E.] Massachusetts Gen Hosp, Dept Dermatol, 40 Blossom St, Boston, MA 02114 USA. [Lo, William C. Y.; Uribe-Patarroyo, Nestor; Nam, Ahhyun S.; Villiger, Martin; Vakoc, Benjamin J.; Bouma, Brett E.] Harvard Med Sch, 40 Blossom St, Boston, MA 02114 USA. [Lo, William C. Y.; Vakoc, Benjamin J.; Bouma, Brett E.] Harvard MIT, Div Hlth Sci & Technol, Cambridge, MA 02142 USA. [Nam, Ahhyun S.] MIT, Dept Mech Engn, 77 Massachusetts Ave, Cambridge, MA 02139 USA. RP Lo, WCY (reprint author), Massachusetts Gen Hosp, Wellman Ctr Photomed, 40 Blossom St, Boston, MA 02114 USA.; Lo, WCY (reprint author), Massachusetts Gen Hosp, Dept Dermatol, 40 Blossom St, Boston, MA 02114 USA.; Lo, WCY (reprint author), Harvard Med Sch, 40 Blossom St, Boston, MA 02114 USA.; Lo, WCY (reprint author), Harvard MIT, Div Hlth Sci & Technol, Cambridge, MA 02142 USA. EM Lo.William@mgh.harvard.edu FU National Institutes of Health [P41 EB015903]; Canadian Institutes of Health Research (CIHR) FX Research reported in this publication was funded in part by the National Institutes of Health P41 EB015903 grant. WCYL was supported by the Canadian Institutes of Health Research (CIHR) Doctoral Foreign Study Award. NR 29 TC 0 Z9 0 U1 0 U2 0 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA POSTFACH 101161, 69451 WEINHEIM, GERMANY SN 1864-063X EI 1864-0648 J9 J BIOPHOTONICS JI J. Biophotonics PD JAN PY 2017 VL 10 IS 1 BP 84 EP 91 DI 10.1002/jbio.201600072 PG 8 WC Biochemical Research Methods; Biophysics; Optics SC Biochemistry & Molecular Biology; Biophysics; Optics GA EL8DB UT WOS:000394849400008 PM 27623742 ER PT J AU Korte, KJ Bountress, KE Tomko, RL Killeen, T Maria, MMS Back, SE AF Korte, Kristina J. Bountress, Kaitlin E. Tomko, Rachel L. Killeen, Therese Maria, Megan Moran-Santa Back, Sudie E. TI Integrated Treatment of PTSD and Substance Use Disorders: The Mediating Role of PTSD Improvement in the Reduction of Depression SO JOURNAL OF CLINICAL MEDICINE LA English DT Article DE posttraumatic stress disorder; PTSD; substance use disorders; alcohol; depression; integrated treatments; prolonged exposure; mediation; treatment ID POSTTRAUMATIC-STRESS-DISORDER; ALCOHOL DEPENDENCE; DSM-IV; TREATMENT PREFERENCES; SYMPTOM INTERPLAY; CLINICAL-TRIALS; SEVERITY; VETERANS; EXPOSURE; COMORBIDITY AB Posttraumatic stress disorder (PTSD) represents one of the most common mental health disorders, particularly among veterans, and is associated with significant distress and impairment. This highly debilitating disorder is further complicated by common comorbid psychiatric disorders, such as substance use disorders (SUD). Individuals with PTSD and co-occurring SUD also commonly present with secondary symptoms, such as elevated depression. Little is known, however, about how these secondary symptoms are related to treatment outcome. The aim of the present study, therefore, was to examine (1) the effects of treatment of comorbid PTSD/SUD on depressive symptoms; and (2) whether this effect was mediated by changes in PTSD severity or changes in SUD severity. Participants were 81 U.S. military veterans (90.1% male) with PTSD and SUD enrolled in a randomized controlled trial examining the efficacy of an integrated, exposure-based treatment (Concurrent Treatment of PTSD and Substance Use Disorders Using Prolonged Exposure; n = 54) versus relapse prevention (n = 27). Results revealed significantly lower depressive symptoms at post-treatment in the COPE group, as compared to the relapse prevention group. Examination of the mechanisms associated with change in depression revealed that reduction in PTSD severity, but not substance use severity, mediated the association between the treatment group and post-treatment depression. The findings underscore the importance of treating PTSD symptoms in order to help reduce co-occurring symptoms of depression in individuals with PTSD/SUD. Clinical implications and avenues for future research are discussed. C1 [Korte, Kristina J.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Bountress, Kaitlin E.; Tomko, Rachel L.; Killeen, Therese; Maria, Megan Moran-Santa; Back, Sudie E.] Med Univ South Carolina, Dept Psychiat & Behav Sci, Charleston, SC 29401 USA. [Back, Sudie E.] Ralph H Johnson Vet Affairs Med Ctr, Charleston, SC 29401 USA. RP Back, SE (reprint author), Med Univ South Carolina, Dept Psychiat & Behav Sci, Charleston, SC 29401 USA.; Back, SE (reprint author), Ralph H Johnson Vet Affairs Med Ctr, Charleston, SC 29401 USA. EM kkorte@mgh.harvard.edu; bountress@musc.edu; tomko@musc.edu; killeen@musc.edu; moranm@musc.edu; backs@musc.edu FU National Institutes of Health [NIDA R01 DA030143, NIAAA T32AA007474, NIDA K02 DA039229, NIMH T32MH18869, NIMH T32MH093310] FX This study was supported by National Institutes of Health grants NIDA R01 DA030143, NIAAA T32AA007474, NIDA K02 DA039229, NIMH T32MH18869 and NIMH T32MH093310. There are no conflicts of interest. NR 46 TC 0 Z9 0 U1 1 U2 1 PU MDPI AG PI BASEL PA ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND SN 2077-0383 J9 J CLIN MED JI J. Clin. Med. PD JAN PY 2017 VL 6 IS 1 AR 9 DI 10.3390/jcm6010009 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA EO2NK UT WOS:000396533000008 ER PT J AU Bramoweth, AD AF Bramoweth, Adam D. TI A Step in the Right Direction: Moving Toward Increased Access to Insomnia Care SO JOURNAL OF CLINICAL SLEEP MEDICINE LA English DT Editorial Material C1 [Bramoweth, Adam D.] VA Pittsburgh Healthcare Syst, Mental Illness Res Educ & Clin Ctr, Ctr Hlth Equ Res & Promot, Pittsburgh, PA USA. RP Bramoweth, AD (reprint author), VA Pittsburgh Healthcare Syst, Res Off Bldg 151R,Univ Dr, Pittsburgh, PA 15240 USA. EM adam.bramoweth@va.gov FU United States Department of Veterans Affairs Health Services Research and Development Service [13-260] FX Dr. Bramoweth has indicated no financial conflicts of interest. Dr. Bramoweth is supported by Career Development Award 13-260 from the United States Department of Veterans Affairs Health Services Research and Development Service. The views expressed are those of the author and do not necessarily represent the views of the United States Department of Veterans Affairs or the United States Government. NR 3 TC 0 Z9 0 U1 0 U2 0 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 2 BP 161 EP 162 DI 10.5664/jcsm.6432 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA EP0AI UT WOS:000397048800003 PM 28095979 ER PT J AU Allister, LM Torres, C Schnall, J Bhatia, K Miller, ES AF Allister, Lauren M. Torres, Carlos Schnall, Jeremy Bhatia, Kriti Miller, Emily S. TI Case Presentations of the Harvard Affiliated Emergency Medicine Residencies SO JOURNAL OF EMERGENCY MEDICINE LA English DT Article ID INDUCED METHEMOGLOBINEMIA; GLUCOSE-6-PHOSPHATE-DEHYDROGENASE DEFICIENCY; DEHYDROGENASE-DEFICIENCY; HYPERBARIC OXYGENATION; SEVERE HEMOLYSIS; INGESTION; FAILURE C1 [Allister, Lauren M.; Miller, Emily S.] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. [Allister, Lauren M.; Bhatia, Kriti; Miller, Emily S.] Harvard Med Sch, Dept Emergency Med, Boston, MA 02118 USA. [Torres, Carlos; Schnall, Jeremy] Massachusetts Gen Hosp, Dept Pediat, Boston, MA 02114 USA. [Torres, Carlos; Schnall, Jeremy] Harvard Med Sch, Dept Pediat, Boston, MA USA. [Bhatia, Kriti] Brigham & Womens Hosp, Dept Emergency Med, 75 Francis St, Boston, MA 02115 USA. RP Miller, ES (reprint author), Harvard Med Sch, Dept Emergency Med, Boston, MA 02118 USA. NR 22 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 0736-4679 EI 1090-1280 J9 J EMERG MED JI J. Emerg. Med. PD JAN PY 2017 VL 52 IS 1 BP 93 EP 97 PG 5 WC Emergency Medicine SC Emergency Medicine GA EO1CD UT WOS:000396434300025 PM 27693073 ER PT J AU Aaronson, EL Filbin, MR Brown, DFM Tobin, K Mort, EA AF Aaronson, Emily L. Filbin, Michael R. Brown, David F. M. Tobin, Kathy Mort, Elizabeth A. TI NEW MANDATED CENTERS FOR MEDICARE AND MEDICAID SERVICES REQUIREMENTS FOR SEPSIS REPORTING: CAUTION FROM THE FIELD SO JOURNAL OF EMERGENCY MEDICINE LA English DT Article DE sepsis; health care quality; access and evaluation; quality indicators; health care quality assessment ID SEPTIC SHOCK; SURVIVING SEPSIS; UNITED-STATES; HEALTH-CARE; PERFORMANCE; MANAGEMENT; EPIDEMIOLOGY; IMPROVEMENT; RESUSCITATION; MULTICENTER AB Background: The release of the Center for Medicare and Medicaid Service's (CMS) latest quality measure, Severe Sepsis/Septic Shock Early Management Bundle (SEP-1), has intensified the long-standing debate over optimal care for severe sepsis and septic shock. Although the last decade of research has demonstrated the importance of comprehensive bundled care in conjunction with compliance mechanisms to reduce patient mortality, it is not clear that SEP-1 achieves this aim. The heterogeneous and often cryptic presentation of severe sepsis and septic shock, along with the multifaceted criteria for the definition of this clinical syndrome, pose a particular challenge for fitting requirements to this disease, and implementation could have unintended consequences. Objective: Following a simulated reporting exercise, in which 50 charts underwent expert review, we aimed to detail the challenges of, and offer suggestions on how to rethink, measuring performance in severe sepsis and septic shock care. Discussion: There were several challenges associated with the design and implementation of this measure. The ambiguous definition of severe sepsis and septic shock, prescriptive fluid volume requirements, rigid reassessment, and complex abstraction logic all raise significant concern. Conclusions: Although SEP-1 represents an important first step in requiring hospitals to improve outcomes for patients with severe sepsis and septic shock, the current approach must be revisited. The volume and complexity of the currently required SEP-1 reporting elements deserve serious consideration and revision before they are used as measures of accountability and tied to reimbursement. (C) 2016 Elsevier Inc. All rights reserved. C1 [Aaronson, Emily L.; Filbin, Michael R.; Brown, David F. M.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA USA. [Aaronson, Emily L.; Tobin, Kathy; Mort, Elizabeth A.] Massachusetts Gen Hosp, Lawrence Ctr Qual & Safety, Boston, MA 02114 USA. [Aaronson, Emily L.; Tobin, Kathy; Mort, Elizabeth A.] Massachusetts Gen Phys Org, Boston, MA USA. [Mort, Elizabeth A.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Med, Boston, MA USA. RP Aaronson, EL (reprint author), Dept Emergency Med, 0 Emerson Pl,Suite 3B, Boston, MA 02115 USA. NR 36 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 0736-4679 EI 1090-1280 J9 J EMERG MED JI J. Emerg. Med. PD JAN PY 2017 VL 52 IS 1 BP 109 EP 116 DI 10.1016/j.jemermed.2016.08.009 PG 8 WC Emergency Medicine SC Emergency Medicine GA EO1CD UT WOS:000396434300036 PM 27720289 ER PT J AU Mateescu, B Kowal, EJK van Balkom, BWM Bartel, S Bhattacharyya, SN Buzas, EI Buck, AH de Candia, P Chow, FWN Das, S Driedonks, TAP Fernandez-Messina, L Haderk, F Hill, AF Jones, JC Van Keuren-Jensen, KR Lai, CP Lasser, C di Liegro, I Lunavat, TR Lorenowicz, MJ Maas, SLN Mager, I Mittelbrunn, M Momma, S Mukherjee, K Nawaz, M Pegtel, DM Pfaffl, MW Schiffelers, RM Tahara, H Thery, C Tosar, JP Wauben, MHM Witwer, KW Nolte-'T Hoen, ENM AF Mateescu, Bogdan Kowal, Emma J. K. van Balkom, Bas W. M. Bartel, Sabine Bhattacharyya, Suvendra N. Buzas, Edit I. Buck, Amy H. de Candia, Paola Chow, Franklin W. N. Das, Saumya Driedonks, Tom A. P. Fernandez-Messina, Lola Haderk, Franziska Hill, Andrew F. Jones, Jennifer C. Van Keuren-Jensen, Kendall R. Lai, Charles P. Laesser, Cecilia di Liegro, Italia Lunavat, Taral R. Lorenowicz, Magdalena J. Maas, Sybren L. N. Maeger, Imre Mittelbrunn, Maria Momma, Stefan Mukherjee, Kamalika Nawaz, Muhammed Pegtel, D. Michiel Pfaffl, Michael W. Schiffelers, Raymond M. Tahara, Hidetoshi Thery, Clotilde Tosar, Juan Pablo Wauben, Marca H. M. Witwer, Kenneth W. Nolte-'t Hoen, Esther N. M. TI Obstacles and opportunities in the functional analysis of extracellular vesicle RNA - an ISEV position paper SO JOURNAL OF EXTRACELLULAR VESICLES LA English DT Article DE Extracellular vesicles; exosomes; non-coding RNA; mRNA; function; sorting; RNA binding proteins; quantification ID REAL-TIME PCR; EXOSOME-MEDIATED TRANSFER; MESSENGER-RNA; MAMMALIAN-CELLS; ENDOTHELIAL-CELLS; DRUG-DELIVERY; HUMAN PLASMA; IN-VIVO; RT-PCR; INFLAMMATORY RESPONSE AB The release of RNA-containing extracellular vesicles (EV) into the extracellular milieu has been demonstrated in a multitude of different in vitro cell systems and in a variety of body fluids. RNA-containing EV are in the limelight for their capacity to communicate genetically encoded messages to other cells, their suitability as candidate biomarkers for diseases, and their use as therapeutic agents. Although EV-RNA has attracted enormous interest from basic researchers, clinicians, and industry, we currently have limited knowledge on which mechanisms drive and regulate RNA incorporation into EV and on how RNA-encoded messages affect signalling processes in EV-targeted cells. Moreover, EV-RNA research faces various technical challenges, such as standardisation of EV isolation methods, optimisation of methodologies to isolate and characterise minute quantities of RNA found in EV, and development of approaches to demonstrate functional transfer of EV-RNA in vivo. These topics were discussed at the 2015 EV-RNA workshop of the International Society for Extracellular Vesicles. This position paper was written by the participants of the workshop not only to give an overview of the current state of knowledge in the field, but also to clarify that our incomplete knowledge - of the nature of EV(-RNA)s and of how to effectively and reliably study them - currently prohibits the implementation of gold standards in EV-RNA research. In addition, this paper creates awareness of possibilities and limitations of currently used strategies to investigate EV-RNA and calls for caution in interpretation of the obtained data. C1 [Mateescu, Bogdan] ETH, Swiss Fed Inst Technol, Dept Biol, Zurich, Switzerland. [Kowal, Emma J. K.] MIT, Dept Biol, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [van Balkom, Bas W. M.] UMC Utrecht, Dept Hypertens & Nephrol, Utrecht, Netherlands. [Bartel, Sabine] Member German Ctr Lung Res DZL, Airway Res Ctr North ARCN, Leibniz Ctr Med & Biosci, Res Ctr Borstel,Expt Asthma Res,Prior Area Asthma, Borstel, Germany. [Bhattacharyya, Suvendra N.; Mukherjee, Kamalika] CSIR Indian Inst Chem Biol, Kolkata, India. [Buzas, Edit I.] Semmelweis Univ, Dept Genet Cell & Immunobiol, Budapest, Hungary. [Buck, Amy H.; Chow, Franklin W. N.] Univ Edinburgh, Res Ctr Immun Infect & Evolut, Sch Biol Sci, Inst Immunol & Infect, Edinburgh, Midlothian, Scotland. [de Candia, Paola] IRCCS MultiMed, Milan, Italy. [Das, Saumya] Massachusetts Gen Hosp, Cardiovasc Res Inst, Boston, MA 02114 USA. [Driedonks, Tom A. P.; Wauben, Marca H. M.; Nolte-'t Hoen, Esther N. M.] Univ Utrecht, Fac Vet Med, Dept Biochem & Cell Biol, Utrecht, Netherlands. [Fernandez-Messina, Lola] Hosp Princesa, Immunol Serv, Madrid, Spain. [Haderk, Franziska] German Canc Res Ctr, Dept Mol Genet, Heidelberg, Germany. [Haderk, Franziska] Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, Dept Med, San Francisco, CA 94143 USA. [Hill, Andrew F.] La Trobe Univ, Trobe Inst Mol Sci, Dept Biochem & Genet, Bundoora, Vic, Australia. [Jones, Jennifer C.] NCI, CCR, Vaccine Branch, Mol Immunogenet & Vaccine Res Sect, Bethesda, MD 20892 USA. [Van Keuren-Jensen, Kendall R.] TGen, Neurogen Div, Phoenix, AZ USA. [Lai, Charles P.] Natl Tsing Hua Univ, Inst Biomed Engn, Hsinchu, Taiwan. [Laesser, Cecilia; Lunavat, Taral R.; Maas, Sybren L. N.] Harvard Med Sch, NeuroDiscovery Ctr, Boston, MA 02114 USA. [Laesser, Cecilia; Lunavat, Taral R.; Maas, Sybren L. N.] Massachusetts Gen Hosp, Ctr Mol Imaging Res, Dept Radiol, Boston, MA 02114 USA. [Laesser, Cecilia; Lunavat, Taral R.; Maas, Sybren L. N.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Laesser, Cecilia; Lunavat, Taral R.; Maas, Sybren L. N.] Univ Gothenburg, Sahlgrenska Acad, Krefting Res Ctr, Dept Internal Med & Clin Nutr, Gothenburg, Sweden. [di Liegro, Italia] Univ Palermo, Dept Expt Biomed & Clin Neurosci, Palermo, Italy. [Lorenowicz, Magdalena J.] Univ Med Ctr Utrecht & Regenerat Med Ctr, Ctr Mol Med, Utrecht, Netherlands. [Maeger, Imre] Univ Oxford, Dept Physiol Anat & Genet, Oxford, England. [Maeger, Imre] Univ Tartu, Inst Technol, Tartu, Estonia. [Mittelbrunn, Maria] Inst Investigac Hosp 12 Octubre, Madrid, Spain. [Momma, Stefan] Goethe Univ Frankfurt, Sch Med, Inst Neurol Edinger Inst, Frankfurt, Germany. [Nawaz, Muhammed] Univ Sao Paulo, Ribeirao Preto Sch Med, Dept Pathol & Forens Med, Sao Paulo, Brazil. [Pegtel, D. Michiel] Vrije Univ Amsterdam Med Ctr, Exosomes Res Grp, Dept Pathol, Amsterdam, Netherlands. [Pfaffl, Michael W.] Tech Univ Munich, Sch Life Sci, Anim Physiol & Immunol, Freising Weihenstephan, Germany. [Schiffelers, Raymond M.] Univ Med Ctr Utrecht, Lab Clin Chem & Haematol, Utrecht, Netherlands. [Tahara, Hidetoshi] Hiroshima Univ, Inst Biomed Hlth Sci, Dept Cell & Mol Biol, Hiroshima, Japan. [Thery, Clotilde] PSL Res Univ, Inst Curie, INSERM U932, Paris, France. [Tosar, Juan Pablo] Univ Republica, Fac Sci, Nucl Res Ctr, Funct Genom Unit,Inst Pasteur Montevideo, Montevideo, Uruguay. [Witwer, Kenneth W.] Johns Hopkins Univ, Sch Med, Dept Mol & Comparat Pathobiol, Baltimore, MD USA. [Witwer, Kenneth W.] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD USA. RP Nolte-'T Hoen, ENM (reprint author), Univ Utrecht, Fac Vet Med, Dept Biochem & Cell Biol, Utrecht, Netherlands. EM e.n.m.nolte@uu.nl RI Jones, Jennifer/C-8691-2015; thery, clotilde/F-6373-2013; OI Jones, Jennifer/0000-0002-9488-7719; thery, clotilde/0000-0001-8294-6884; Nawaz, Muhammad /0000-0002-0792-8296 FU NIH Common Fund [1U19CA179513-01]; European Research Council under the European Union [337581]; FAPESP (Sao Paulo Research Foundation) [12/24574-3]; CAPES (Coordination for the Improvement of Higher Education Personnel) [BEX 7057/15-6] FX BM is supported by grant 1U19CA179513-01 from the NIH Common Fund. ENMN-TH receives funding from the European Research Council under the European Union's Seventh Framework Programme (FP/2007-2013)/ERC Grant Agreement number 337581. MN received funding from FAPESP (Sao Paulo Research Foundation, Proc. No. 12/24574-3) and CAPES (Coordination for the Improvement of Higher Education Personnel, Proc No. BEX 7057/15-6). NR 247 TC 0 Z9 0 U1 3 U2 3 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND SN 2001-3078 J9 J EXTRACELL VESICLES JI J. Extracell. Vesicles PY 2017 VL 6 AR 1286095 DI 10.1080/20013078.2017.1286095 PG 33 WC Cell Biology SC Cell Biology GA EN7CF UT WOS:000396159000001 PM 28326170 ER PT J AU Skaar, E Ranhoff, AH Nordrehaug, JE Forman, DE Schaufel, MA AF Skaar, Elisabeth Ranhoff, Anette Hylen Nordrehaug, Jan Erik Forman, Daniel E. Schaufel, Margrethe Aase TI Conditions for autonomous choice: a qualitative study of older adults' experience of decision-making in TAVR SO JOURNAL OF GERIATRIC CARDIOLOGY LA English DT Article DE Aortic stenosis; Older adults; Patient-centered care; Shared decision-making; Trans-catheter aortic valve replacement ID AORTIC-VALVE IMPLANTATION; PREFERENCES; STENOSIS; CARE; INVOLVEMENT; DEMENTIA; SURGERY; TRUST; RISK AB Background Patient autonomy is a leading principle in bioethics and a basis for shared decision making. This study explores conditions for an autonomous choice experienced by older adults who recently underwent trans-catheter aortic valve replacement (TAVR). Methods Qualitative study entailing semi-structured interviews of a purposive sample of ten older (range 73-89, median 83.5 years) adults after TAVR (median 23 days). The study setting was a cardiac department at a university hospital performing TAVR since 2010. Analysis was by systematic text condensation. Results Even when choice seemed hard or absent, TAVR-patients deliberately took the chance offered them by processing risk assessment, ambivalence and fate. They regarded declining the treatment to be worse than accepting the risk related to the procedure. The experience of being thoroughly advised by their physician formed the basis of an autonomous trust. The trust they felt for the physicians' recommendations mitigated ambivalence about the procedure and risks. TAVR patients expressed feelings consistent with self-empowerment and claimed that it had to be their decision. Even so, choosing the intervention as an obligation to their family or passively accepting it was also reported. Conclusions Older TAVR patients' experience of an autonomous decision may encompass frank tradeoff; deliberate physician dependency as well as a resilient self-view. Physicians should be especially aware of how older adults' subtle cognitive declines and inclinations to preserve their identities which can influence their medical decision making when obtaining informed consent. Cardiologists and other providers may also use these insights to develop new strategies that better respond to such inherent complexities. C1 [Skaar, Elisabeth] Haukeland Hosp, Dept Heart Dis, POB 1400, N-5020 Bergen, Norway. [Skaar, Elisabeth; Ranhoff, Anette Hylen; Nordrehaug, Jan Erik] Univ Bergen, Dept Clin Sci, Bergen, Norway. [Skaar, Elisabeth; Ranhoff, Anette Hylen] Haraldsplass Deaconess Hosp, Kavli Res Ctr Geriatr & Dementia, Bergen, Norway. [Forman, Daniel E.] Univ Pittsburgh Med Ctr, VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. [Schaufel, Margrethe Aase] Uni Res Hlth, Res Unit Gen Practice, Bergen, Norway. [Schaufel, Margrethe Aase] Haukeland Hosp, Dept Thorac Med, Bergen, Norway. RP Skaar, E (reprint author), Haukeland Hosp, Dept Heart Dis, POB 1400, N-5020 Bergen, Norway. EM elisabeth.skaar@helse-bergen.no FU Grieg Foundation; Department of Heart Disease; Haukeland University Hospital; Kavli Research Centre for Geriatrics and Dementia, Haraldsplass Deaconess Hospital, Bergen FX We would like to thank the participants in this study, and professor Kirsti Malterud for valuable comments. This study was mainly supported by Grants from Grieg Foundation, Department of Heart Disease, Haukeland University Hospital and Kavli Research Centre for Geriatrics and Dementia, Haraldsplass Deaconess Hospital, Bergen. NR 33 TC 0 Z9 0 U1 0 U2 0 PU SCIENCE PRESS PI BEIJING PA 16 DONGHUANGCHENGGEN NORTH ST, BEIJING 100717, PEOPLES R CHINA SN 1671-5411 J9 J GERIATR CARDIOL JI J. Geriatr. Cardiol. PY 2017 VL 14 IS 1 BP 42 EP 48 DI 10.11909/j.issn.1671-5411.2017.01.007 PG 7 WC Cardiac & Cardiovascular Systems; Geriatrics & Gerontology SC Cardiovascular System & Cardiology; Geriatrics & Gerontology GA EN4QB UT WOS:000395990900007 PM 28270841 ER PT J AU Ozsahin, DU Blackberg, L El Fakhri, G Sabet, H AF Ozsahin, D. Uzun Blackberg, L. El Fakhri, G. Sabet, H. TI GATE simulation of a new design of pinhole SPECT system for small animal brain imaging SO JOURNAL OF INSTRUMENTATION LA English DT Article; Proceedings Paper CT 14th Topical Seminar on Innovative Particle and Radiation Detectors CY OCT 03-06, 2016 CL Siena, ITALY DE Detector modelling and simulations I (interaction of radiation with matter, interaction of photons with matter, interaction of hadrons with matter, etc); Gamma camera, SPECT, PET PET/CT, coronary CT angiography (CTA); Gamma detectors (scintillators, CZT, HPG, HgI etc); Medical-image reconstruction methods and algorithms, computer-aided software ID DETECTORS; PET AB Small animal SPECT imaging has gained an increased interest over the past decade since it is an excellent tool for developing new drugs and tracers. Therefore, there is a huge effort on the development of cost-effective SPECT detectors with high capabilities. The aim of this study is to simulate the performance characteristics of new designs for a cost effective, stationary SPECT system dedicated to small animal imaging with a focus on mice brain. The conceptual design of this SPECT system platform, Stationary Small Animal SSA-SPECT, is to use many pixelated CsI:TI detector modules with 0.4 mm x 0.4 mm pixels in order to achieve excellent intrinsic detector resolution where each module is backed by a single pinhole collimator with 0.3 mm hole diameter. In this work, we present the simulation results of four variations of the SSA-SPECT platform where the number of detector modules and FOV size is varied while keeping the detector size and collimator hole size constant. Using the NEMA NU-4 protocol, we performed spatial resolution, sensitivity, image quality simulations followed by a Derenzo-like phantom evaluation. The results suggest that all four SSA-SPECT systems can provide better than 0.063% system sensitivity and < 1.5 mm FWHM spatial resolution without resolution recovery or other correction techniques. Specifically, SSA-SPECT-1 showed a system sensitivity of 0.09% in combination with 1.1 mm FWHM spatial resolution. C1 [Ozsahin, D. Uzun; Blackberg, L.; El Fakhri, G.; Sabet, H.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Radiol, 55 Fruit St, Boston, MA 02115 USA. [Ozsahin, D. Uzun] Near East Univ, TRNC, Dept Biomed Engn, Near East Blvd, CY-99138 Nicosia, Cyprus. [Blackberg, L.] Uppsala Univ, Dept Phys & Astron, Box 516, SE-75120 Uppsala, Sweden. RP Ozsahin, DU (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Dept Radiol, 55 Fruit St, Boston, MA 02115 USA.; Ozsahin, DU (reprint author), Near East Univ, TRNC, Dept Biomed Engn, Near East Blvd, CY-99138 Nicosia, Cyprus. EM dilber.uzunozsahin@neu.edu.tr FU U.S. National Institute of Health [1R03EB020762-01, 1R21EB020162-01A1]; Scientific and Technological Research Council of Turkey (TUBITAK); Center of Excellence, Near East University; Swedish Research Council (VR) FX This work was supported in part by the U.S. National Institute of Health under Grant No. 1R03EB020762-01 and 1R21EB020162-01A1. D.U.O. acknowledges support from the Scientific and Technological Research Council of Turkey (TUBITAK) and Center of Excellence, Near East University, L.B. acknowledges financial support from the Swedish Research Council (VR). NR 18 TC 0 Z9 0 U1 0 U2 0 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 1748-0221 J9 J INSTRUM JI J. Instrum. PD JAN PY 2017 VL 12 AR C01085 DI 10.1088/1748-0221/12/01/C01085 PG 8 WC Instruments & Instrumentation SC Instruments & Instrumentation GA EN1KG UT WOS:000395768300085 ER PT J AU Gago-Diaz, M Brion, M Gallego, P Calvo, F Robledo-Carmona, J Saura, D Sanchez, V Bermejo, J Sevilla, T Newton-Cheh, C Carracedo, A Muehlschlegel, JD Garcia-Dorado, D Body, SC Evangelista, A AF Gago-Diaz, Marina Brion, Maria Gallego, Pastora Calvo, Francisco Robledo-Carmona, Juan Saura, Daniel Sanchez, Violeta Bermejo, Javier Sevilla, Teresa Newton-Cheh, Christopher Carracedo, Angel Muehlschlegel, J. Daniel Garcia-Dorado, David Body, Simon C. Evangelista, Artur TI The genetic component of bicuspid aortic valve and aortic dilation. An exome-wide association study SO JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY LA English DT Article DE Aortic dilation; Bicuspid aortic valve; Complex trait; Exome-wide association study; Genetics ID NOTCH1 MUTATIONS; DISEASE; ANEURYSMS; DISSECTIONS; DILATATION; CONSORTIUM; FREQUENCY; BAVCON; SIZE AB Background: Bicuspid aortic valve is the most common cardiovascular congenital malformation affecting 2% of the general population. The incidence of life-threatening complications, the high heritability, and familial clustering rates support the interest in identifying risk or protective genetic factors. The main objective of the present study was to identify population-based genetic variation associated with bicuspid aortic valve and concomitant ascending aortic dilation. Materials and methods: A cross-sectional exome-wide association study was conducted in 565 Spanish cases and 484 controls. Single-marker and gene-based association analyses enriched for low frequency and rare genetic variants were performed on this discovery stage cohort and for the subsets of cases with and without ascending aortic dilation. Discovery-stage association signals and additional markers indirectly associated with bicuspid aortic valve, were genotyped in a replication cohort that comprised 895 Caucasian cases and 1483 controls. Results: Although none of the association signals were consistent across series, the involvement of HMCN2 in calcium metabolism and valve degeneration caused by calcium deposit, and a nominal but not genome-wide significant association, supported it as an interesting gene for follow-up studies on the genetic susceptibility to bicuspid aortic valve. Conclusions: The absence of a genome-wide significant association signal shows this valvular malformation may be more genetically complex than previously believed. Exhaustive phenotypic characterization, even larger datasets, and collaborative efforts are needed to detect the combination of rare variants conferring risk which, along with specific environmental factors, could be causing the development of this disease. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Gago-Diaz, Marina; Brion, Maria] Complexo Hosp Univ Santiago de Compostela, Xenet Enfermidades Cardiovasc & Oftalmolox, Inst Invest Sanitaria Santiago de Compostela, Santiago De Compostela, Spain. [Gago-Diaz, Marina; Brion, Maria; Carracedo, Angel] Univ Santiago de Compostela, Grp Med Xenom, Inst Investigat Sanitaria Santiago de Compostela, Fdn Publ Galega Med Xenom, Santiago De Compostela, Spain. [Gallego, Pastora] Hosp Univ Virgen Macarena, Serv Cardiol, Seville, Spain. [Calvo, Francisco] Complexo Hosp Univ Vigo, Serv Cardiol, Vigo, Spain. [Robledo-Carmona, Juan] Hosp Univ Virgen Victoria, Serv Cardiol, Malaga, Spain. [Saura, Daniel] Hosp Clin Univ Virgen Arrixaca, Serv Cardiol, Murcia, Spain. [Sanchez, Violeta] Hosp Univ 12 Octubre, Serv Cardiol, Madrid, Spain. [Bermejo, Javier] Hosp Gen Univ Gregorio Maranon, Serv Cardiol, Madrid, Spain. [Sevilla, Teresa] Hosp Clin Univ Valladolid, Serv Cardiol, Valladolid, Spain. [Newton-Cheh, Christopher] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Newton-Cheh, Christopher] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Newton-Cheh, Christopher] Harvard Med Sch, Boston, MA USA. [Newton-Cheh, Christopher; Muehlschlegel, J. Daniel; Body, Simon C.] MIT, Broad Inst, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Newton-Cheh, Christopher; Muehlschlegel, J. Daniel; Body, Simon C.] Harvard Univ, Cambridge, MA 02138 USA. [Carracedo, Angel] King Abdulaziz Univ, Ctr Excellence Genom Med Res, Jeddah, Saudi Arabia. [Muehlschlegel, J. Daniel; Body, Simon C.] Brigham & Womens Hosp, Anesthesia & Pain Management, 75 Francis St, Boston, MA 02115 USA. [Garcia-Dorado, David; Evangelista, Artur] Hosp Univ Vall dHebron, Serv Cardiol, Barcelona, Spain. RP Brion, M (reprint author), Complexo Hosp Univ Santiago de Compostela, Inst Invest Sanitaria Santiago de Compostela IDIS, Travesia Choupana S-N,Lab 1, Santiago De Compostela 15706, A Coruna, Spain. EM maria.brion@usc.es OI Sanchez, Violeta/0000-0001-7967-8233; Saura, Daniel/0000-0002-7824-2814 FU Plan Estatal de I + D + i; Subdireccion General de Evaluacion y Fomento de la Investigacion (ISCIII-SGEFI) from Instituto de Salud Carlos III (ISCIII); Fondo Europeo de Desarrollo Regional (FEDER) [PI11/01081, RD12/0042/0021, PI13/00933, RD12/0042/0037, PT13/0001]; National Institutes of Health [R01HL114823] FX This work was supported by the Plan Estatal de I + D + i 2008-2011 and 2013-2016, Subdireccion General de Evaluacion y Fomento de la Investigacion (ISCIII-SGEFI) from Instituto de Salud Carlos III (ISCIII) and Fondo Europeo de Desarrollo Regional (FEDER) [grant numbers PI11/01081, RD12/0042/0021 - Programme 3 Red de Investigation Cardiovascular, PI13/00933, RD12/0042/0037, and PT13/0001 to CEGEN-PRB2-ISCIII]; and the National Institutes of Health [grant R01HL114823 to SCB]. NR 47 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0022-2828 EI 1095-8584 J9 J MOL CELL CARDIOL JI J. Mol. Cell. Cardiol. PD JAN PY 2017 VL 102 BP 3 EP 9 DI 10.1016/j.yjmcc.2016.11.012 PG 7 WC Cardiac & Cardiovascular Systems; Cell Biology SC Cardiovascular System & Cardiology; Cell Biology GA EO8UU UT WOS:000396966800002 PM 27894865 ER PT J AU Arvold, ND Cefalu, M Wang, Y Zigler, C Schrag, D Dominici, F AF Arvold, Nils D. Cefalu, Matthew Wang, Yun Zigler, Corwin Schrag, Deborah Dominici, Francesca TI Comparative effectiveness of radiotherapy with vs. without temozolomide in older patients with glioblastoma SO JOURNAL OF NEURO-ONCOLOGY LA English DT Article DE Glioblastoma; Radiotherapy; Temozolomide; Elderly; Survival ID ADJUVANT TEMOZOLOMIDE; PLUS CONCOMITANT; ELDERLY-PATIENTS; MULTIFORME SURVIVAL; RADIATION-THERAPY; PROPENSITY SCORE; PHASE-3 TRIAL; EPIDEMIOLOGY; CANCER; GLIOMA AB It is unknown whether the addition of temozolomide (TMZ) to radiotherapy (RT) is associated with improved overall survival (OS) among older glioblastoma patients. We performed a retrospective cohort SEER-Medicare analysis of 1652 patients aged a65 years with glioblastoma who received a10 fractions of RT from 2005 to 2009, or from 1995 to 1999 before TMZ was available. Three cohorts were assembled based on diagnosis year and treatment initiated within 60 days of diagnosis: (1) 2005-2009 and TMZ/RT, (2) 2005-2009 and RT only, or (3) 1995-1999 and RT only. Associations with OS were estimated using Cox proportional hazards models and propensity score analyses; OS was calculated starting 60 days after diagnosis. Pre-specified sensitivity analyses were performed among patients who received long-course RT (a27 fractions). Median survival estimates were 7.4 (IQR, 3.3-14.7) months for TMZ/RT, 5.9 (IQR, 2.6-12.1) months for RT alone in 2005-2009, and 5.6 (IQR, 2.7-9.6) months for RT alone in 1995-1999. OS at 2 years was 10.1 % for TMZ/RT, 7.1 % for RT in 2005-2009, and 4.7 % for RT in 1995-1999. Adjusted models suggested decreased mortality risk for TMZ/RT compared to RT in 2005-2009 (AHR, 0.86; 95 % CI, 0.76-0.98) and RT in 1995-1999 (AHR, 0.71; 95 % CI, 0.57-0.90). Among patients from 2005 to 2009 who received long-course RT, however, the addition of TMZ did not significantly improve survival (AHR, 0.91; 95 % CI, 0.80-1.04). In summary, among a large cohort of older glioblastoma patients treated in a real-world setting, the addition of TMZ to RT was associated with a small survival gain. C1 [Arvold, Nils D.] St Lukes Canc Ctr, St Lukes Radiat Oncol Associates, Lakeview Bldg, Duluth, MN 55802 USA. [Arvold, Nils D.] Univ Minnesota, Whiteside Inst Clin Res, 1001 East Super St,Suite L101, Duluth, MN 55802 USA. [Cefalu, Matthew; Wang, Yun; Zigler, Corwin; Dominici, Francesca] Harvard Sch Publ Hlth, Dept Biostat, Bldg 2,4th Floor,655 Huntington Ave, Boston, MA 02115 USA. [Schrag, Deborah] Dana Farber Canc Inst, Dept Med, 44 Binney St, Boston, MA 02115 USA. RP Arvold, ND (reprint author), St Lukes Canc Ctr, St Lukes Radiat Oncol Associates, Lakeview Bldg, Duluth, MN 55802 USA.; Arvold, ND (reprint author), Univ Minnesota, Whiteside Inst Clin Res, 1001 East Super St,Suite L101, Duluth, MN 55802 USA. EM nils.arvold@slhduluth.com FU National Cancer Institute of the National Institutes of Health [P01CA134294-06]; Agency for Healthcare Research and Quality [K18 HS21991] FX This work was supported by grants from the National Cancer Institute of the National Institutes of Health (P01CA134294-06 to F.D.), and from the Agency for Healthcare Research and Quality (K18 HS21991 to F.D.). Contents of this publication are solely the responsibility of the authors and no official endorsement by the National Cancer Institute, National Institutes of Health, Agency for Healthcare Research and Quality, or the U.S. Department of Health and Human Services is intended or should be inferred. NR 38 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0167-594X EI 1573-7373 J9 J NEURO-ONCOL JI J. Neuro-Oncol. PD JAN PY 2017 VL 131 IS 2 BP 301 EP 311 DI 10.1007/s11060-016-2294-7 PG 11 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA EL0WM UT WOS:000394342500011 PM 27770280 ER PT J AU Raleigh, DR Tomlin, B Del Buono, B Roddy, E Sear, K Byer, L Felton, E Banerjee, A Torkildson, J Samuel, D Horn, B Braunstein, SE Haas-Kogan, DA Mueller, S AF Raleigh, David R. Tomlin, Bryan Del Buono, Benedict Roddy, Erika Sear, Katherine Byer, Lennox Felton, Erin Banerjee, Anu Torkildson, Joseph Samuel, David Horn, Biljana Braunstein, Steve E. Haas-Kogan, Daphne A. Mueller, Sabine TI Survival after chemotherapy and stem cell transplant followed by delayed craniospinal irradiation is comparable to upfront craniospinal irradiation in pediatric embryonal brain tumor patients SO JOURNAL OF NEURO-ONCOLOGY LA English DT Article DE Medulloblastoma; Supratentorial primitive neuroectodermal tumor; Pineoblastoma; Radiation; Chemotherapy; Stem cell transplant ID EARLY-CHILDHOOD MEDULLOBLASTOMA; CONFORMAL RADIATION-THERAPY; HEDGEHOG PATHWAY INHIBITOR; HIGH-RISK MEDULLOBLASTOMA; HIGH-DOSE CHEMOTHERAPY; THAN 3 YEARS; NONMETASTATIC MEDULLOBLASTOMA; POSTOPERATIVE CHEMOTHERAPY; INTERNATIONAL-SOCIETY; MULTICENTER TRIAL AB Pediatric embryonal brain tumor patients treated with craniospinal irradiation (CSI) are at risk for adverse effects, with greater severity in younger patients. Here we compare outcomes of CSI vs. high-dose chemotherapy (HD), stem cell transplant (SCT) and delayed CSI in newly diagnosed patients. Two hundred one consecutive patients treated for medulloblastoma (72 %), supratentorial primitive neuroectodermal tumor (sPNET; 18 %) or pineoblastoma (10 %) at two institutions between 1988 and 2014 were retrospectively identified. Progression free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method and compared by log-rank tests. Adjuvant CSI regimens were used for 56 % of patients (upfront-CSI), and HD/SCT regimens were used in 32 % of patients. HD/SCT patients were significantly younger than those receiving upfront-CSI (2.9 vs. 7.8 years; P < 0.0001). There were no differences in metastases, extent of resection, or CSI dose between upfront-CSI and HD/SCT patients, but median follow-up was shorter in the HD/SCT group (6.2 vs. 3.9 years; P = 0.007). There were no significant outcome differences between upfront-CSI and HD/SCT patients who received CSI as a prophylaxis or following relapse (OS 66 % vs. 61 %, P = 0.13; PFS 67 % vs. 62 %, P = 0.12). Outcomes were equivalent when restricting analyses to HD/SCT patients who received prophylactic CSI prior to relapse (OS 66 % vs. 65 %, P = 0.5; PFS 67 % vs. 74 %, P = 0.8). At last follow-up, 48 % of HD/SCT patients had received neither definitive nor salvage radiotherapy. In this retrospective cohort, outcomes with adjuvant HD/SCT followed by delayed CSI are comparable to upfront-CSI for carefully surveyed pediatric embryonal brain tumor patients. Future prospective studies are required to validate this finding, and also to assess the impact of delayed CSI on neurocognitive outcomes. C1 [Raleigh, David R.; Braunstein, Steve E.] Univ Calif San Francisco, Dept Radiat Oncol, San Francisco, CA USA. [Tomlin, Bryan] Calif State Univ Chanel Isl, Dept Econ, Camarillo, CA USA. [Del Buono, Benedict; Roddy, Erika; Sear, Katherine; Byer, Lennox; Felton, Erin; Banerjee, Anu; Horn, Biljana; Mueller, Sabine] Univ Calif San Francisco, Dept Pediat, San Francisco, CA 94143 USA. [Torkildson, Joseph] UCSF Benioff Childrens Hosp Oakland, Pediat Hematol Oncol, Oakland, CA USA. [Samuel, David] Valley Childrens Healthcare, Pediat Hematol Oncol, Madera, CA USA. [Haas-Kogan, Daphne A.] Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA. [Mueller, Sabine] Univ Calif San Francisco, Dept Neurol Neurosurg & Pediat, Sandler Neurosci 550, 625 Nelson Rising Lane,402B,Box 0434, San Francisco, CA 94143 USA. RP Mueller, S (reprint author), Univ Calif San Francisco, Dept Pediat, San Francisco, CA 94143 USA.; Mueller, S (reprint author), Univ Calif San Francisco, Dept Neurol Neurosurg & Pediat, Sandler Neurosci 550, 625 Nelson Rising Lane,402B,Box 0434, San Francisco, CA 94143 USA. EM Sabine.Mueller@ucsf.edu NR 28 TC 0 Z9 0 U1 2 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0167-594X EI 1573-7373 J9 J NEURO-ONCOL JI J. Neuro-Oncol. PD JAN PY 2017 VL 131 IS 2 BP 359 EP 368 DI 10.1007/s11060-016-2307-6 PG 10 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA EL0WM UT WOS:000394342500017 PM 27778212 ER PT J AU Talaei-Khoei, M Riklin, E Merker, VL Sheridan, MR Jordan, JT Plotkin, SR Vranceanu, AM AF Talaei-Khoei, Mojtaba Riklin, Eric Merker, Vanessa L. Sheridan, Monica R. Jordan, Justin T. Plotkin, Scott R. Vranceanu, Ana-Maria TI First use of patient reported outcomes measurement information system (PROMIS) measures in adults with neurofibromatosis SO JOURNAL OF NEURO-ONCOLOGY LA English DT Article DE Neurofibromatosis; PROMIS; Physical; Social; Psychological ID QUALITY-OF-LIFE; ITEM RESPONSE THEORY; SCHWANNOMATOSIS; PROGRESS; HEALTH; TYPE-1 AB The patient reported outcomes measurement information system (PROMIS) provides clinicians and researchers access to reliable, validated measures of physical, mental, and social well-being. The use of PROMIS can facilitate comparisons among clinical subpopulations and with the U.S. general population. We report on the first study using PROMIS measures in patients with neurofibromatosis (NF). Eighty-six adult patients (mean age = 44; 55% female; 87% white; 50% NF1, 41% NF2 and 9% schwannomatosis) completed a battery of PROMIS computerized adaptive tests (CATs). Across all PROMIS instruments, mean scores for each CAT were between 48.97 and 52.60, which is within +/- 0.5 SD of the U.S. general population norms. However, scores were distributed across a broad range for each PROMIS measure (+/- 3 SDs). Clinically meaningful scores (defined > 1 SD impairment) were observed in 20% (pain interference), 17% (pain behavior), 16% (physical function), 16% (anxiety), 16% (depression), 15% (satisfaction with social roles), 13% (fatigue), 6% (anger), and 5% (satisfaction with discretionary social activities) of the sample. All PROMIS measures were highly interrelated in bivariate analysis (P <=.001). There were no differences in PROMIS scores by disease type (NF1, NF2 and schwannomatosis), or self reported learning disabilities, or compared with the US population. Scores suggest a broad continuum of symptoms and functioning in patients with NF that is not affected by NF type, as well as interrelation among the physical and psychosocial domains as measured by PROMIS. PROMIS measures may be useful in clinical practice to monitor changes in symptoms and functioning over time, as well as in clinical trials to determine patient reported changes during drug and psychosocial clinical trials. C1 [Talaei-Khoei, Mojtaba] Harvard Med Sch, Massachusetts Gen Hosp, Hand & Upper Extrem Serv, Boston, MA USA. [Riklin, Eric] Harvard Med Sch, Benson Henry Inst Mind Body Med, Massachusetts Gen Hosp, Dept Psychiat, Boston, MA USA. [Merker, Vanessa L.; Sheridan, Monica R.; Jordan, Justin T.; Plotkin, Scott R.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Neurol, Boston, MA USA. [Merker, Vanessa L.; Sheridan, Monica R.; Jordan, Justin T.; Plotkin, Scott R.] Harvard Med Sch, Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. [Vranceanu, Ana-Maria] Harvard Med Sch, Massachusetts Gen Hosp, Dept Psychiat, Behav Med Serv, One Bowdoin Sq,7th Floor, Boston, MA 02114 USA. RP Vranceanu, AM (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Dept Psychiat, Behav Med Serv, One Bowdoin Sq,7th Floor, Boston, MA 02114 USA. EM avranceanu@mgh.harvard.edu OI Merker, Vanessa/0000-0002-4542-5227 FU National Institutes of Health, U.S. Department of Defense; Children's Tumor Foundation FX The funding was provided by National Institutes of Health, U.S. Department of Defense and Children's Tumor Foundation. NR 18 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0167-594X EI 1573-7373 J9 J NEURO-ONCOL JI J. Neuro-Oncol. PD JAN PY 2017 VL 131 IS 2 BP 413 EP 419 DI 10.1007/s11060-016-2314-7 PG 7 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA EL0WM UT WOS:000394342500023 PM 27900643 ER PT J AU Markel, SF Andrews, AM Lutton, EM Mu, DK Hudry, E Hyman, BT Maguire, CA Ramirez, SH AF Markel, Steven F. Andrews, Allison M. Lutton, Evan M. Mu, Dakai Hudry, Eloise Hyman, Bradely T. Maguire, Casey A. Ramirez, Servio H. TI Trafficking of adeno-associated virus vectors across a model of the blood-brain barrier; a comparative study of transcytosis and transduction using primary human brain endothelial cells SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE adeno-associated virus; blood-brain barrier; gene therapy; neurological disorders ID SPINAL MUSCULAR-ATROPHY; GENE-DELIVERY; ADSORPTIVE ENDOCYTOSIS; NONHUMAN-PRIMATES; IN-VIVO; TRANSENDOTHELIAL MIGRATION; NERVOUS-SYSTEM; VIRAL VECTORS; ADULT MICE; AAV AB Developing therapies for central nervous system (CNS) diseases is exceedingly difficult because of the blood-brain barrier (BBB). Notably, emerging technologies may provide promising new options for the treatment of CNS disorders. Adeno-associated virus serotype 9 (AAV9) has been shown to transduce cells in the CNS following intravascular administration in rodents, cats, pigs, and non-human primates. These results suggest that AAV9 is capable of crossing the BBB. However, mechanisms that govern AAV9 transendothelial trafficking at the BBB remain unknown. Furthermore, possibilities that AAV9 may transduce brain endothelial cells or affect BBB integrity still require investigation. Using primary human brain microvascular endothelial cells as a model of the human BBB, we performed transduction and transendothelial trafficking assays comparing AAV9 to AAV2, a serotype that does not cross the BBB or transduce endothelial cells effectively in vivo. Results of our in vitro studies indicate that AAV9 penetrates brain microvascular endothelial cells barriers more effectively than AAV2, but has reduced transduction efficiency. In addition, our data suggest that (i) AAV9 penetrates endothelial barriers through an active, cell-mediated process, and (ii) AAV9 fails to disrupt indicators of BBB integrity such as transendothelial electrical resistance, tight junction protein expression/localization, and inflammatory activation status. Overall, this report shows how human brain endothelial cells configured in BBB models can be utilized for evaluating transendothelial movement and transduction kinetics of various AAV capsids. Importantly, the use of a human in vitro BBB model can provide import insight into the possible effects that candidate AVV gene therapy vectors may have on the status of BBB integrity. C1 [Markel, Steven F.; Andrews, Allison M.; Lutton, Evan M.; Ramirez, Servio H.] Temple Univ, Dept Pathol & Lab Med, Lewis Katz Sch Med, Philadelphia, PA 19122 USA. [Markel, Steven F.; Andrews, Allison M.; Ramirez, Servio H.] Temple Univ, Ctr Subst Abuse Res, Lewis Katz Sch Med, Philadelphia, PA 19122 USA. [Mu, Dakai; Hudry, Eloise; Hyman, Bradely T.; Maguire, Casey A.] Massachusetts Gen Hosp, Dept Neurol, Charlestown, MA USA. [Hyman, Bradely T.; Maguire, Casey A.] Harvard Med Sch, NeuroDiscovery Ctr, Boston, MA USA. [Hudry, Eloise; Hyman, Bradely T.] Massachusetts Gen Hosp, Alzheimer Res Unit, Inst Neurodegenerat Dis, Charlestown, MA USA. [Ramirez, Servio H.] Temple Univ, Shriners Hosp Pediat Res Ctr, Lewis Katz Sch Med, Philadelphia, PA 19122 USA. RP Maguire, CA (reprint author), Massachusetts Gen Hosp, Ctr Neurosci, Bldg 149,13th St, Charlestown, MA 02129 USA.; Ramirez, SH (reprint author), Temple Univ, Dept Pathol & Lab Med, Sch Med, 3500 N Broad St,MERB 844, Philadelphia, PA 19140 USA. EM cmaguire@mgh.harvard.edu; servio@temple.edu OI andrews, allison/0000-0003-1752-7450 FU National Institutes of Health/National Institute on Drug Abuse (NIH/NIDA) [T32 DA007237]; NIH/National Institute of Neurological Disorders and Stroke (NINDS) [R01 NS086570-01]; Shriners Hospitals for Children [85110-PHI-14]; American Brain Tumor Association Discovery Grant FX This work was supported by National Institutes of Health/National Institute on Drug Abuse (NIH/NIDA) T32 DA007237 (SFM and AMA), NIH/National Institute of Neurological Disorders and Stroke (NINDS) R01 NS086570-01 (SHR), The Shriners Hospitals for Children 85110-PHI-14 (SHR), and the American Brain Tumor Association Discovery Grant (CAM). We thank the laboratory of Dr. Yuri Persidsky for the use of key equipment and technical expertise of lead scientist Nancy Lee Reichenbach. The authors declare no competing financial interests. NR 39 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3042 EI 1471-4159 J9 J NEUROCHEM JI J. Neurochem. PD JAN PY 2017 VL 140 IS 2 BP 216 EP 230 DI 10.1111/jnc.13861 PG 15 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA EL5DD UT WOS:000394640900004 ER PT J AU Shen, BY Mukai, S AF Shen, Bailey Y. Mukai, Shizuo TI A Portable, Inexpensive, Nonmydriatic Fundus Camera Based on the Raspberry Pi (R) Computer SO JOURNAL OF OPHTHALMOLOGY LA English DT Article ID PHOTOGRAPHY; SMARTPHONE AB Purpose. Nonmydriatic fundus cameras allow retinal photography without pharmacologic dilation of the pupil. However, currently available nonmydriatic fundus cameras are bulky, not portable, and expensive. Taking advantage of recent advances in mobile technology, we sought to create a nonmydriatic fundus camera that was affordable and could be carried in a white coat pocket. Methods. We built a point-and-shoot prototype camera using a Raspberry Pi computer, an infrared-sensitive camera board, a dual infrared and white light light-emitting diode, a battery, a 5-inch touchscreen liquid crystal display, and a disposable 20-diopter condensing lens. Our prototype camera was based on indirect ophthalmoscopy with both infrared and white lights. Results. The prototype camera measured 133mmx 91mmx 45mm and weighed 386 grams. The total cost of the components, including the disposable lens, was $ 185.20. The camera was able to obtain good-quality fundus images without pharmacologic dilation of the pupils. Conclusion. A fully functional, inexpensive, handheld, nonmydriatic fundus camera can be easily assembled from a relatively small number of components. With modest improvements, such a camera could be useful for a variety of healthcare professionals, particularly those who work in settings where a traditional table-mounted nonmydriatic fundus camera would be inconvenient. C1 [Shen, Bailey Y.] Univ Illinois, Illinois Eye & Ear Infirm, Dept Ophthalmol, 1855 West Taylor St, Chicago, IL 60612 USA. [Mukai, Shizuo] Harvard Med Sch, Massachusetts Eye & Ear Infirm, Retina Serv, 243 Charles St, Boston, MA 02114 USA. RP Mukai, S (reprint author), Harvard Med Sch, Massachusetts Eye & Ear Infirm, Retina Serv, 243 Charles St, Boston, MA 02114 USA. EM Shizuo_Mukai@meei.harvard.edu NR 13 TC 0 Z9 0 U1 0 U2 0 PU HINDAWI LTD PI LONDON PA ADAM HOUSE, 3RD FLR, 1 FITZROY SQ, LONDON, WIT 5HE, ENGLAND SN 2090-004X EI 2090-0058 J9 J OPHTHALMOL JI J. Ophthalmol. PY 2017 AR 4526243 DI 10.1155/2017/4526243 PG 5 WC Medicine, Research & Experimental; Ophthalmology SC Research & Experimental Medicine; Ophthalmology GA EO6ZW UT WOS:000396842000001 ER PT J AU Ali, HM Berggreen, E Nguyen, D Ali, RW Van Dyke, TE Hasturk, H Mustafa, M AF Ali, Hiba Mohamed Berggreen, Ellen Nguyen, Daniel Ali, Raouf Wahab Van Dyke, Thomas E. Hasturk, Hatice Mustafa, Manal TI Dental plaque microbial profiles of children from Khartoum, Sudan, with congenital heart defects SO JOURNAL OF ORAL MICROBIOLOGY LA English DT Article DE Children; congenital heart defects; dental biofilm; microbial profiles; real-time quantitative polymerase chain reaction; checkerboard DNA-DNA hybridization ID DNA-DNA HYBRIDIZATION; STREPTOCOCCUS-MUTANS; PERIODONTAL-DISEASE; ORAL MICROBIOME; PERMANENT TEETH; CARIES; ENDOCARDITIS; DIVERSITY; HEALTH; COMMUNITIES AB Few studies have focused on the bacterial species associated with the deterioration of the dental and gingival health of children with congenital heart defects (CHD). The aims of this study were (1) to examine the dental plaque of children with CHD in order to quantify bacterial load and altered bacterial composition compared with children without CHD; and (2) to investigate the correlation between the level of caries and gingivitis and dental biofilm bacteria among those children. In this cross-sectional study, participants were children (312 years) recruited in Khartoum State, Sudan. A total of 80 CHD cases from the Ahmed Gasim Cardiac Centre and 80 healthy controls from randomly selected schools and kindergartens were included. Participants underwent clinical oral examinations for caries (decayed, missing, and filled teeth indices [DMFT] for primary dentition, and DMFT for permanent dentition), and gingivitis (simplified gingival index [GI]). Pooled dental biofilm samples were obtained from four posterior teeth using paper points. Real-time quantitative polymerase chain reaction was used for the detection and quantification of Streptococcus mutans, Streptococcussanguinis, and Lactobacillus acidophilus. Checkerboard DNA-DNA hybridization was used for the detection of 40 additional bacterial species. CHD cases had a significantly higher caries experience (DMFT = 4.1 vs. 2.3, p < 0.05; DMFT = 1.4 vs. 0.7, p < 0.05) and a higher mean number of examined teeth with gingivitis (4.2 vs. 2.0; p < 0.05) compared with controls. S. mutans counts were significantly higher among the CHD cases (p < 0.05). Checkerboard results revealed that 18/40 bacterial species exhibited significantly higher mean counts among CHD cases (p < 0.01). Correlation analyses revealed that among CHD cases, the detection levels of Tannerella forsythia, Campylobacter rectus, Fusobacterium nucleatum subsp. vincentii, F. nucleatum subsp. nucleatum, and F. nucleatum subsp. polymorphum were highly positively correlated with GI. CHD cases harbor more cariogenic and periodontopathogenic bacterial species in their dental plaque, which correlated with higher levels of caries and gingivitis. C1 [Ali, Hiba Mohamed] Univ Bergen, Fac Med & Dent, Dept Clin Dent, Bergen, Norway. [Berggreen, Ellen] Univ Bergen, Fac Med & Dent, Dept Biomed, Bergen, Norway. [Nguyen, Daniel; Van Dyke, Thomas E.; Hasturk, Hatice] Forsyth Inst, Dept Periodont, Cambridge, MA USA. [Ali, Raouf Wahab] Univ Sci & Technol, Dept Periodont, Khartoum, Sudan. [Van Dyke, Thomas E.] Harvard Sch Dent Med, Dept Oral Med Infect & Immun, Div Periodontol, Boston, MA USA. [Mustafa, Manal] Oral Hlth Ctr Expertise Western Norway, Bergen, Norway. RP Ali, HM (reprint author), Univ Bergen, Fac Med & Dent, Dept Clin Dent, Bergen, Norway. EM Hiba.Mohammedali@student.uib.no FU Faculty of Medicine and Dentistry, Department of Clinical Dentistry, University of Bergen, University of Science and Technology, Omdurman, Sudan; Ahmed Gasim Cardiac Centre, Khartoum, Sudan; NIH/NIDCR grant [DE025020] FX Supported by The Faculty of Medicine and Dentistry, Department of Clinical Dentistry, University of Bergen, University of Science and Technology, Omdurman, Sudan and Ahmed Gasim Cardiac Centre, Khartoum, Sudan and NIH/NIDCR grant DE025020 (TVD). NR 64 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 1281556 DI 10.1080/20002297.2017.1281556 PG 10 WC Microbiology SC Microbiology GA EO5VH UT WOS:000396760500001 ER PT J AU Mougeot, JLC Stevens, CB Paster, BJ Brennan, MT Lockhart, PB Mougeot, FKB AF Mougeot, J-L. C. Stevens, C. B. Paster, B. J. Brennan, M. T. Lockhart, P. B. Mougeot, F. K. B. TI Porphyromonas gingivalis is the most abundant species detected in coronary and femoral arteries SO JOURNAL OF ORAL MICROBIOLOGY LA English DT Article DE Oral microbiome; metagenomics; HOMINGS; atherosclerosis; P. gingivalis ID PERIODONTAL PATHOGENS; HEART-DISEASE; ATHEROSCLEROSIS; ANTIBODIES; SAMPLES; DIHYDROCERAMIDES; IDENTIFICATION; ENDOCARDITIS; MICROBIOME; LESIONS AB An association between oral bacteria and atherosclerosis has been postulated. A limited number of studies have used 16S RNA gene sequencing-based metagenomics approaches to identify bacteria at the species level from atherosclerotic plaques in arterial walls. The objective of this study was to establish detailed oral microbiome profiles, at both genus and species level, of clinically healthy coronary and femoral artery tissues from patients with atherosclerosis. Tissue specimens were taken from clinically non- atheroscleroticareas of coronary or femoral arteries used for attachment of bypass grafts in 42 patients with atherosclerotic cardiovascular disease. Bacterial DNA was sequenced using the MiSeq platform, and sequence reads were screened in silico for nearly 600 oral species using the HOMINGS ProbeSeq species identification program. The number of sequence reads matched to species or genera were used for statistical analyses. A total of 230 and 118 species were detected in coronary and femoral arteries, respectively. Unidentified species detected by genus-specific probes consisted of 45 and 30 genera in coronary and in femoral artery tissues, respectively. Overall, 245 species belonging to 95 genera were detected in coronary and femoral arteries combined. The most abundant species were Porphyromonas gingivalis, Enterococcus faecalis, and Finegoldia magna based on species probes. Porphyromonas, Escherichia, Staphylococcus, Pseudomonas, and Streptococcus genera represented 88.5% mean relative abundance based on combined species and genus probe detections. Porphyromonas was significantly more abundant than Escherichia (i.e.46.8% vs. 19.3%; p = 0.0005). This study provides insight into the presence and types of oral microbiome bacterial species found in clinically non-atherosclerotic arteries. C1 [Mougeot, J-L. C.; Stevens, C. B.; Brennan, M. T.; Lockhart, P. B.; Mougeot, F. K. B.] Carolinas HealthCare Syst, Cannon Res Ctr, Dept Oral Med, Charlotte, NC 28203 USA. [Paster, B. J.] Forsyth Inst, Dept Microbiol, Cambridge, MA USA. [Paster, B. J.] Harvard Sch Dent Med, Dept Oral Med Infect & Immun, Boston, MA USA. RP Mougeot, FKB (reprint author), Carolinas HealthCare Syst, Cannon Res Ctr, Dept Oral Med, Charlotte, NC 28203 USA. EM farah.mougeot@carolinashealthcare.org FU Carolinas HealthCare System's Research fund FX This study was funded by Carolinas HealthCare System's Research fund. We thank Dr. Joseph Cook, Dr. Jeremiah Holleman, Jenene Noll, Louise Kent, and other clinical staff for their help with patient samples and data collection, and Dr. Craig Murdoch laboratory, Shirley Coleman, Darla Morton, and Alexis Kokaras for DNA isolation/processing. We also thank Drs. Gillian Smith, Marcello Riggio, and Martin Thornhill for helpful discussions. NR 36 TC 0 Z9 0 U1 1 U2 1 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 1281562 PG 9 WC Microbiology SC Microbiology GA EO5VL UT WOS:000396760900001 PM 28326156 ER PT J AU Martin, JT Kim, DH Milby, AH Pfeifer, CG Smith, LJ Elliott, DM Smith, HE Mauck, RL AF Martin, John T. Kim, Dong Hwa Milby, Andrew H. Pfeifer, Christian G. Smith, Lachlan J. Elliott, Dawn M. Smith, Harvey E. Mauck, Robert L. TI In Vivo Performance of an Acellular Disc-Like Angle Ply Structure (DAPS) for Total Disc Replacement in a Small Animal Model SO JOURNAL OF ORTHOPAEDIC RESEARCH LA English DT Article DE intervertebral disc; tissue engineering; acellular biomaterials; total disc replacement ID INTERVERTEBRAL DISC; LUMBAR DISC; ANNULUS FIBROSUS; CELL PHENOTYPE; MOUSE MODEL; DEGENERATION; COMPLICATIONS; MECHANICS; SCAFFOLDS; TRANSPORT AB Total intervertebral disc replacement with a biologic engineered disc may be an alternative to spinal fusion for treating end-stage disc disease. In previous work, we developed disc-like angle ply structures (DAPS) that replicate the structure and function of the native disc and a rat tail model to evaluate DAPS in vivo. Here, we evaluated a strategy in which, after in vivo implantation, endogenous cells could colonize the acellular DAPS and form an extracellular matrix organized by the DAPS topographical template. To do so, acellular DAPS were implanted into the caudal spines of rats and evaluated over 12 weeks by mechanical testing, histology, and microcomputed tomography. An external fixation device was used to stabilize the implant site and various control groups were included to evaluate the effect of immobilization. There was robust tissue formation within the DAPS after implantation and compressive mechanical properties of the implant matched that of the native motion segment. Immobilization provided a stable site for fibrous tissue formation after either a discectomy or a DAPS implantation, but bony fusion eventually resulted, with segments showing intervertebral bridging after long-term implantation, a process that was accelerated by the implanted DAPS. Thus, while compressive mechanical properties were replicated after DAPS implantation, methods to actively prevent fusion must be developed. Future work will focus on limiting fusion by remobilizing the motion segment after a period of integration, delivering pro-chondrogenic factors, and pre-seeding DAPS with cells prior to implantation. (C) 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. C1 [Martin, John T.; Kim, Dong Hwa; Milby, Andrew H.; Pfeifer, Christian G.; Smith, Lachlan J.; Smith, Harvey E.; Mauck, Robert L.] Univ Penn, Dept Orthopaed Surg, 426 B Stemmler Hall,36th St & Hamilton Walk, Philadelphia, PA 19104 USA. [Martin, John T.; Milby, Andrew H.; Pfeifer, Christian G.; Smith, Lachlan J.; Smith, Harvey E.; Mauck, Robert L.] Philadelphia VA Med Ctr, Translat Musculoskeletal Res Ctr, Philadelphia, PA 19104 USA. [Martin, John T.; Mauck, Robert L.] Univ Penn, Dept Mech Engn & Appl Mech, Philadelphia, PA 19104 USA. [Pfeifer, Christian G.] Univ Regensburg, Med Ctr, Dept Trauma Surg, Regensburg, Germany. [Smith, Lachlan J.; Smith, Harvey E.] Univ Penn, Dept Neurosurg, Philadelphia, PA 19104 USA. [Elliott, Dawn M.] Univ Delaware, Dept Biomed Engn, Newark, DE USA. [Mauck, Robert L.] Univ Penn, Dept Bioengn, Philadelphia, PA 19104 USA. RP Mauck, RL (reprint author), Univ Penn, Dept Orthopaed Surg, 426 B Stemmler Hall,36th St & Hamilton Walk, Philadelphia, PA 19104 USA.; Mauck, RL (reprint author), Philadelphia VA Med Ctr, Translat Musculoskeletal Res Ctr, Philadelphia, PA 19104 USA.; Mauck, RL (reprint author), Univ Penn, Dept Mech Engn & Appl Mech, Philadelphia, PA 19104 USA.; Mauck, RL (reprint author), Univ Penn, Dept Bioengn, Philadelphia, PA 19104 USA. EM Lemauck@mail.med.upenn.edu FU Department of Defense [OR090090]; Department of Veterans Affairs [I01 RX000211]; National Institutes of Health, through the Penn Center for Musculoskeletal Disorders [P30 AR050950] FX Grant sponsor: Department of Defense; Grant number: #OR090090; Grant sponsor: Department of Veterans Affairs; Grant number: #I01 RX000211; Grant sponsor: National Institutes of Health; Grant number: #P30 AR050950. NR 40 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0736-0266 EI 1554-527X J9 J ORTHOP RES JI J. Orthop. Res. PD JAN PY 2017 VL 35 IS 1 BP 23 EP 31 DI 10.1002/jor.23310 PG 9 WC Orthopedics SC Orthopedics GA EK5SO UT WOS:000393986300003 PM 27227357 ER PT J AU Cooper, RA AF Cooper, Rory A. TI Commentary on WHO GATE Initiative SO JOURNAL OF SPINAL CORD MEDICINE LA English DT Editorial Material C1 [Cooper, Rory A.] VA Pittsburgh Hlth Care Syst, Human Engn Resrch Lab, Pittsburgh, PA USA. RP Cooper, RA (reprint author), VA Pittsburgh Hlth Care Syst, Human Engn Res Lab 151R 1, 7180 Highland Dr,Bldg 4,2nd Floor, Pittsburgh, PA 15206 USA. EM rcooper@pitt.edu NR 1 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 1079-0268 EI 2045-7723 J9 J SPINAL CORD MED JI J. Spinal Cord. Med. PY 2017 VL 40 IS 1 BP 2 EP 4 DI 10.1080/10790268.2016.1224542 PG 3 WC Clinical Neurology SC Neurosciences & Neurology GA EL5FX UT WOS:000394648100001 PM 27636193 ER PT J AU Wu, YK Liu, HY Kelleher, A Pearlman, J Ding, D Cooper, RA AF Wu, Yu-Kuang Liu, Hsin-Yi Kelleher, Annmarie Pearlman, Jonathan Ding, Dan Cooper, Rory A. TI Power seat function usage and wheelchair discomfort for power wheelchair users SO JOURNAL OF SPINAL CORD MEDICINE LA English DT Article DE Wheelchairs; Rehabilitation ID SPINAL-CORD-INJURY; TILT-IN-SPACE; ASSESSMENT-TOOL; PRESSURE; RECLINE; LEGRESTS; FLEXION; EMG AB Objectives: To investigate correlations between power seat functions (PSFs) usage and wheelchair discomfort. Design: Quasi-experimental design: Time series design. Setting: In-home trial in participants' home/community. Participants: Thirteen power wheelchair users who independently used power wheelchairs equipped with PSFs as their primary means of mobility. Main Outcome Measures: PSF usage variables include the frequency of performing repositioning and using PSFs (tilt, recline, legrests and seat elevation), wheelchair occupancy, and driving distance. The Tool for Assessing Wheelchair disComfort (TAWC) were used to evaluate general discomfort and discomfort intensity. Results: Spearman correlation coefficient showed that the frequency of using tilt, recline, and legrest is significantly correlated with discomfort intensity. Multiple regression analysis with backward stepwise indicated that these functions can explain 43.8% of the variance (R2 =.438, F(3,33) = 8.588, P < 0.01) in the discomfort intensity score. The best-first decision tree shows that the frequency of using the legrest function was the top node, followed by recline and tilt functions. The overall accuracy of prediction with ten-fold cross validation for discomfort intensity was 79.4%. Conclusions: For people who used power wheelchairs equipped with PSFs, correlation analysis and regression modeling provided evidence from the quantitative data that increasing the frequency of using PSFs may decrease wheelchair discomfort. Future studies should include interventions to encourage people to use their PSFs appropriately. C1 [Wu, Yu-Kuang; Liu, Hsin-Yi; Kelleher, Annmarie; Pearlman, Jonathan; Ding, Dan; Cooper, Rory A.] Vet Affairs Pittsburgh Healthcare Syst, Human Engn Res Labs, Pittsburgh, PA USA. [Wu, Yu-Kuang; Liu, Hsin-Yi; Kelleher, Annmarie; Pearlman, Jonathan; Ding, Dan; Cooper, Rory A.] Vet Affairs Pittsburgh Healthcare Syst, Dept Rehabil Sci & Technol, Pittsburgh, PA USA. RP Cooper, RA (reprint author), VA Pittsburgh Healthcare Syst, 6425 Penn Ave,Suite 400, Pittsburgh, PA 15206 USA. EM rcooper@pitt.edu FU National Science Foundation [EEC0540865]; VA RR& DVA RR&D (Merit Review Grant) [B6591R]; University of Pittsburgh FX This research was completed with the support of the National Science Foundation (Grant #EEC0540865 - Quality of Life Technology Engineering Research Center), VA RR&D (Merit Review Grant # B6591R - Powered Seating Function Usage among Veterans-Compliance and Coaching), and the University of Pittsburgh. NR 30 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 1079-0268 EI 2045-7723 J9 J SPINAL CORD MED JI J. Spinal Cord. Med. PY 2017 VL 40 IS 1 BP 62 EP 69 DI 10.1080/10790268.2016.1192360 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA EL5FX UT WOS:000394648100010 PM 27366954 ER PT J AU Sanguansak, T Morley, K Morley, M Kusakul, S Lee, R Shieh, E Yospaiboon, Y Bhoomibunchoo, C Chai-ear, S Joseph, A Agarwal, I AF Sanguansak, Thuss Morley, Katharine Morley, Michael Kusakul, Suwat Lee, Ramon Shieh, Eric Yospaiboon, Yosanan Bhoomibunchoo, Chavakij Chai-ear, Siriwatana Joseph, Anthony Agarwal, Isha TI Comparing smartphone camera adapters in imaging post-operative cataract patients SO JOURNAL OF TELEMEDICINE AND TELECARE LA English DT Article DE Smart phone camera; telemedicine; cataract surgery; smart phone adapters ID DIAGNOSIS; TELEOPHTHALMOLOGY; IPHONE AB Introduction: The goal of this study is to compare image quality and clinical confidence for managing post-operative cataract patients based on anterior segment smartphone images obtained in real-world settings using four types of adapters: (a) macro lens (ML), (b) ML with augmented light-emitting diode (LED) illumination (ML-LED), (c) no adapter (NA) and (d) slit lamp (SL) adapter. Methods: Anterior segment images were obtained from 190 eyes after cataract surgery using an eight-megapixel iPhone 6 smartphone camera with four adapters: ML, ML-LED, NA, and SL. Smartphone images were subjectively rated by ophthalmologists as acceptable or not acceptable for: (a) image quality for evaluating the anterior segment structures and (b) reader confidence in clinically managing post-operative patients based on smartphone images. Results: NA, ML-LED, and SL had the highest scores for image quality with 100%, 93.7%, and 86.3% judged as acceptable, respectively. NA, SL, and ML-LED were also rated highest in clinical confidence with 100%, 98%, and 93.2% having acceptable levels, respectively. ML was judged lowest in both image quality (61.1% acceptable) and clinical confidence (37.4% acceptable). Discussion: This study represents the first effort to compare different smartphone camera adapters' ability to image the anterior segment of the eye in a real-world setting. Our study shows that ML-LED, NA, and SL adapters were acceptable for visualizing anterior segment structures to physician readers in 86-100% of cases. When coupled with visual acuity, intro-ocular pressure and history, these images can result in acceptable clinical confidence in 93-100% of cases. C1 [Sanguansak, Thuss; Yospaiboon, Yosanan; Bhoomibunchoo, Chavakij] Khon Kaen Univ, Fac Med, Khon Kaen, Thailand. [Morley, Katharine] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Morley, Michael] Harvard Med Sch, Ophthalm Consultants Boston, Boston, MA USA. [Kusakul, Suwat] Nong Bua Lamphu Prov Hosp, Dept Ophthalmol, Nong Bua Lamphu, Thailand. [Lee, Ramon] Univ Southern Calif, USC Eye Inst, Los Angeles, CA 90089 USA. [Shieh, Eric] Univ Calif Los Angeles, David Geffen Sch Med, Jules Stein Eye Inst, Los Angeles, CA 90024 USA. [Chai-ear, Siriwatana] Udon Thani Prov Hosp, Dept Ophthalmol, Udon Thani, Thailand. [Joseph, Anthony] Tufts Univ, Ophthalm Consultants Boston, Medford, MA 02155 USA. [Agarwal, Isha] Harvard Med Sch, Boston, MA USA. RP Morley, M (reprint author), Harvard Univ, Ophthalm Consultants Boston, 50 Stanford St, Boston, MA 02114 USA. EM mgmorley@eyeboston.com FU Center for Eye Research and Education FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The authors received funding from The Center for Eye Research and Education. NR 10 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1357-633X EI 1758-1109 J9 J TELEMED TELECARE JI J. Telemed. Telecare PD JAN PY 2017 VL 23 IS 1 BP 36 EP 43 DI 10.1177/1357633X15625400 PG 8 WC Health Care Sciences & Services SC Health Care Sciences & Services GA EK9QM UT WOS:000394259000005 PM 26851243 ER PT J AU Altieri, L Hu, J Nguyen, A Cockburn, M Chiu, M Cotliar, J Kim, J Peng, D Crew, A AF Altieri, Lisa Hu, Jenny Nguyen, Andrew Cockburn, Myles Chiu, Melvin Cotliar, Jonathan Kim, Jenny Peng, David Crew, Ashley TI Interobserver reliability of teledermatology across all Fitzpatrick skin types SO JOURNAL OF TELEMEDICINE AND TELECARE LA English DT Article DE Telecare; teledermatology; telehealth; telemedicine; ehealth ID FORWARD TELEDERMATOLOGY; CONSULT SYSTEM; COST-BENEFIT; SAFETY-NET; REAL-TIME; MANAGEMENT; CARE; AGREEMENT; REFERRALS; DIAGNOSIS AB Introduction: Demand for dermatologic services in safety net hospitals, which disproportionately serve patients with darker coloured skin, is growing. Teledermatology has the potential to increase access and improve outcomes, but studies have yet to demonstrate the reliability of teledermatology for all Fitzpatrick skin types. Methods: We assessed the reliability of teledermatologists' diagnoses and management recommendations for store-and-forward teledermatology in patients with lightly pigmented (Fitzpatrick skin types I-III) versus darkly pigmented (Fitzpatrick skin types IV-VI) skin, when compared to in-person diagnosis and management decisions. This prospective study enrolled 232 adult patients, presenting with new, visible skin complaints in a Los Angeles county dermatology clinic. Forty-seven percent of patients were Fitzpatrick skin types I-III, and 53% were Fitzpatrick skin types IV-VI. Results: Percent concordance for the identical primary diagnosis was 53.2% in lighter (Fitzpatrick I-III) skin types and 56.0% in darker (Fitzpatrick IV-VI) skin types. There was no statistically significant difference in concordance rates between lighter and darker skin types for primary diagnosis. Concordance rates for diagnostic testing, clinic-based therapy, and treatments were similar in both groups of Fitzpatrick skin types. Discussion: These results suggest that teledermatology is reliable for the diagnosis and management of patients with all Fitzpatrick skin types. C1 [Altieri, Lisa] Univ Calif Los Angeles, David Geffen Sch Med, 10833 Le Conte Ave, Los Angeles, CA 90095 USA. [Hu, Jenny; Chiu, Melvin; Kim, Jenny] Univ Calif Los Angeles, Div Dermatol, Los Angeles, CA 90024 USA. [Nguyen, Andrew; Cockburn, Myles] Univ Southern Calif, Dept Prevent Med, Los Angeles, CA 90089 USA. [Cockburn, Myles; Peng, David; Crew, Ashley] Univ Southern Calif, Dept Dermatol, Los Angeles, CA 90089 USA. [Chiu, Melvin; Kim, Jenny] Vet Affairs Greater Los Angeles Healthcare Syst, Dermatol Serv, Los Angeles, CA USA. [Cotliar, Jonathan] City Hope Natl Med Ctr, Div Dermatol, 1500 E Duarte Rd, Duarte, CA 91010 USA. RP Altieri, L (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, 10833 Le Conte Ave, Los Angeles, CA 90095 USA. EM laltieri@mednet.ucla.edu NR 21 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1357-633X EI 1758-1109 J9 J TELEMED TELECARE JI J. Telemed. Telecare PD JAN PY 2017 VL 23 IS 1 BP 68 EP 73 DI 10.1177/1357633X15621226 PG 6 WC Health Care Sciences & Services SC Health Care Sciences & Services GA EK9QM UT WOS:000394259000009 PM 26729754 ER PT J AU Farrell, TW Widera, E Rosenberg, L Rubin, CD Naik, AD Braun, U Torke, A Li, I Vitale, C Shega, J AF Farrell, Timothy W. Widera, Eric Rosenberg, Lisa Rubin, Craig D. Naik, Aanand D. Braun, Ursula Torke, Alexia Li, Ina Vitale, Caroline Shega, Joseph CA Amer Geriatrics Soc TI AGS Position Statement: Making Medical Treatment Decisions for Unbefriended Older Adults SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE unbefriended; capacity assessment; surrogate decision maker; substituted judgment; best interest; ethics committee; position statement ID HOSPITAL CARDIAC-ARREST; INDIVIDUALS; SURVIVAL; OUTCOMES; GUARDIANSHIP; SURROGATES; CAPACITY; CARE AB In this position statement, we define unbefriended older adults as patients who: (1) lack decisional capacity to provide informed consent to the medical treatment at hand; (2) have not executed an advance directive that addresses the medical treatment at hand and lack capacity to do so; and (3) lack family, friends or a legally authorized surrogate to assist in the medical decision-making process. Given the vulnerable nature of this population, clinicians, health care teams, ethics committees and other stakeholders working with unbefriended older adults must be diligent when formulating treatment decisions on their behalf. The process of arriving at a treatment decision for an unbefriended older adult should be conducted according to standards of procedural fairness and include capacity assessment, a search for potentially unidentified surrogate decision makers (including non-traditional surrogates) and a team-based effort to ascertain the unbefriended older adult's preferences by synthesizing all available evidence. A concerted national effort is needed to help reduce the significant state-to-state variability in legal approaches to unbefriended patients. Proactive efforts are also needed to identify older adults, including adult orphans, at risk for becoming unbefriended and to develop alternative approaches to medical decision making for unbefriended older adults.This document updates the 1996 AGS position statement on unbefriended older adults. C1 [Farrell, Timothy W.] Univ Utah, Sch Med, Salt Lake City, UT 84112 USA. [Farrell, Timothy W.] VA Salt Lake City Geriatr Res Educ & Clin Ctr, Salt Lake City, UT USA. [Widera, Eric] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Widera, Eric] San Francisco VA Med Ctr, San Francisco, CA USA. [Rosenberg, Lisa] Roseman Univ Hlth Sci, 2963 Kedleston St, Las Vegas, NV 89135 USA. [Rubin, Craig D.] Univ Texas Southwestern Med Ctr Dallas, 5323 Harry Hines Blvd, Dallas, TX 75390 USA. [Naik, Aanand D.; Braun, Ursula] Baylor Coll Med, Houston, TX 77030 USA. [Naik, Aanand D.; Braun, Ursula] Michael E DeBakey VA Med Ctr, Houston, TX USA. [Torke, Alexia] Indiana Univ, 1101 West 10th St, Indianapolis, IN 46202 USA. [Li, Ina] Christiana Care Hlth Syst, N 1400 Washington St,Suite 327, Wilmington, DE 19801 USA. [Vitale, Caroline] Univ Michigan, Ann Arbor, MI 48109 USA. [Vitale, Caroline] VA Ann Arbor Healthcare Syst, Ann Arbor, MI USA. [Shega, Joseph] VITAS Hosp Care Healthcare, Gotha, FL USA. [Shega, Joseph] Univ Cent Florida, Gotha, FL USA. [Farrell, Timothy W.] Univ Utah, Sch Med, VA Salt Lake City Geriatr Res Educ & Clin Ctr, 30 N 1900 E,AB 193 SOM, Salt Lake City, UT 84132 USA. [Widera, Eric] Univ Calif San Francisco, San Francisco VA Med Ctr, NHCU, SFVAMC Bldg 208, San Francisco, CA 94121 USA. [Naik, Aanand D.] Michael E DeBakey VA Med Ctr, 2002 Holcombe 152, Houston, TX 77030 USA. [Naik, Aanand D.] Baylor Coll Med, 2002 Holcombe 152, Houston, TX 77030 USA. [Braun, Ursula] Michael E DeBakey VA Med Ctr, 1 Baylor Plz,MS230, Houston, TX 77030 USA. [Braun, Ursula] Baylor Coll Med, 1 Baylor Plz,MS230, Houston, TX 77030 USA. [Vitale, Caroline] Univ Michigan, VA Ann Arbor Healthcare Syst, 2215 Fuller Rd,GRECC 11G, Ann Arbor, MI 48105 USA. [Shega, Joseph] Univ Cent Florida, VITAS Healthcare, Volunteer Fac, 9616 Lake Hugh Dr, Gotha, FL 34734 USA. [Shega, Joseph] Univ Cent Florida, Med, 9616 Lake Hugh Dr, Gotha, FL 34734 USA. RP Farrell, TW (reprint author), Univ Utah, Sch Med, Salt Lake City, UT 84112 USA.; Farrell, TW (reprint author), VA Salt Lake City Geriatr Res Educ & Clin Ctr, Salt Lake City, UT USA.; Farrell, TW (reprint author), Univ Utah, Sch Med, VA Salt Lake City Geriatr Res Educ & Clin Ctr, 30 N 1900 E,AB 193 SOM, Salt Lake City, UT 84132 USA. FU AGS operating budget FX Financial support for the development of this paper comes exclusively from the AGS operating budget. NR 35 TC 1 Z9 1 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0002-8614 EI 1532-5415 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD JAN PY 2017 VL 65 IS 1 BP 14 EP E5 DI 10.1111/jgs.14586 PG 7 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA EL3WZ UT WOS:000394551300003 ER PT J AU Ashburner, JM Go, AS Chang, YC Fang, MC Fredman, L Applebaum, KM Singer, DE AF Ashburner, Jeffrey M. Go, Alan S. Chang, Yuchiao Fang, Margaret C. Fredman, Lisa Applebaum, Katie M. Singer, Daniel E. TI Influence of Competing Risks on Estimating the Expected Benefit of Warfarin in Individuals with Atrial Fibrillation Not Currently Taking Anticoagulants: The Anticoagulation and Risk Factors in Atrial Fibrillation Study SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE anticoagulation; stroke; atrial fibrillation ID HEART RHYTHM ASSOCIATION; STROKE PREVENTION; REGRESSION-MODELS; PREDICTING STROKE; MANAGEMENT; DEATH; GUIDELINES; DISEASE; ADULTS AB ObjectivesTo provide greater understanding of the real world effect of anticoagulation on stroke risk over several years. DesignCohort study. SettingAnticoagulation and Risk Factors in Atrial Fibrillation Study community-based cohort. ParticipantsAdults with nonvalvular atrial fibrillation (AF) between 1996 and 2003 (13,559). MeasurementsAll events were clinician adjudicated. Extended Cox regression with longitudinal warfarin exposure was used to estimate cause-specific hazard ratios (HRs) for thromboembolism and the competing risk event (all cause death). The Fine and Gray subdistribution regression approach was used to estimate this association while accounting for competing death events. As a secondary analysis, follow-up was limited to 1, 3, and 5 years. ResultsThe rate of death was much higher in the group not taking warfarin (8.1 deaths/100 person-years (PY)) than in the group taking warfarin (5.5 deaths/100 PY). The cause-specific HR indicated a large reduction in thromboembolism with warfarin use (adjusted HR = 0.57, 95% confidence interval (CI) = 0.50-0.65), although this association was substantially attenuated after accounting for competing death events (adjusted HR = 0.87, 95% CI = 0.77-0.99). In analyses limited to 1 year of follow-up, with fewer competing death events, the results for models that did and did not account for competing risks were similar. ConclusionAnalyses accounting for competing death events may provide a more-realistic estimate of the longer-term stroke prevention benefits of anticoagulants than traditional noncompeting risk analyses for individuals with AF, particularly those who are not currently treated with anticoagulants. C1 [Ashburner, Jeffrey M.; Chang, Yuchiao; Singer, Daniel E.] Massachusetts Gen Hosp, Div Gen Internal Med, 50 Staniford St,9th Floor, Boston, MA 02114 USA. [Ashburner, Jeffrey M.; Fredman, Lisa] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Go, Alan S.] Kaiser Permanente Northern Calif, Div Res, Oakland, CA USA. [Go, Alan S.] Univ Calif San Francisco, Dept Epidemiol Biostat & Med, San Francisco, CA 94143 USA. [Go, Alan S.] Stanford Univ, Sch Med, Dept Hlth Res & Policy, Stanford, CA 94305 USA. [Fang, Margaret C.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Applebaum, Katie M.] George Washington Univ, Dept Environm & Occupat Hlth, Milken Inst Sch Publ Hlth, Washington, DC USA. RP Ashburner, JM (reprint author), Massachusetts Gen Hosp, Div Gen Internal Med, 50 Staniford St,9th Floor, Boston, MA 02114 USA. EM jashburner@mgh.harvard.edu FU National Institute on Aging [R01 AG15478, K23 AG028978]; National Heart, Lung and Blood Institute [U19 HL91179, RC2HL101589]; Eliot B. and Edith C. Shoolman fund of Massachusetts General Hospital (Boston, MA) FX This study was supported by the National Institute on Aging (R01 AG15478 and K23 AG028978); the National Heart, Lung and Blood Institute (U19 HL91179 and RC2HL101589); and the Eliot B. and Edith C. Shoolman fund of Massachusetts General Hospital (Boston, MA). Dr. Ashburner had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. NR 32 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0002-8614 EI 1532-5415 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD JAN PY 2017 VL 65 IS 1 BP 35 EP 41 DI 10.1111/jgs.14516 PG 7 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA EL3WZ UT WOS:000394551300011 PM 27861698 ER PT J AU Sarkar, U Lyles, C Steinman, M Huang, ES Moffet, HH Whitmer, RA Warton, EM Karter, AJ AF Sarkar, Urmimala Lyles, Courtney Steinman, Michael Huang, Elbert S. Moffet, Howard H. Whitmer, Rachel A. Warton, E. Margaret Karter, Andrew J. TI Changes in Medication Use After Dementia Diagnosis in an Observational Cohort of Individuals with Diabetes Mellitus SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE polypharmacy; dementia; diabetes mellitus ID NORTHERN CALIFORNIA DISTANCE; DIFFERENCE-IN-DIFFERENCES; OLDER PATIENTS; GLYCEMIC CONTROL; SOCIAL SUPPORT; BLOOD-GLUCOSE; FOLLOW-UP; ADULTS; COMPLICATIONS; POPULATION AB ObjectivesTo assess changes in medication use after a diagnosis of dementia in individuals with type 2 diabetes mellitus. DesignDifference-in-differences analysis of changes in the number of dispensed chronic medications between individuals with and without newly diagnosed dementia. SettingIntegrated healthcare delivery system, Kaiser Permanente Northern California. ParticipantsIndividuals aged 50 and older without prevalent dementia with type 2 diabetes mellitus enrolled in a baseline survey. During 5 years of follow-up, 193 individuals with a new diagnosis of dementia were identified, and risk-set sampling was used to randomly select five reference subjects per case matched on 5-year age categories and sex (965 matched participants), resulting in an analytical sample of 1,158. MeasurementsThe exposure was new diagnosis of dementia. The primary outcome was change in number of current chronic medications (total, cardiovascular (blood pressure and lipid control), diabetes mellitus) at three times: 1 year before index date (preindex date), date of diagnosis of dementia or matched reference date (index date), and up to 1 year after index date or end of follow-up if censored before 1 year (postindex date). ResultsAfter adjustment, the number of chronic medications and the subset of cardiovascular medications declined after a dementia diagnosis in the overall cohort and in age-, sex-, and time-matched reference individuals, but the decline was significantly greater in the group with dementia (0.71 medications fewer than the reference group, P = .02). The number of diabetes mellitus medications declined in both groups, but the declines were not statistically different (0.18 medications fewer than the reference group, P = .008). ConclusionsUse of cardiometabolic medications fell after a diagnosis of dementia, as recommended in national guidelines. C1 [Sarkar, Urmimala; Lyles, Courtney] Univ Calif San Francisco, Div Gen Internal Med, Ctr Vulnerable Populat, San Francisco, CA 94143 USA. [Steinman, Michael] Univ Calif San Francisco, Div Geriatr, San Francisco, CA 94143 USA. [Steinman, Michael] San Francisco VA Med Ctr, San Francisco, CA 94143 USA. [Huang, Elbert S.] Univ Chicago, Sch Med, Chicago, IL 60637 USA. [Moffet, Howard H.; Whitmer, Rachel A.; Warton, E. Margaret; Karter, Andrew J.] Kaiser Permanente, Div Res, Oakland, CA USA. RP Sarkar, U (reprint author), UCSF SFGH, 1001 Potrero Ave,Box 1364, San Francisco, CA 94110 USA. EM urmimala.sarkar@ucsf.edu FU National Institute of Diabetes and Digestive and Kidney Diseases Grant [R01 DK081796]; Agency for Healthcare Research and Quality [K99022408]; National Institutes of Health [DK080726]; National Institute on Aging (NIA) Paul Beeson Career Development Award [1K23-AG030999]; NIA Claude Pepper Older Americans Independence Center Award [P30 AG044281]; [P30HS023558]; [P60MD006902]; [P30 DK092949]; [K24 DK105340] FX Dr. Urmimala Sarkar had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. This research was directly funded by National Institute of Diabetes and Digestive and Kidney Diseases Grant R01 DK081796 (Karter, Moffet, Warton, Huang). Other support included P30HS023558 (Sarkar), P60MD006902 (Karter), P30 DK092949 (Huang), K24 DK105340 (Huang), Agency for Healthcare Research and Quality K99022408 (Lyles), National Institutes of Health Grant DK080726 (Moffet), National Institute on Aging (NIA) Paul Beeson Career Development Award 1K23-AG030999 and NIA Claude Pepper Older Americans Independence Center Award P30 AG044281 (Steinman). NR 40 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0002-8614 EI 1532-5415 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD JAN PY 2017 VL 65 IS 1 BP 77 EP 82 DI 10.1111/jgs.14429 PG 6 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA EL3WZ UT WOS:000394551300016 PM 27642180 ER PT J AU Soones, T Federman, A Leff, B Siu, AL Ornstein, K AF Soones, Tacara Federman, Alex Leff, Bruce Siu, Albert L. Ornstein, Katherine TI Two-Year Mortality in Homebound Older Adults: An Analysis of the National Health and Aging Trends Study SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE homebound; United States; epidemiology; cross-sectional studies; mortality ID LATE-LIFE DISABILITY; HOME-BASED PRIMARY; PRIMARY-CARE; RISK; SPACE; COMORBIDITY; POPULATION; IMPAIRMENT; PREVALENCE; DEPRESSION AB ObjectivesTo determine the association between homebound status and mortality. DesignCross-sectional. SettingAnnual, in-person interviews. ParticipantsA nationally representative sample of community-dwelling, Medicare beneficiaries aged 65 and older enrolled in the National Health and Aging Trends Study between 2011 and 2013 (N = 6,400). MeasurementsTwo-year mortality and prevalence of homebound status in the year before death are described using three categories of homebound status: homebound (never or rarely left home in the last month), semihomebound (left home with assistance, needed help or had difficulty), and nonhomebound (left home without help or difficulty). ResultsIn unadjusted analyses, 2-year mortality was 40.3% in homebound participants, 21.3% in those who were semihomebound and 5.8% in those who were nonhomebound. Homebound status was associated with greater 2-year mortality, adjusted for sociodemographic characteristics, comorbidities, and functional status (hazard ratio = 2.08; 95% confidence interval = 1.63-2.65, P < .001). Half of older community-dwelling Medicare beneficiaries were homebound in the year before death. ConclusionHomebound status is associated with greater risk of death independent of functional impairment and comorbidities. To improve outcomes for homebound older adults and the many older adults who will become homebound in the last year of life, providers and policymakers need to extend healthcare services from hospitals and clinics to the homes of vulnerable individuals. C1 [Soones, Tacara; Siu, Albert L.; Ornstein, Katherine] Icahn Sch Med Mt Sinai, Dept Geriatr & Palliat Med, One Gustave Levy Pl,Box 1070, New York, NY 10029 USA. [Federman, Alex; Ornstein, Katherine] Icahn Sch Med Mt Sinai, Div Gen Internal Med, Dept Med, New York, NY 10029 USA. [Leff, Bruce] Johns Hopkins Univ, Dept Med, Div Geriatr Med, Baltimore, MD USA. [Leff, Bruce] Johns Hopkins Univ, Dept Community & Publ Hlth, Sch Nursing, Baltimore, MD USA. [Leff, Bruce] Johns Hopkins Univ, Dept Hlth Policy & Management, Bloomberg Sch Publ Hlth, Baltimore, MD 21218 USA. [Siu, Albert L.] James J Peters Vet Affairs Med Ctr, Geriatr Res Educ & Clin Ctr, Bronx, NY USA. [Ornstein, Katherine] Icahn Sch Med Mt Sinai, Inst Translat Epidemiol, New York, NY 10029 USA. RP Soones, T (reprint author), Icahn Sch Med Mt Sinai, Dept Geriatr & Palliat Med, One Gustave Levy Pl,Box 1070, New York, NY 10029 USA. EM tacara.soones@mssm.edu FU Voluntary Landmark Health; National Institute on Aging (NIA) [U01AG32947]; NIA [K01AG047923]; National Palliative Care Research Center FX Dr. Bruce Leff is on the boards of directors of the American Academy of Home Care Medicine and the Voluntary Alliance for Home Health Quality and Innovation. He is also a paid member of the advisory board of Voluntary Landmark Health.; NHATS is sponsored by Grant U01AG32947 from the National Institute on Aging (NIA). Dr. Ornstein was supported by Grant K01AG047923 from NIA and by the National Palliative Care Research Center. NR 40 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0002-8614 EI 1532-5415 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD JAN PY 2017 VL 65 IS 1 BP 123 EP 129 DI 10.1111/jgs.14467 PG 7 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA EL3WZ UT WOS:000394551300022 PM 27641001 ER PT J AU Scangas, GA Remenschneider, AK Su, BM Shrime, MG Metson, R AF Scangas, George A. Remenschneider, Aaron K. Su, Brooke M. Shrime, Mark G. Metson, Ralph TI Cost Utility Analysis of Endoscopic Sinus Surgery for Chronic Rhinosinusitis With and Without Nasal Polyposis SO LARYNGOSCOPE LA English DT Article DE chronic sinusitis; health utility; cost-effectiveness; endoscopic sinus surgery; evidence-based medicine; health care economics; patient-reported outcomes; quality of life ID ADULT CHRONIC RHINOSINUSITIS; EXPENDITURE PANEL SURVEY; WILLINGNESS-TO-PAY; QUALITY-OF-LIFE; UNITED-STATES; HEALTH STATES; ECONOMIC-EVALUATION; OUTCOMES; COMPLICATIONS; DISEASE AB Objective: To evaluate the cost-effectiveness of endoscopic sinus surgery (ESS) compared to medical therapy for patients with chronic rhinosinusitis (CRS) with and without nasal polyposis (NP). Study Design: Cohort-style Markov decision-tree economic model with a 36-year time horizon. Methods: Two cohorts of 229 CRS patients with and without NP who underwent ESS were compared with a matched cohort of 229 CRS patients from the Medical Expenditures Survey Panel database (Agency for Healthcare Research and Quality, Rockville, MD) who underwent medical management. Utility scores were calculated from sequential patient responses to the EuroQol five-dimensions questionnaire. Decision-tree analysis and a 10-state Markov model utilized published event probabilities and primary data to calculate long-term costs and utility. The primary outcome was the incremental cost per quality adjusted life year (QALY). Thorough sensitivity analyses were performed. Results: The reference case for CRS with NP yielded an incremental cost-effectiveness ratio (ICER) for ESS versus medical therapy of $5,687.111/QALY. The reference case for CRS without NP yielded an ICER of $5,405.111/QALY. The cost-effectiveness acceptability curve in both cases demonstrated 95% certainty that the ESS strategy was the most cost-effective option at a willingness-to-pay threshold of $20,000/QALY or higher. These results were robust to one-way and probabilistic sensitivity analysis. Conclusion: This study demonstrates the cost-effectiveness of ESS compared to medical therapy alone for the management of CRS patients both with and without NP. The presence of nasal polyps was not found to affect the overall cost-effectiveness of ESS. C1 [Scangas, George A.; Remenschneider, Aaron K.; Shrime, Mark G.; Metson, Ralph] Harvard Med Sch, Dept Otolaryngol, Boston, MA USA. [Shrime, Mark G.] Harvard Med Sch, Program Global Surg & Social Change, Boston, MA USA. [Scangas, George A.; Remenschneider, Aaron K.; Shrime, Mark G.; Metson, Ralph] Massachusetts Eye & Ear Infirm, Dept Otolaryngol, Boston, MA 02114 USA. [Su, Brooke M.] Univ Calif San Francisco, Sch Med, San Francisco, CA USA. RP Scangas, GA (reprint author), Massachusetts Eye & Ear Infirm, 243 Charles St, Boston, MA 02114 USA. EM george_scangas@meei.harvard.edu FU Board Committee on Quality at the Massachusetts Eye and Ear Infirmary FX This work was supported by a funding grant from the Board Committee on Quality at the Massachusetts Eye and Ear Infirmary. The authors have no other funding, financial relationships, or conflicts of interest to disclose. NR 74 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0023-852X EI 1531-4995 J9 LARYNGOSCOPE JI Laryngoscope PD JAN PY 2017 VL 127 IS 1 BP 29 EP 37 DI 10.1002/lary.26169 PG 9 WC Medicine, Research & Experimental; Otorhinolaryngology SC Research & Experimental Medicine; Otorhinolaryngology GA EL9PB UT WOS:000394951400019 PM 27440486 ER PT J AU Cohen, NA AF Cohen, Noam A. TI The Genetics of the Bitter Taste Receptor T2R38 in Upper Airway Innate Immunity and Implications for Chronic Rhinosinusitis SO LARYNGOSCOPE LA English DT Article DE T2R38; chronic rhinosinusitis; cilia; interkingdom signaling; host-pathogen interactions ID NONPOLYPOID CHRONIC RHINOSINUSITIS; BIOFILM-FORMING BACTERIA; NITRIC-OXIDE; PSEUDOMONAS-AERUGINOSA; CHEMOSENSORY CELLS; ANTIMICROBIAL ACTIVITY; CHRONIC SINUSITIS; PERCEPTION; INFLAMMATION; CILIOGENESIS AB Objective: Chronic rhinosinusitis (CRS) refractory to therapeutic intervention may involve a particularly resistant infection known as a bacterial biofilm. Critical to biofilm formation is the microbial process of quorum sensing whereby microbes secrete factors that regulate the expression of microbial genes involved in biofilm formation, persistence, and virulence. Here, we review recent work demonstrating that the bitter taste receptor T2R38, expressed on the apical surface of the sinonasal epithelium, serves a sentinel role in eavesdropping on microbial quorum-sensing communications and regulates localized innate biocidal defenses. Furthermore, studies investigating whether cilia are necessary for T2R38 expression and function in the upper airway are presented. Methods: Primary human sinonasal air-liquid interface cultures were used to elucidate cellular pathways responsive to quorum-sensing molecules, whereas clinical studies investigated the contribution of T2R38 polymorphisms to recalcitrant chronic rhinosinusitis. Results: T2R38 is stimulated by acyl-homoserine lactones, gram-negative quorum-sensing molecules, and subsequently activates nitric oxide-dependent innate immune responses. The formation of mature cilia is necessary for T2R38 expression and function, and polymorphisms that underlie T2R38 functionality appear to be involved in susceptibility to upper respiratory infection and recalcitrant CRS. Conclusion: Taste receptors are emerging as critical components of early-phase respiratory innate immunity, detecting molecules used by microbes to communicate and stimulating localized host defenses. Genetic polymorphisms are very common within the taste receptors, and recent linkage studies have demonstrated associations of taste receptor genetics with CRS. Lastly, ciliogenesis, which is often impacted in CRS, is critical for the functional expression of T2R38. C1 [Cohen, Noam A.] Univ Penn, Hosp Univ Penn, Sch Med, Dept Otorhinolaryngol Head & Neck Surg, 5th Floor Ravdin Bldg,3400 Spruce St, Philadelphia, PA 19104 USA. [Cohen, Noam A.] Philadelphia Vet Affairs Med Ctr, Philadelphia, PA USA. [Cohen, Noam A.] Monett Chem Senses Ctr, Philadelphia, PA USA. RP Cohen, NA (reprint author), Univ Penn, Hosp Univ Penn, Sch Med, Dept Otorhinolaryngol Head & Neck Surg, 5th Floor Ravdin Bldg,3400 Spruce St, Philadelphia, PA 19104 USA. EM cohenn@uphs.upenn.edu OI Cohen, Noam/0000-0002-9462-3932 FU USPHS grant [R01DC013588] FX Funded in part by USPHS grant R01DC013588. The author has no other funding, financial relationships, or conflicts of interest to disclose. NR 53 TC 1 Z9 1 U1 4 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0023-852X EI 1531-4995 J9 LARYNGOSCOPE JI Laryngoscope PD JAN PY 2017 VL 127 IS 1 BP 44 EP 51 DI 10.1002/lary.26198 PG 8 WC Medicine, Research & Experimental; Otorhinolaryngology SC Research & Experimental Medicine; Otorhinolaryngology GA EL9PB UT WOS:000394951400021 PM 27650657 ER PT J AU Randolph, GW Kamani, D AF Randolph, Gregory W. Kamani, Dipti TI Intraoperative Electrophysiologic Monitoring of the Recurrent Laryngeal Nerve During Thyroid and Parathyroid Surgery: Experience With 1,381 Nerves at Risk SO LARYNGOSCOPE LA English DT Article DE Recurrent laryngeal nerve; intraoperative nerve monitoring; vocal cord paralysis; nerve mapping; electromyography ID ASSOCIATION STATEMENT; ENDOCRINE SURGEONS; VAGUS NERVE; INJURY; ELECTROMYOGRAPHY; MANAGEMENT; PARALYSIS; CANCER; COMPLICATIONS; VISUALIZATION AB Objectives: The electrophysiologic responses of 1,381 recurrent laryngeal nerves (RLN) during monitored neck surgery were recorded and reviewed. Study Design: Retrospective case series. Methods: With institutional review board approval, we reviewed thyroid and other neck surgeries performed with intraoperative nerve monitoring (IONM) between the years 1995 and 2006. This list yielded consecutively monitored 1,381 RLNs, with over 3,000 hours of monitoring experience. All patients underwent preoperative and postoperative laryngoscopy. In an initial subset of patients, both hook-wire and endotracheal tube (ETT) surface electrodes were utilized. Normative stimulation parameters; postoperative vocal cord function prognostication using monitoring data; and false-positive, false-negative, and passive electrophysiologic responses were evaluated Results: Hook-wire electrodes and ETT surface electrodes were found to have good correlation in terms of amplitude (correlation coefficient, R = 0.89). Nerve stimulation of 1 to 2 mA resulted in an ipsilateral biphasic response, with 3.3 ms mean latency and 900 mu V mean amplitude. Permanent and temporary RLN paralysis rates were 0% and 0.7%, respectively. Specificity of electromyography (EMG) loss of signal (LOS) postoperative vocal cord paralysis (VCP) detection was 99.9%, and sensitivity was 33%. Negative predictive value of EMG LOS at the end of surgery in the prediction of postoperative VCP was 99.6%, whereas its positive predictive value for VCP was 75%. Conclusion: Intraoperative nerve monitoring of the RLN during thyroid and other neck surgeries can aid in the nerve mapping, nerve identification, and prognostication of postoperative vocal cord function, which in turn can influence the surgeon's decision to proceed to bilateral surgery. C1 [Randolph, Gregory W.; Kamani, Dipti] Massachusetts Eye & Ear Infirm, Div Thyroid & Parathyroid Surg, Dept Otolaryngol, 243 Charles St, Boston, MA 02114 USA. [Randolph, Gregory W.; Kamani, Dipti] Harvard Med Sch, Boston, MA USA. [Randolph, Gregory W.] Massachusetts Gen Hosp, Dept Surg, Div Surg Oncol, Boston, MA 02114 USA. RP Randolph, GW (reprint author), Massachusetts Eye & Ear Infirm, Div Thyroid & Parathyroid Surg, Dept Otolaryngol, 243 Charles St, Boston, MA 02114 USA. EM Gregory_Randolph@meei.harvard.edu FU John and Claire Bertucci Thyroid Research fund FX The John and Claire Bertucci Thyroid Research fund supported this research. The authors have no funding, financial relationships, or conflicts of interest to disclose. NR 49 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0023-852X EI 1531-4995 J9 LARYNGOSCOPE JI Laryngoscope PD JAN PY 2017 VL 127 IS 1 BP 280 EP 286 DI 10.1002/lary.26166 PG 7 WC Medicine, Research & Experimental; Otorhinolaryngology SC Research & Experimental Medicine; Otorhinolaryngology GA EL9PB UT WOS:000394951400056 PM 27389369 ER PT J AU Lu, IC Wu, CW Chang, PY Chen, HY Tseng, KY Randolph, GW Cheng, KI Chiang, FY AF Lu, I-Cheng Wu, Che-Wei Chang, Pi-Ying Chen, Hsiu-Ya Tseng, Kuang-Yi Randolph, Gregory W. Cheng, Kuang-I Chiang, Feng-Yu TI In Response to Reversal of Rocuronium-Induced Neuromuscular Blockade by Sugammadex Allows for Optimization of Neural Monitoring of the Recurrent Laryngeal Nerve SO LARYNGOSCOPE LA English DT Letter C1 [Lu, I-Cheng] Kaohsiung Med Univ, Fac Med, Coll Med,Kaohsiung Med Univ Hosp, Dept Anesthesiol,Kaohsiung Municipal Hsiao Kang H, Kaohsiung, Taiwan. [Wu, Che-Wei; Chiang, Feng-Yu] Kaohsiung Med Univ, Fac Med, Kaohsiung Med Univ Hosp, Dept Otolaryngol Head & Neck Surg,Coll Med, Kaohsiung, Taiwan. [Chang, Pi-Ying; Chen, Hsiu-Ya; Tseng, Kuang-Yi] Kaohsiung Med Univ, Kaohsiung Med Univ Hosp, Dept Anesthesiol, Kaohsiung, Taiwan. [Randolph, Gregory W.] Harvard Med Sch, Div Thyroid & Parathyroid Surg, Dept Laryngol & Otol,Massachusetts Gen Hosp, Massachusetts Eye & Ear Infirm,Div Surg Oncol,Dep, Boston, MA USA. [Cheng, Kuang-I] Kaohsiung Med Univ, Fac Med, Coll Med, Dept Anesthesiol,Kaohsiung Med Univ Hosp, Kaohsiung, Taiwan. RP Lu, IC (reprint author), Kaohsiung Med Univ, Fac Med, Coll Med,Kaohsiung Med Univ Hosp, Dept Anesthesiol,Kaohsiung Municipal Hsiao Kang H, Kaohsiung, Taiwan. NR 4 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0023-852X EI 1531-4995 J9 LARYNGOSCOPE JI Laryngoscope PD JAN PY 2017 VL 127 IS 1 BP E51 EP E52 DI 10.1002/lary.26036 PG 2 WC Medicine, Research & Experimental; Otorhinolaryngology SC Research & Experimental Medicine; Otorhinolaryngology GA EL9PB UT WOS:000394951400010 PM 27112230 ER PT J AU Nocera, AL Meurer, AT Miyake, MM Sadow, PM Han, X Bleier, BS AF Nocera, Angela L. Meurer, Ana T. Miyake, Marcel M. Sadow, Peter M. Han, Xue Bleier, Benjamin S. TI Secreted P-Glycoprotein Is a Noninvasive Biomarker of Chronic Rhinosinusitis SO LARYNGOSCOPE LA English DT Article DE P-glycoprotein; secreted P-gp; biomarker; chronic rhinosinusitis; chronic rhinosinusitis with nasal polyps. ID SINONASAL EPITHELIAL-CELLS; MAJOR BASIC-PROTEIN; NASAL POLYPS; MARKER AB Objective: The discovery of noninvasive biomarkers of chronic rhinosinusitis (CRS) is critical to enable our ability to provide prognostic information and targeted medical therapy. Epithelial P-glycoprotein (P-gp) is overexpressed in CRS and exists in an extracellular, secreted form. The objective of this study was to determine whether secreted P-gp concentrations are elevated in CRS and can be used to predict disease severity. Methods: Institutional review board-approved study examining mucus concentrations of P-gp in 36 patients (10 control, 16 CRS without nasal polyps [CRSsNP], and 10 CRS with nasal polyps [CRSwNP]). P-gp concentrations were determined by enzyme-linked immunosorbent assay and normalized to total protein (TP). Clinical indices of disease severity, including the Sino-Nasal Outcomes Test (SNOT-22) and Lund-Mackay score, were collected for all patients. Results: Secreted P-gp concentration was significantly higher in CRS versus control patients (mean +/- standard deviation; 247.8 +/- 224.8 vs. 102.4 +/- 81.7 pcg P-gp/mu g TP, P = 0.022). A threshold value of 250 pcg/mu g TP was used to differentiate low versus high secretors. High P-gp secretors with CRS (sNP and wNP, n = 9) demonstrated significantly higher SNOT-22 and Lund-Mackay scores (57.1 +/- 7.9 and 13.9 +/- 7.3) versus low secretors (38.3 +/- 23.9 and 6.8 +/- 7.3; P = 0.030 and P = 0.013, respectively) and had a significantly higher proportion of CRSwNP (66.7%) versus the low secretors (23.5%, n = 17, P 0.046). Conclusion: P-gp secretion levels are significantly elevated in patients with CRS. High P-gp secretion is associated with a higher incidence of CRSwNP and confers worse subjective and objective measures of disease severity. The presence of elevated P-gp secretion may therefore represent a novel noninvasive biomarker of CRS and could be used to predict patients who may benefit from P-gp inhibitory therapeutic strategies. C1 [Nocera, Angela L.; Meurer, Ana T.; Miyake, Marcel M.; Bleier, Benjamin S.] Harvard Med Sch, Massachusetts Eye & Ear Infirm, Boston, MA USA. [Sadow, Peter M.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Pathol, Boston, MA USA. [Han, Xue] Boston Univ, Dept Biomed Engn, Boston, MA 02215 USA. RP Bleier, BS (reprint author), 243 Charles St, Boston, MA 02114 USA. EM benjamin_bleier@meei.harvard.edu NR 18 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0023-852X EI 1531-4995 J9 LARYNGOSCOPE JI Laryngoscope PD JAN PY 2017 VL 127 IS 1 BP E1 EP E4 DI 10.1002/lary.26249 PG 4 WC Medicine, Research & Experimental; Otorhinolaryngology SC Research & Experimental Medicine; Otorhinolaryngology GA EL9PB UT WOS:000394951400001 PM 27577924 ER PT J AU Heljasvaara, R Aikio, M Ruotsalainen, H Pihlajaniemi, T AF Heljasvaara, Ritva Aikio, Mari Ruotsalainen, Heli Pihlajaniemi, Taina TI Collagen XVIII in tissue homeostasis and dysregulation - Lessons learned from model organisms and human patients SO MATRIX BIOLOGY LA English DT Review DE membrane; Knobloch syndrome; Multiplexin; Heparan sulphate proteoglycan ID ANGIOGENESIS INHIBITOR ENDOSTATIN; HEPARAN-SULFATE PROTEOGLYCANS; BASEMENT-MEMBRANE ZONES; CELL LUNG-CANCER; MONOCYTE CHEMOATTRACTANT PROTEIN-1; RECOMBINANT HUMAN ENDOSTATIN; HUMAN ENDOTHELIAL-CELLS; KNOBLOCH-SYNDROME; ALZHEIMERS-DISEASE; DEFICIENT MICE AB Collagen XVIII is a ubiquitous basement membrane (BM) proteoglycan produced in three tissue-specific isoforms that differ in their N-terminal non-collagenous sequences, but share collagenous and C-terminal non-collagenous domains. The collagenous domain provides flexibility to the large collagen XVIII molecules on account of multiple interruptions in collagenous sequences. Each isoform has a complex multi-domain structure that endows it with an ability to perform various biological functions. The long isoform contains a frizzled-like (Fz) domain with Wnt-inhibiting activity and a unique domain of unknown function (DUF959), which is also present in the medium isoform. All three isoforms share an N-terminal laminin-G-like/thrombospondin-1 sequence whose specific functions still remain unconfirmed. The proteoglycan nature of the isoforms further increases the functional diversity of collagen XVIII. An anti-angiogenic domain termed endostatin resides in the C-terminus of collagen XVIII and is proteolytically cleaved from the parental molecule during the BM breakdown for example in the process of tumour progression. Recombinant endostatin can efficiently reduce tumour angiogenesis and growth in experimental models by inhibiting endothelial cell migration and proliferation or by inducing their death, but its efficacy against human cancers is still a subject of debate. Mutations in the COL18A1 gene result in Knobloch syndrome, a genetic disorder characterised mainly by severe eye defects and encephalocele and, occasionally, other symptoms. Studies with gene-modified mice have elucidated some aspects of this rare disease, highlighting in particular the importance of collagen XVIII in the development of the eye. Research with model organisms have also helped in determining other structural and biological functions of collagen XVIII, such as its requirement in the maintenance of BM integrity and its emerging roles in regulating cell survival, stem or progenitor cell maintenance and differentiation and inflammation. In this review, we summarise current knowledge on the properties and endogenous functions of collagen XVIII in normal situations and tissue dysregulation. When data is available, we discuss the functions of the distinct isoforms and their specific domains. (C) 2016 Elsevier B.V. All rights reserved. C1 [Heljasvaara, Ritva; Ruotsalainen, Heli; Pihlajaniemi, Taina] Univ Oulu, Fac Biochem & Mol Med, Bioctr Oulu, Oulu Ctr Cell Matrix Res, FIN-90014 Oulu, Finland. [Heljasvaara, Ritva] Univ Bergen, Ctr Canc Biomarkers CCBIO, Dept Biomed, N-5009 Bergen, Norway. [Aikio, Mari] Harvard Med Sch, Dana Farber Canc Inst, Boston, MA 02115 USA. [Aikio, Mari] Harvard Med Sch, Dept Cell Biol, Boston, MA 02115 USA. RP Heljasvaara, R (reprint author), Univ Oulu, Fac Biochem & Mol Med, POB 5400, FIN-90014 Oulu, Finland. EM ritva.heljasvaara@oulu.fi FU Health Science Council of the Academy of Finland (Centre of Excellence) [251314]; Sigrid Juselius Foundation; Cancer Society of Northern Finland FX This study was supported by the Health Science Council of the Academy of Finland (Centre of Excellence 2012-2017 Grant 251314), by Sigrid Juselius Foundation and by the Cancer Society of Northern Finland. NR 185 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0945-053X EI 1569-1802 J9 MATRIX BIOL JI Matrix Biol. PD JAN PY 2017 VL 57-58 SI SI BP 55 EP 75 DI 10.1016/j.matbio.2016.10.002 PG 21 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA EP0KI UT WOS:000397075800005 PM 27746220 ER PT J AU Fallahi-Sichani, M Becker, V Izar, B Baker, GJ Lin, JR Boswell, SA Shah, P Rotem, A Garraway, LA Sorger, PK AF Fallahi-Sichani, Mohammad Becker, Verena Izar, Benjamin Baker, Gregory J. Lin, Jia-Ren Boswell, Sarah A. Shah, Parin Rotem, Asaf Garraway, Levi A. Sorger, Peter K. TI Adaptive resistance of melanoma cells to RAF inhibition via reversible induction of a slowly dividing de-differentiated state SO MOLECULAR SYSTEMS BIOLOGY LA English DT Article DE adaptive and reversible drug resistance; BRAF(V600E) melanomas; de-differentiated NGFR(High) state; RAF and MEK inhibitors ID BRAF-MUTANT MELANOMA; LARGE GENE LISTS; ACQUIRED-RESISTANCE; METASTATIC MELANOMA; CONFERS RESISTANCE; INDUCED APOPTOSIS; UP-REGULATION; SINGLE CELLS; CANCER-CELLS; RNA-SEQ AB Treatment of BRAF-mutant melanomas with MAP kinase pathway inhibitors is paradigmatic of the promise of precision cancer therapy but also highlights problems with drug resistance that limit patient benefit. We use live-cell imaging, single-cell analysis, and molecular profiling to show that exposure of tumor cells to RAF/MEK inhibitors elicits a heterogeneous response in which some cells die, some arrest, and the remainder adapt to drug. Drug-adapted cells up-regulate markers of the neural crest (e.g., NGFR), a melanocyte precursor, and grow slowly. This phenotype is transiently stable, reverting to the drug-naive state within 9 days of drug withdrawal. Transcriptional profiling of cell lines and human tumors implicates a c-Jun/ECM/FAK/Src cascade in de-differentiation in about one-third of cell lines studied; drug-induced changes in c-Jun and NGFR levels are also observed in xenograft and human tumors. Drugs targeting the c-Jun/ECM/FAK/Src cascade as well as BET bromodomain inhibitors increase the maximum effect (E-max) of RAF/MEK kinase inhibitors by promoting cell killing. Thus, analysis of reversible drug resistance at a single-cell level identifies signaling pathways and inhibitory drugs missed by assays that focus on cell populations. C1 [Fallahi-Sichani, Mohammad; Becker, Verena; Baker, Gregory J.; Boswell, Sarah A.; Sorger, Peter K.] Harvard Med Sch, Dept Syst Biol, Program Therapeut Sci, Boston, MA 02115 USA. [Izar, Benjamin; Shah, Parin; Rotem, Asaf; Garraway, Levi A.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Izar, Benjamin; Garraway, Levi A.] Broad Inst Harvard & MIT, Cambridge, MA USA. [Lin, Jia-Ren; Sorger, Peter K.] Harvard Med Sch, HMS LINCS Ctr, Boston, MA 02115 USA. [Lin, Jia-Ren; Sorger, Peter K.] Harvard Med Sch, Lab Syst Pharmacol, Boston, MA 02115 USA. [Garraway, Levi A.; Sorger, Peter K.] Harvard Med Sch, Ludwig Ctr Harvard, Boston, MA 02115 USA. RP Fallahi-Sichani, M; Sorger, PK (reprint author), Harvard Med Sch, Dept Syst Biol, Program Therapeut Sci, Boston, MA 02115 USA.; Sorger, PK (reprint author), Harvard Med Sch, HMS LINCS Ctr, Boston, MA 02115 USA.; Sorger, PK (reprint author), Harvard Med Sch, Lab Syst Pharmacol, Boston, MA 02115 USA.; Sorger, PK (reprint author), Harvard Med Sch, Ludwig Ctr Harvard, Boston, MA 02115 USA. EM mohammad_fallahisichani@hms.harvard.edu; peter_sorger@hms.harvard.edu FU NIH [U54-HL127365, CA139980, GM107618]; NCI [K99CA194163]; Merck Fellowship of the Life Sciences Research Foundation; Adelson Medical Research Foundation; Melanoma Research Alliance; Ludwig Center at Harvard; DFCI Wong Family Award FX This work was funded by NIH grants U54-HL127365, CA139980, and GM107618 (to PKS), and NCI grant K99CA194163 (to MF-S), a Merck Fellowship of the Life Sciences Research Foundation (to MF-S), grants from the Adelson Medical Research Foundation and the Melanoma Research Alliance (to LAG), the Ludwig Center at Harvard (to PKS and LAG), and a DFCI Wong Family Award (to BI). We thank the Nikon Imaging Center and ICCB-Longwood Screening Facility at HMS, the BWH Pathology Core and J Reyes, SH Davis, KW Karhohs, G Lahav, G Berriz, J Muhlich, E Williams, D Wrobel, R Benezra, A Bradley, MW Covert, J Goedhart, A Miyawaki, C Shamu, NS Gray, C Yoon, LN Kwong, GM Murphy, and C Lian for reagents and assistance. NR 61 TC 1 Z9 1 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1744-4292 J9 MOL SYST BIOL JI Mol. Syst. Biol. PD JAN PY 2017 VL 13 IS 1 AR 905 DI 10.15252/msb.20166796 PG 24 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EK5QK UT WOS:000393980700001 PM 28069687 ER PT J AU Zangabad, PS Karimi, M Mehdizadeh, F Malekzad, H Ghasemi, A Bahrami, S Zare, H Moghoofei, M Hekmatmanesh, A Hamblin, MR AF Zangabad, Parham Sahandi Karimi, Mahdi Mehdizadeh, Fatemeh Malekzad, Hedieh Ghasemi, Alireza Bahrami, Sajad Zare, Hossein Moghoofei, Mohsen Hekmatmanesh, Amin Hamblin, Michael R. TI Nanocaged platforms: modification, drug delivery and nanotoxicity. Opening synthetic cages to release the tiger SO NANOSCALE LA English DT Review ID VIRUS-LIKE PARTICLES; HEAT-SHOCK PROTEINS; MESOPOROUS SILICA NANOPARTICLES; COWPEA MOSAIC-VIRUS; HEPATITIS-B-VIRUS; NANOSCALE BUILDING-BLOCKS; PHASE-CHANGE MATERIALS; IN-VIVO APPLICATIONS; NEAR-INFRARED LIGHT; GOLD NANOCAGES AB Nanocages (NCs) have emerged as a new class of drug-carriers, with a wide range of possibilities in multi-modality medical treatments and theranostics. Nanocages can overcome such limitations as high toxicity caused by anti-cancer chemotherapy or by the nanocarrier itself, due to their unique characteristics. These properties consist of: (1) a high loading-capacity (spacious interior); (2) a porous structure (analogous to openings between the bars of the cage); (3) enabling smart release (a key to unlock the cage); and (4) a low likelihood of unfavorable immune responses (the outside of the cage is safe). In this review, we cover different classes of NC structures such as virus-like particles (VLPs), protein NCs, DNA NCs, supramolecular nanosystems, hybrid metal-organic NCs, gold NCs, carbon-based NCs and silica NCs. Moreover, NC-assisted drug delivery including modification methods, drug immobilization, active targeting, and stimulus-responsive release mechanisms are discussed, highlighting the advantages, disadvantages and challenges. Finally, translation of NCs into clinical applications, and an up-to-date assessment of the nanotoxicology considerations of NCs are presented. C1 [Karimi, Mahdi] Iran Univ Med Sci, Cellular & Mol Res Ctr, Tehran, Iran. [Karimi, Mahdi; Bahrami, Sajad] Iran Univ Med Sci, Fac Adv Technol Med, Dept Med Nanotechnol, Tehran, Iran. [Karimi, Mahdi; Hamblin, Michael R.] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. [Zangabad, Parham Sahandi] Tabriz Univ Med Sci TUOMS, RCPN, Tabriz, Iran. [Zangabad, Parham Sahandi; Malekzad, Hedieh] Iran Univ Med Sci, ANNRG, Tehran, Iran. [Zangabad, Parham Sahandi; Ghasemi, Alireza] Sharif Univ Technol, Dept Mat Sci & Engn, Tehran 113659466, Iran. [Zangabad, Parham Sahandi; Bahrami, Sajad] Univ Sci Educ & Res Network USERN, NRA, Tehran, Iran. [Mehdizadeh, Fatemeh] Univ Tabriz, Dept Appl Chem, Tabriz, Iran. [Zare, Hossein] Iran Univ Sci Technol, Mat Sci & Engn Dept, Biomat Grp, POB 1684613114, Tehran, Iran. [Moghoofei, Mohsen] Iran Univ Med Sci, Dept Virol, Fac Med, Tehran, Iran. [Hekmatmanesh, Amin] Lappeenranta Univ Technol, Laboratory Intelligent Machines, Lappeenranta, Finland. [Hamblin, Michael R.] Harvard Med Sch, Dept Dermatol, Boston, MA 02115 USA. [Hamblin, Michael R.] Harvard MIT, Div Hlth Sci & Technol, Cambridge, MA 02139 USA. RP Karimi, M (reprint author), Iran Univ Med Sci, Cellular & Mol Res Ctr, Tehran, Iran.; Karimi, M (reprint author), Iran Univ Med Sci, Fac Adv Technol Med, Dept Med Nanotechnol, Tehran, Iran.; Karimi, M; Hamblin, MR (reprint author), Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA.; Hamblin, MR (reprint author), Harvard Med Sch, Dept Dermatol, Boston, MA 02115 USA.; Hamblin, MR (reprint author), Harvard MIT, Div Hlth Sci & Technol, Cambridge, MA 02139 USA. EM m_karimy2006@yahoo.com; Hamblin@helix.mgh.harvard.edu FU US NIH [R01AI050875] FX MRH was supported by US NIH grant R01AI050875. NR 382 TC 0 Z9 0 U1 3 U2 3 PU ROYAL SOC CHEMISTRY PI CAMBRIDGE PA THOMAS GRAHAM HOUSE, SCIENCE PARK, MILTON RD, CAMBRIDGE CB4 0WF, CAMBS, ENGLAND SN 2040-3364 EI 2040-3372 J9 NANOSCALE JI Nanoscale PY 2017 VL 9 IS 4 BP 1356 EP 1392 DI 10.1039/c6nr07315h PG 37 WC Chemistry, Multidisciplinary; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary; Physics, Applied SC Chemistry; Science & Technology - Other Topics; Materials Science; Physics GA EM6KZ UT WOS:000395422800002 ER PT J AU Song, WW Dai, MH Xuan, LH Cao, ZJ Zhou, SS Lang, C Lv, K Xu, MS Kong, J AF Song, Wenwen Dai, Minhui Xuan, Lihua Cao, Zhijian Zhou, Sisi Lang, Courtney Lv, Kun Xu, Maosheng Kong, Jian TI Sensorimotor Cortical Neuroplasticity in the Early Stage of Bell's Palsy SO NEURAL PLASTICITY LA English DT Article ID PRIMARY MOTOR CORTEX; PHANTOM LIMB PAIN; LOW-BACK-PAIN; FUNCTIONAL CONNECTIVITY; BRAIN PLASTICITY; FACIAL PALSY; RECOVERY; STROKE; REORGANIZATION; FMRI AB Neuroplasticity is a common phenomenon in the human brain following nerve injury. It is defined as the brain's ability to reorganize by creating new neural pathways in order to adapt to change. Here, we use task-related and resting-state fMRI to investigate neuroplasticity in the primary sensory (S1) andmotor cortex (M1) in patients with acute Bell's palsy (BP). We found that the period directly following the onset of BP (less than 14 days) is associated with significant decreases in regional homogeneity (ReHo), fractional amplitude of low frequency fluctuations (fALFF), and intrinsic connectivity contrast (ICC) values in the contralateral S1/M1 and in ReHo and ICC values in the ipsilateral S1/M1, compared to healthy controls. The regions with decreased ReHo, fALFF, and ICC values were in both the face and hand region of S1/M1 as indicated by resting-state fMRI but not task-related fMRI. Our results suggest that the early stages of BP are associated with functional neuroplasticity in both the face and hand regions of S1/M1 and that resting-state functional fMRI may be a sensitive tool to detect these early stages of plasticity in patient populations. C1 [Song, Wenwen; Dai, Minhui; Xuan, Lihua; Cao, Zhijian; Zhou, Sisi; Lv, Kun; Xu, Maosheng] Zhejiang Chinese Med Univ, Affiliated Hosp 1, Hangzhou, Zhejiang, Peoples R China. [Song, Wenwen; Lang, Courtney; Kong, Jian] Massachusetts Gen Hosp, Dept Psychiat, Charlestown, MA 02129 USA. [Song, Wenwen; Lang, Courtney; Kong, Jian] Harvard Med Sch, Charlestown, MA 02129 USA. RP Xu, MS (reprint author), Zhejiang Chinese Med Univ, Affiliated Hosp 1, Hangzhou, Zhejiang, Peoples R China.; Kong, J (reprint author), Massachusetts Gen Hosp, Dept Psychiat, Charlestown, MA 02129 USA. EM xums166@zcmu.edu.cn; jkong2@mgh.harvard.edu FU Construction Funds of Key Subjects of Colleges and Universities in Zhejiang Province [ZJGK2012-80-160]; NIH/NCCIH [R01AT006364, R01 AT008563, R21AT008707, P01 AT006663] FX The study is supported by the Construction Funds of Key Subjects of Colleges and Universities in Zhejiang Province [Grant no. ZJGK2012-80-160]. Jian Kong is supported by R01AT006364, R01 AT008563, R21AT008707, and P01 AT006663 from NIH/NCCIH. NR 53 TC 0 Z9 0 U1 1 U2 1 PU HINDAWI LTD PI LONDON PA ADAM HOUSE, 3RD FLR, 1 FITZROY SQ, LONDON, WIT 5HE, ENGLAND SN 2090-5904 EI 1687-5443 J9 NEURAL PLAST JI Neural. Plast. PY 2017 AR 8796239 DI 10.1155/2017/8796239 PG 8 WC Neurosciences SC Neurosciences & Neurology GA EN7NY UT WOS:000396190700001 ER PT J AU Love, MN Clark, DG Cochran, JN Den Beste, KA Geldmacher, DS Benzinger, TL Gordon, BA Morris, JC Bateman, RJ Roberson, ED AF Love, Marissa Natelson Clark, David G. Cochran, J. Nicholas Den Beste, Kyle A. Geldmacher, David S. Benzinger, Tammie L. Gordon, Brian A. Morris, John C. Bateman, Randall J. Roberson, Erik D. TI Clinical, imaging, pathological, and biochemical characterization of a novel presenilin 1 mutation (N135Y) causing Alzheimer's disease SO NEUROBIOLOGY OF AGING LA English DT Article DE Alzheimer's disease; Presenilin 1; PET scan; Elecrtoencephalography ID MISSENSE MUTATIONS; IN-VIVO; ONSET; GENE; BETA; MICE; A-BETA-42; MECHANISM; MRI; PET AB We present 2 cases of early-onset Alzheimer's disease due to a novel N135Y mutation in PSEN1. The proband presented with memory and other cognitive symptoms at age 32. Detailed clinical characterization revealed initial deficits in memory with associated dysarthria, progressing to involve executive dysfunction, spastic gait, and episodic confusion with polyspike discharges on long-term electroencephalography. Amyloid-and FDG-PET scans showed typical results of Alzheimer's disease. By history, the proband's father had developed cognitive symptoms at age 42 and died at age 48. Neuropathological evaluation confirmed Alzheimer's disease, with moderate to severe amyloid angiopathy. Skeletal muscle showed type 2 fiberepredominant atrophy with pale central clearing. Genetic testing of the proband revealed an N135Y missense mutation in PSEN1. This mutation was predicted to be pathogenic by in silico analysis. Biochemical analysis confirmed that the mutation caused an increased Ab42/Ab40 ratio, consistent with other PSEN1 mutations and with a loss of presenilin function. Published by Elsevier Inc. C1 [Love, Marissa Natelson; Clark, David G.; Geldmacher, David S.; Roberson, Erik D.] Univ Alabama Birmingham, Alzheimers Dis Ctr, Birmingham, AL USA. [Love, Marissa Natelson; Clark, David G.; Cochran, J. Nicholas; Den Beste, Kyle A.; Geldmacher, David S.; Roberson, Erik D.] Univ Alabama Birmingham, Dept Neurol, UAB Stn, Birmingham, AL 35294 USA. [Love, Marissa Natelson; Clark, David G.] Birmingham VA Med Ctr, Dept Neurol, Birmingham, AL USA. [Clark, David G.] Med Univ South Carolina, Ralph H Johnson VA Med Ctr, Dept Neurol, Charleston, SC USA. [Cochran, J. Nicholas; Den Beste, Kyle A.; Roberson, Erik D.] Univ Alabama Birmingham, Ctr Neurodegenerat & Expt Therapeut, Birmingham, AL USA. [Geldmacher, David S.; Roberson, Erik D.] Univ Alabama Birmingham, McKnight Brain Inst, Birmingham, AL USA. [Benzinger, Tammie L.; Gordon, Brian A.; Morris, John C.; Bateman, Randall J.] Washington Univ, Sch Med, Dept Neurol, Dominantly Inherited Alzheimers Network, St Louis, MO 63110 USA. [Benzinger, Tammie L.; Gordon, Brian A.] Washington Univ, Mallinckrodt Inst Radiol, Sch Med, St Louis, MO USA. RP Clark, DG (reprint author), 96 Jonathan Lucas St,301 CSB MSC 606, Charleston, SC 29425 USA. EM clarkda@musc.edu FU National Institutes of Health [R01NS075487, U19AG032438, U-01-AG042791]; National Institute on Aging [U19AG032438]; Veterans Administration [E6553W] FX This research was supported by the National Institutes of Health (R01NS075487, U19AG032438, and U-01-AG042791), the National Institute on Aging (U19AG032438), and the Veterans Administration (E6553W). NR 37 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-4580 EI 1558-1497 J9 NEUROBIOL AGING JI Neurobiol. Aging PD JAN PY 2017 VL 49 AR 216.e7 DI 10.1016/j.neurobiolaging.2016.09.020 PG 7 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA EK5PG UT WOS:000393977700028 ER PT J AU Wang, DW Yuan, XB Hu, CY Zhang, B Gao, HF Wang, D Chi, JJ Jing, Q Wu, SL Wu, CL AF Wang, Dongwen Yuan, Xiaobin Hu, Caoyang Zhang, Bin Gao, Hongfei Wang, Dong Chi, Junjie Jing, Qiang Wu, Shulin Wu, Chin-Lee TI Endoplasmic Reticulum Stress Is Involved in Apoptosis of Detrusor Muscle in Streptozocin-Induced Diabetic Rats SO NEUROUROLOGY AND URODYNAMICS LA English DT Article DE apoptosis; diabetic cystopathy; endoplasmic reticulum stress ID UNFOLDED PROTEIN RESPONSE; DORSAL-ROOT GANGLIA; BLADDER DYSFUNCTION; OXIDATIVE STRESS; CELL-DEATH; KIDNEY-DISEASE; SMOOTH-MUSCLE; ER STRESS; CYSTOPATHY; CASPASE-12 AB Aims: Endoplasmic reticulum stress (ERS) has been proven to be associated with apoptosis and plays a critical role in the development of many diabetic complications. In the pathogenesis of diabetic cystopathy (DCP), the role of ERS is still unclear. Our study is aimed at the investigation of the involvement of ERS-associated detrusor muscle apoptosis in streptozocin (STZ)-induced diabetic rats. Methods: At different timepoints (4, 8, 12, and 16 weeks after induction of type 1 diabetic rat models), hematoxylin & eosin (H&E) staining was performed to assess the histological changes of the diabetic detrusor; the sub-cellular ultrastructure, especially the zone of endoplasmic reticulum (ER), was observed by transmission electron microscopy (TEM), and the terminal deoxynucleotidyl transferase-mediated DNA nick-end labeling (TUNEL) staining was used to identify the enhanced apoptosis. Moreover, the expression of three hallmarks of ERS-associated apoptosis, including glucose-regulated protein 78 (GRP78), CCAAT/enhancer-binding protein homologous protein (CHOP), and caspase12, was detected by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot. Results: Light microscopic impairments of histology, including progressive loosely packed muscle bundles and increased fibrous tissue, can be seen; the ultrastructural changes featuring the swollen and fused cisternaes in ER zone and deformed nucleus were also observed in the detrusor smooth muscle (DSM). Increased apoptosis and elevated expression of GRP78, CHOP, and caspase12 at both protein and mRNA levels in a time-dependent fashion were detected. Conclusions: The occurrence of ERS-associated apoptosis may be involved in the development of DCP and may contribute to the diabetic detrusor impairment. (C) 2015 Wiley Periodicals, Inc. C1 [Wang, Dongwen; Yuan, Xiaobin; Hu, Caoyang; Zhang, Bin; Gao, Hongfei; Wang, Dong; Chi, Junjie; Jing, Qiang] Shanxi Med Univ, Coll Clin Med 1, Taiyuan, Shanxi, Peoples R China. [Wang, Dongwen; Yuan, Xiaobin; Hu, Caoyang; Zhang, Bin; Gao, Hongfei; Wang, Dong; Chi, Junjie; Jing, Qiang] Shanxi Med Univ, Hosp 1, Dept Urol, 56 Xinjiannan Rd, Taiyuan 030001, Shanxi, Peoples R China. [Wu, Chin-Lee] Harvard Med Sch, Massachusetts Gen Hosp, Dept Urol, Boston, MA USA. [Wu, Shulin; Wu, Chin-Lee] Harvard Med Sch, Massachusetts Gen Hosp, Dept Pathol, Boston, MA USA. RP Wang, DW (reprint author), Shanxi Med Univ, Hosp 1, Dept Urol, 56 Xinjiannan Rd, Taiyuan 030001, Shanxi, Peoples R China. EM urology2007@126.com FU Natural Science Foundation of China [81370861]; Excellent Doctoral Foundation of Shanxi Provincial Education Ministry [20133070] FX Grant sponsor: Natural Science Foundation of China; Grant number: 81370861; Grant sponsor: Excellent Doctoral Foundation of Shanxi Provincial Education Ministry; Grant number: 20133070 NR 53 TC 1 Z9 1 U1 3 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0733-2467 EI 1520-6777 J9 NEUROUROL URODYNAM JI Neurourol. Urodyn. PD JAN PY 2017 VL 36 IS 1 BP 65 EP 72 DI 10.1002/nau.22886 PG 8 WC Urology & Nephrology SC Urology & Nephrology GA EL5MZ UT WOS:000394666500009 PM 26370333 ER PT J AU Markland, AD Burgio, KL Beasley, TM David, SL Redden, DT Goode, PS AF Markland, Alayne D. Burgio, Kathryn L. Beasley, T. Mark David, Shannon L. Redden, David T. Goode, Patricia S. TI Psychometric Evaluation of an Online and Paper Accidental Bowel Leakage Questionnaire: The ICIQ-B Questionnaire SO NEUROUROLOGY AND URODYNAMICS LA English DT Article DE accidental bowel leakage; fecal incontinence; functional bowel disorders; psychometric evaluation; quality of life; questionnaire ID QUALITY-OF-LIFE; FORM HEALTH SURVEY; FECAL INCONTINENCE; ANAL INCONTINENCE; CONCEPTUAL-FRAMEWORK; SEVERITY; PATIENT; SYMPTOM; EPIDEMIOLOGY; RELIABILITY AB Aims: To evaluate the psychometric properties of an online versus paper US-English version of the International Consultation on Incontinence Questionnaire-Bowel (ICIQ-B). Methods: The ICIQ-B includes 17 items under 3 domains: bowel pattern (5 items), bowel control (7 items), and quality of life (5 items). We recruited community-dwelling adults seeking treatment for >= monthly bowel leakage from specialty clinics within a VA medical center and university affiliate. An online versus paper version was evaluated at baseline, 2 weeks later, and 3 months after nonsurgical treatments per usual care. We assessed test-retest reliability (Pearson correlations) at 2 weeks, internal consistency (Cronbach's alpha), and convergent validity (Pearson correlations). Sensitivity to change was the difference between the baseline and post-treatment (3-month) scores. Results: Mean age was 58.0 +/- 11.9; 36% Veterans, 52% women. At baseline, 2 weeks, and 3 months, we found no differences in the online vs paper scores for the bowel control and quality of life domains. The ICIQ-B demonstrated fair internal consistency for the bowel pattern domain (Cronbach's alpha = 0.36-0.54). Internal consistency on the bowel pattern domain was better with the paper version than the online version at 2 weeks (P<0.05) and 3 months (P<0.01) with no difference at baseline. All other domains had good internal consistency (Cronbach's alpha>0.80), good retest reliability (r >= 0.70, P<0.001), domain-specific convergent validity for stool consistency (P<0.05), incontinence severity (P <= 0.002), and quality of life impact (P<0.05). After nonsurgical treatments, we found a reasonable response to change (P <= 0.05). Conclusions: Online and paper versions had robust psychometric data for use among U.S. men and women, including Veterans. (C) 2015 Wiley Periodicals, Inc. C1 [Markland, Alayne D.; Burgio, Kathryn L.; Beasley, T. Mark; Goode, Patricia S.] Univ Alabama Birmingham, Med Ctr, Birmingham Dept Vet Affairs, Birmingham Atlanta Geriatr Res Educ & Clin Ctr, Birmingham, AL 35294 USA. [Markland, Alayne D.; Burgio, Kathryn L.; Goode, Patricia S.] Univ Alabama Birmingham, Dept Med, Div Gerontol Geriatr & Palliat Care, Birmingham, AL 35294 USA. [Beasley, T. Mark; Redden, David T.] Univ Alabama Birmingham, Sch Publ Hlth, Dept Biostat, Birmingham, AL 35294 USA. [David, Shannon L.] North Dakota State Univ, Dept Hlth Nutr & Exercise Sci, Fargo, ND USA. RP Markland, AD (reprint author), Birmingham VA Med Ctr, Div Gerontol Geriatr & Palliat Care, UAB Dept Med, GRECC 11-G,900 South 18th St, Birmingham, AL 35233 USA. EM amarkland@aging.uab.edu FU Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development [I01 RX000315-01] FX Grant sponsor: Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development; Grant number: I01 RX000315-01 NR 24 TC 1 Z9 1 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0733-2467 EI 1520-6777 J9 NEUROUROL URODYNAM JI Neurourol. Urodyn. PD JAN PY 2017 VL 36 IS 1 BP 166 EP 170 DI 10.1002/nau.22905 PG 5 WC Urology & Nephrology SC Urology & Nephrology GA EL5MZ UT WOS:000394666500026 PM 26473313 ER PT J AU Brody, AL Zorick, T Hubert, R Hellemann, GS Balali, S Kawasaki, SS Garcia, LY Enoki, R Abraham, P Young, P McCreary, C AF Brody, Arthur L. Zorick, Todd Hubert, Robert Hellemann, Gerhard S. Balali, Shabnam Kawasaki, Sarah S. Garcia, Lizette Y. Enoki, Ryutaro Abraham, Paul Young, Paulina McCreary, Charles TI Combination Extended Smoking Cessation Treatment Plus Home Visits for Smokers With Schizophrenia: A Randomized Controlled Trial SO NICOTINE & TOBACCO RESEARCH LA English DT Article ID NICOTINE REPLACEMENT THERAPY; SUSTAINED-RELEASE BUPROPION; PSYCHIATRIC RATING-SCALE; FAGERSTROM-TEST; MENTAL-ILLNESS; CLINICAL-TRIAL; CIGARETTE-SMOKING; BIPOLAR DISORDER; ATYPICAL ANTIPSYCHOTICS; TRANSDERMAL NICOTINE AB Introduction: The majority of people with schizophrenia have a diagnosis of tobacco dependence during their lifetime. A major obstacle to reducing the burden of cigarette smoking in this population is that these smokers have lower quit rates when undergoing standard treatment compared to smokers with no mental illness. We sought to determine if combination extended treatment (COMBEXT) and home visits (HV) would lead to improved outcomes in smokers with schizophrenia. Methods: Thirty-four cigarette smokers with schizophrenia completed either COMB-EXT with HV, COMB-EXT without HV, or treatment as usual (TAU) (random assignment). COMB-EXT consisted of group cognitive-behavioral therapy (CBT), bupropion, nicotine patch, and nicotine lozenge, which were initiated within 2 weeks and continued for 26 weekly visits. HV consisted of biweekly visits to the home with assessment of secondhand smoke (SHS) exposure and brief behavioral therapy with participants and others in the home environment. TAU consisted of group CBT plus serial single or combination medication trials as per standard care. Results: Smokers with schizophrenia who received COMB-EXT (with or without HV) had greater reductions in cigarettes per day than those treated with TAU (both ps <.01). In addition, 7-day point prevalence abstinence rates for the three groups were 45%, 20%, and 8%, respectively, which was significantly higher for COMB-EXT plus HV than TAU (.2(1) = 4.8, p =.03). Groups did not differ significantly in the number of adverse events, and HV were easily scheduled. Conclusion: COMB-EXT improves outcomes for smokers with schizophrenia. HV appeared to provide additional benefit for smoking cessation in this treatment-resistant population. Implications: The clear benefit found here of rapidly initiated, combination, extended treatment over TAU suggests that aggressive and extended treatment should be considered in clinical practice for smokers with schizophrenia. Furthermore, HV to address SHS exposure showed initial promise for assisting smokers with schizophrenia in maintaining abstinence, indicating that this intervention may be worthy of future research. C1 [Brody, Arthur L.; Zorick, Todd; Hubert, Robert; Hellemann, Gerhard S.; Balali, Shabnam; Garcia, Lizette Y.; Enoki, Ryutaro; Abraham, Paul; Young, Paulina; McCreary, Charles] VA Greater Los Angeles Healthcare Syst, Dept Psychiat, Los Angeles, CA USA. [Brody, Arthur L.] Univ Calif San Diego, Dept Psychiat, 3350 La Jolla Village Dr 116A, San Diego, CA 92161 USA. [Kawasaki, Sarah S.] Hlth Care Homeless, Dept Primary Care, Baltimore, MD USA. RP Brody, AL (reprint author), Univ Calif San Diego, Dept Psychiat, 3350 La Jolla Village Dr 116A, San Diego, CA 92161 USA. EM abrody@ucsd.edu FU National Institute on Drug Abuse [R01 DA20872]; Department of Veterans Affairs Office of Research and Development (CSR&D Merit Review Award) [I01 CX000412]; Tobacco-Related Disease Research Program [23XT-0002] FX This work was supported by the National Institute on Drug Abuse (grant number R01 DA20872), the Department of Veterans Affairs Office of Research and Development (CSR&D Merit Review Award I01 CX000412), and the Tobacco-Related Disease Research Program (grant number #23XT-0002). The funders had no role in the design, conduct, or reporting of this study. NR 87 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1462-2203 EI 1469-994X J9 NICOTINE TOB RES JI Nicotine Tob. Res. PD JAN PY 2017 VL 19 IS 1 BP 68 EP 76 DI 10.1093/ntr/ntw190 PG 9 WC Substance Abuse; Public, Environmental & Occupational Health SC Substance Abuse; Public, Environmental & Occupational Health GA EP0DD UT WOS:000397056100009 PM 27613888 ER PT J AU Cruzat, A Qazi, Y Hamrah, P AF Cruzat, Andrea Qazi, Yureeda Hamrah, Pedram TI In Vivo Confocal Microscopy of Corneal Nerves in Health and Disease SO OCULAR SURFACE LA English DT Article DE corneal dystrophies; corneal nerves; corneal sensitivity; corneal surgery; diabetes; keratoconus; in vivo confocal microscopy; pain; peripheral neuropathy ID COLLAGEN CROSS-LINKING; DRY EYE DISEASE; DIABETIC PERIPHERAL NEUROPATHY; CONTACT-LENS WEAR; ANTERIOR LAMELLAR KERATOPLASTY; LASER-SCANNING MICROSCOPY; FUCHS ENDOTHELIAL DYSTROPHY; BASEMENT-MEMBRANE DYSTROPHY; HERPES-ZOSTER OPHTHALMICUS; REFLECTED-LIGHT MICROSCOPE AB In vivo confocal microscopy (IVCM) is becoming an indispensable tool for studying corneal physiology and disease. Enabling the dissection of corneal architecture at a cellular level, this technique offers fast and noninvasive in vivo imaging of the cornea with images comparable to those of ex vivo histochemical techniques. Corneal nerves bear substantial relevance to clinicians and scientists alike, given their pivotal roles in regulation of corneal sensation, maintenance of epithelial integrity, as well as proliferation and promotion of wound healing. Thus, IVCM offers a unique method to study corneal nerve alterations in a myriad of conditions, such as ocular and systemic diseases and following corneal surgery, without altering the tissue microenvironment. Of particular interest has been the correlation of corneal subbasal nerves to their function, which has been studied in normal eyes, contact lens wearers, and patients with keratoconus, infectious keratitis, corneal dystrophies, and neurotrophic keratopathy. Longitudinal studies have applied IVCM to investigate the effects of corneal surgery on nerves, demonstrating their regenerative capacity. IVCM is increasingly important in the diagnosis and management of systemic conditions such as peripheral diabetic neuropathy and, more recently, in ocular diseases. In this review, we outline the principles and applications of IVCM in the study of corneal nerves in various ocular and systemic diseases. C1 [Cruzat, Andrea; Qazi, Yureeda; Hamrah, Pedram] Harvard Med Sch, Dept Ophthalmol, Massachusetts Eye & Ear Infirm, Cornea & Refract Surg Serv, Boston, MA USA. [Cruzat, Andrea] Pontificia Univ Catolica Chile, Dept Ophthalmol, Santiago, Chile. [Hamrah, Pedram] Tufts Univ, Sch Med, Tufts Med Ctr, Boston Image Reading Ctr, Boston, MA 02111 USA. [Hamrah, Pedram] Tufts Univ, Sch Med, Tufts Med Ctr, Cornea Serv,New England Eye Ctr,Dept Ophthalmol, Boston, MA 02111 USA. RP Hamrah, P (reprint author), Tufts Med Ctr, Dept Ophthalmol, Boston, MA 02111 USA. EM Pedram.hamrah@tufts.edu FU NIH [R01-EY022695, R21-EY025393]; Falk Medical Research Foundation; Research to Prevent Blindness FX Financial Support: NIH R01-EY022695 (PH), NIH R21-EY025393 (PH), Falk Medical Research Foundation (PH), and a Career Development Award from Research to Prevent Blindness (PH). The funding organizations had no role in the design or conduct of this work. NR 359 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1542-0124 EI 1937-5913 J9 OCUL SURF JI Ocul. Surf. PD JAN PY 2017 VL 15 IS 1 BP 15 EP 47 PG 33 WC Ophthalmology SC Ophthalmology GA EO0RD UT WOS:000396404700003 PM 27771327 ER PT J AU Hamrah, P Qazi, Y Shahatit, B Dastjerdi, MH Pavan-Langston, D Jacobs, DS Rosenthal, P AF Hamrah, Pedram Qazi, Yureeda Shahatit, Bashar Dastjerdi, Mohammad H. Pavan-Langston, Deborah Jacobs, Deborah S. Rosenthal, Perry TI Corneal Nerve and Epithelial Cell Alterations in Corneal Allodynia: An In Vivo Confocal Microscopy Case Series SO OCULAR SURFACE LA English DT Article DE confocal microscopy; corneal allodynia; epithelial cells; in vivo confocal microscopy; nerve ID DRY EYE DISEASE; LASER-SCANNING MICROSCOPY; OPTICAL COHERENCE TOMOGRAPHY; HERPES-ZOSTER OPHTHALMICUS; PRIMARY SJOGRENS-SYNDROME; VERSUS-HOST-DISEASE; NEUROPATHIC PAIN; OCULAR SURFACE; ULTRASOUND BIOMICROSCOPY; NEURONAL PLASTICITY AB Purpose: To investigate morphological changes of the corneal epithelium and subbasal nerves in patients with corneal allodynia using in vivo confocal microscopy (IVCM). Design: Case-control study of patients with corneal allodynia and healthy controls. Methods: Ten eyes of six patients were diagnosed with corneal allodynia at a single center and compared to fifteen healthy eyes. IVCM of the central cornea was performed on all subjects and controls. Images were retrospectively analyzed numbers of total corneal subbasal nerves, main trunks and branches, total nerve length and density, nerve branching, and tortuosity, superficial and basal epithelial cell densities, and superficial epithelial cell size. Results: Corneal allodynia was seen in patients with dry eye disease, recurrent corneal erosion syndrome, exposure to ultraviolet radiation, and Accutane use. Compared to controls, patients with corneal allodynia had a significant decrease in the total numbers of subbasal nerves (P=.014), nerve branches (P=.006), total nerve length (P=.0029), total nerve density (P=.0029) and superficial and basal epithelial cell densities (P=.0004, P=.0036) with an increase in superficial epithelial cell size (P=.016). There were no statistically significant differences in the number of subbasal nerve main trunks (P=.09), nerve branching (P=.21), and nerve tortuosity (P=.05). Conclusions: Corneal IVCM enables near-histological visualization and quantification of the cellular and neural changes in corneal allodynia. Regardless of etiology, corneal allodynia is associated with decreased corneal epithelial cell densities, increased epithelial cell size, and decreased numbers and lengths of subbasal nerves despite an unremarkable slit-lamp examination. Therefore, IVCM may be useful in the management of patients with corneal allodynia. C1 [Hamrah, Pedram] Tufts Univ Sch Med, Tufts Med Ctr, Boston Image Reading Ctr, Boston, MA USA. [Hamrah, Pedram] Tufts Univ Sch Med, Tufts Med Ctr, New England Eye Ctr, Dept Ophthalmol,Cornea Serv, Boston, MA USA. [Hamrah, Pedram; Qazi, Yureeda; Shahatit, Bashar] Harvard Med Sch, Ocular Surface Imaging Ctr, Boston, MA USA. [Hamrah, Pedram; Dastjerdi, Mohammad H.; Pavan-Langston, Deborah; Jacobs, Deborah S.] Harvard Med Sch, Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Cornea & Refract Surg Serv, Boston, MA USA. [Jacobs, Deborah S.] Boston Fdn Sight, Needham, MA USA. [Rosenthal, Perry] Boston Eye Pain Fdn, Chestnut Hill, MA USA. RP Hamrah, P (reprint author), Tufts Univ Sch Med, New England Eye Ctr, Tufts Med Ctr, FACS, 800 Washington St, Boston, MA 02111 USA. EM pedram.hamrah@tufts.edu NR 112 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1542-0124 EI 1937-5913 J9 OCUL SURF JI Ocul. Surf. PD JAN PY 2017 VL 15 IS 1 BP 139 EP 151 PG 13 WC Ophthalmology SC Ophthalmology GA EO0RD UT WOS:000396404700011 PM 27816571 ER PT J AU Yuan, HF He, ML Cheng, F Bai, R da Silva, SR Aguiar, RCT Gao, SJ AF Yuan, Hongfeng He, Meilan Cheng, Fan Bai, Rosemary da Silva, Suzane Ramos Aguiar, Ricardo C. T. Gao, Shou-Jiang TI Tenovin-6 inhibits proliferation and survival of diffuse large B-cell lymphoma cells by blocking autophagy SO ONCOTARGET LA English DT Article DE tenovin-6; diffuse large B-cell lymphoma; autophagy; sirtuins; p53 ID CHRONIC LYMPHOCYTIC-LEUKEMIA; STEM-CELLS; LYSOSOME FUSION; CANCER-THERAPY; C-MYC; ACTIVATION; SIRT1; P53; APOPTOSIS; DEATH AB Diffuse large B-cell lymphoma (DLBCL) is one of the most aggressive non-Hodgkin lymphomas. It is curable but one-third of cases are refractory to therapy or relapse after initial response highlighting the urgent need for developing novel therapeutic approaches. Targeting sirtuins, particularly SIRT1 by genetic approaches or using pharmaceutical inhibitor tenovin-6, has shown promising therapeutic potential in various hematopoietic malignancies. However, it remains unknown whether these approaches are effective for DLBCL. In this study, we have found that tenovin-6 potently inhibits the proliferation and survival of DLBCL cells. Surprisingly, specific knockdown of SIRT1/2/3 has no effect on DLBCL. Mechanistically, tenovin-6 increases the level of microtubule-associated protein 1 light chain 3B (LC3B)-II in a SIRT1/2/3- and p53-independent manner in DLBCL cell lines. Tenovin-6-mediated increase of LC3B-II is through inhibition of classical autophagy pathway. Furthermore, inhibition of the autophagy pathway by using other inhibitors or by knocking down key genes in the pathway impairs cell proliferation and survival of DLBCL cells. These results indicate that targeting the autophagic pathway could be a novel therapeutic strategy for DLBCL and that precaution should be taken to interpret data where tenovin-6 was used as an inhibitor of sirtuins. C1 [Yuan, Hongfeng; He, Meilan; Cheng, Fan; Bai, Rosemary; da Silva, Suzane Ramos; Gao, Shou-Jiang] Univ Southern Calif, Keck Sch Med, Dept Mol Microbiol & Immunol, Los Angeles, CA USA. [Aguiar, Ricardo C. T.] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA. [Aguiar, Ricardo C. T.] Univ Texas Hlth Sci Ctr San Antonio, Canc Therapy & Res Ctr, San Antonio, TX 78229 USA. [Aguiar, Ricardo C. T.] South Texas Vet Hlth Care Syst, Audie Murphy VA Hosp, San Antonio, TX USA. RP Gao, SJ (reprint author), Univ Southern Calif, Keck Sch Med, Dept Mol Microbiol & Immunol, Los Angeles, CA USA. EM shoujiag@usc.edu FU NIH [CA096512, CA124332, CA132637, CA177377, CA213275, DE025465, CA197153]; CPRIT [RP140452, RP150277]; VA Merit Award [I01-BX001882] FX This work was supported by grants from NIH (CA096512, CA124332, CA132637, CA177377, CA213275, DE025465 and CA197153) to S-J Gao; RCT Aguiar was supported by grants from the CPRIT (RP140452 and RP150277) and a VA Merit Award (I01-BX001882). NR 64 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 9 BP 14912 EP 14924 DI 10.18632/oncotarget.14741 PG 13 WC Oncology; Cell Biology SC Oncology; Cell Biology GA EN4YV UT WOS:000396013700057 ER PT J AU Chae, YK Ranganath, K Hammerman, PS Vaklavas, C Mohindra, N Kalyan, A Matsangou, M Costa, R Carneiro, B Villaflor, VM Cristofanilli, M Giles, FJ AF Chae, Young Kwang Ranganath, Keerthi Hammerman, Peter S. Vaklavas, Christos Mohindra, Nisha Kalyan, Aparna Matsangou, Maria Costa, Ricardo Carneiro, Benedito Villaflor, Victoria M. Cristofanilli, Massimo Giles, Francis J. TI Inhibition of the fibroblast growth factor receptor (FGFR) pathway: the current landscape and barriers to clinical application SO ONCOTARGET LA English DT Review DE fibroblast growth factor receptor inhibition ID CELL LUNG-CANCER; ADVANCED SOLID TUMORS; TYROSINE KINASE INHIBITORS; I DOSE-ESCALATION; 8P11 MYELOPROLIFERATIVE SYNDROME; ADVANCED UROTHELIAL CARCINOMA; POTENT ANTITUMOR-ACTIVITY; T(4/14) MULTIPLE-MYELOMA; GENE COPY NUMBER; ACQUIRED-RESISTANCE AB The fibroblast growth factor/fibroblast growth factor receptor (FGF/FGFR) is a tyrosine kinase signaling pathway that has a fundamental role in many biologic processes including embryonic development, tissue regeneration, and angiogenesis. Increasing evidence indicates that this pathway plays a critical role in oncogenesis via gene amplification, activating mutations, or translocation in tumors of various histologies. With multiplex sequencing technology, the detection of FGFR aberrations has become more common and is tied to cancer cell proliferation, resistance to anticancer therapies, and neoangiogenesis. Inhibition of FGFR signaling appears promising in preclinical studies, suggesting a pathway of clinical interest in the development of targeted therapy. Phase I trials have demonstrated a manageable toxicity profile. Currently, there are multiple FGFR inhibitors under study with many non-selective (multi-kinase) inhibitors demonstrating limited clinical responses. As we progress from the first generation of non-selective drugs to the second generation of selective FGFR inhibitors, it is clear that FGFR aberrations do not behave uniformly across cancer types; thus, a deeper understanding of biomarker strategies is undoubtedly warranted. This review aims to consolidate data from recent clinical trials with a focus on selective FGFR inhibitors. As Phase II clinical trials emerge, concentration on patient selection as it pertains to predicting response to therapy, feasible methods for overcoming toxicity, and the likelihood of combination therapies should be utilized. We will also discuss qualities that may be desirable in future generations of FGFR inhibitors, with the hope that overcoming these current barriers will expedite the availability of this novel class of medications. C1 [Chae, Young Kwang; Mohindra, Nisha; Kalyan, Aparna; Matsangou, Maria; Costa, Ricardo; Carneiro, Benedito; Villaflor, Victoria M.; Cristofanilli, Massimo; Giles, Francis J.] Div Hematol Oncol, Dev Therapeut Program, Chicago, IL 60612 USA. [Chae, Young Kwang; Mohindra, Nisha; Kalyan, Aparna; Matsangou, Maria; Carneiro, Benedito; Villaflor, Victoria M.; Cristofanilli, Massimo; Giles, Francis J.] Northwestern Univ, Robert H Lurie Comprehens Canc Ctr, Chicago, IL 60611 USA. [Chae, Young Kwang; Ranganath, Keerthi; Mohindra, Nisha; Kalyan, Aparna; Matsangou, Maria; Carneiro, Benedito; Villaflor, Victoria M.; Cristofanilli, Massimo; Giles, Francis J.] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Hammerman, Peter S.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Vaklavas, Christos] Univ Alabama Birmingham, Div Hematol Oncol, Birmingham, AL 35294 USA. RP Chae, YK (reprint author), Div Hematol Oncol, Dev Therapeut Program, Chicago, IL 60612 USA.; Chae, YK (reprint author), Northwestern Univ, Robert H Lurie Comprehens Canc Ctr, Chicago, IL 60611 USA.; Chae, YK (reprint author), Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. EM young.chae@northwestern.edu NR 146 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 9 BP 16052 EP 16074 DI 10.18632/oncotarget.14109 PG 23 WC Oncology; Cell Biology SC Oncology; Cell Biology GA EN4YV UT WOS:000396013700148 ER PT J AU Mereu, E Pellegrino, E Scarfo, I Inghirami, G Piva, R AF Mereu, Elisabetta Pellegrino, Elisa Scarfo, Irene Inghirami, Giorgio Piva, Roberto TI The heterogeneous landscape of ALK negative ALCL SO ONCOTARGET LA English DT Review DE anaplastic large cell lymphoma; molecular classification; therapy; ALK negative ID LARGE-CELL LYMPHOMA; PERIPHERAL T-CELL; GENE-EXPRESSION ANALYSIS; BRENTUXIMAB VEDOTIN SGN-35; REED-STERNBERG CELLS; ANAPLASTIC LYMPHOMA; KINASE-ACTIVITY; STAT3 ACTIVATION; HODGKINS-DISEASE; CANCER AB Anaplastic Large Cell Lymphoma (ALCL) is a clinical and biological heterogeneous disease including systemic ALK positive and ALK negative entities. Whereas ALK positive ALCLs are molecularly characterized and readily diagnosed, specific immunophenotypic or genetic features to define ALK negative ALCL are missing, and their distinction from other T-cell non-Hodgkin lymphomas (T-NHLs) can be controversial. In recent years, great advances have been made in dissecting the heterogeneity of ALK negative ALCLs and in providing new diagnostic and treatment options for these patients. A new revision of the World Health Organization (WHO) classification promoted ALK negative ALCL to a definite entity that includes cytogenetic subsets with prognostic implications. However, a further understanding of the genetic landscape of ALK negative ALCL is required to dictate more effective therapeutic strategies specifically tailored for each subgroup of patients. C1 [Mereu, Elisabetta; Pellegrino, Elisa; Inghirami, Giorgio; Piva, Roberto] Univ Torino, Dept Mol Biotechnol & Hlth Sci, Ctr Expt Res & Med Studies, Turin, Italy. [Scarfo, Irene] Harvard Med Sch, Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. [Inghirami, Giorgio] Weill Cornell Med Coll, Dept Pathol & Lab Med, New York, NY USA. RP Piva, R (reprint author), Univ Torino, Dept Mol Biotechnol & Hlth Sci, Ctr Expt Res & Med Studies, Turin, Italy. EM roberto.piva@unito.it FU Investigator Grant [IG-13358]; Special Program Molecular Clinical Oncology [5 x 1000, 10007]; Associazione Italiana per la Ricerca sul Cancro (AIRC), Milan, Italy [TO_Call2_2012_0061]; Compagnia di San Paolo, Turin, Italy [2014_1105]; Fondazione CRT, Turin, Italy FX This work has been supported by: Investigator Grant IG-13358 and Special Program Molecular Clinical Oncology 5 x 1000 No. 10007, Associazione Italiana per la Ricerca sul Cancro (AIRC), Milan, Italy; Grant TO_Call2_2012_0061, Compagnia di San Paolo, Turin, Italy; Grant 2014_1105, Fondazione CRT, Turin, Italy. NR 113 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 11 BP 18525 EP 18536 PG 12 WC Oncology; Cell Biology SC Oncology; Cell Biology GA EO7NN UT WOS:000396877500093 ER PT J AU Shi, LH Qin, XQ Wang, HJ Xia, YH Li, YY Chen, XJ Shang, L Tai, YT Feng, XY Acharya, P Acharya, C Xu, Y Deng, SH Hao, M Zou, DH Zhao, YZ Ru, K Qiu, LG An, G AF Shi, Lihui Qin, Xiaoqi Wang, Huijun Xia, Yonghui Li, Yuanyuan Chen, Xuejing Shang, Lei Tai, Yu-Tzu Feng, Xiaoyan Acharya, Prakrati Acharya, Chirag Xu, Yan Deng, Shuhui Hao, Mu Zou, Dehui Zhao, Yaozhong Ru, Kun Qiu, Lugui An, Gang TI Elevated neutrophil-to-lymphocyte ratio and monocyte-to-lymphocyte ratio and decreased platelet-to-lymphocyte ratio are associated with poor prognosis in multiple myeloma SO ONCOTARGET LA English DT Article DE multiple myeloma; inflammation mark ID IN-SITU HYBRIDIZATION; HEPATOCELLULAR-CARCINOMA; TUMOR MICROENVIRONMENT; DISEASE PROGRESSION; DENDRITIC CELLS; CANCER PATIENTS; BONE-MARROW; INFLAMMATION; SURVIVAL; IMPACT AB Elevated inflammatory markers are associated with poor outcomes in various types of cancers; however, their clinical significance in multiple myeloma (MM) have seldom been explored. This study investigated the prognostic relevance of neutrophilto- lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and monocyte-tolymphocyte ratio (MLR) in MM. Totally 559 MM patients were included in this study. NLR, PLR and MLR were calculated from whole blood counts prior to therapy. Kaplan-Meier curves and multivariate Cox proportional models were used for the evaluation of the survival. It has shown that newly diagnosed MM patients were characterized by high NLR and MLR. Elevated NLR and MLR and decreased PLR were associated with unfavorable clinicobiological features. Applying cut-offs of 4 (NLR), 100 (PLR) and 0.3 (MLR), elevated NLR, MLR and decreased PLR showed a negative impact on outcome. Importantly, elevated NLR and decreased PLR were independent prognostic factors for progression-free survival. Thus, elevated NLR and MLR, and decreased PLR predict poor clinical outcome in MM patients and may serve as the cost-effective and readily available prognostic biomarkers. C1 [Shi, Lihui; Qin, Xiaoqi; Wang, Huijun; Xia, Yonghui; Li, Yuanyuan; Chen, Xuejing; Shang, Lei; Feng, Xiaoyan; Xu, Yan; Deng, Shuhui; Hao, Mu; Zou, Dehui; Zhao, Yaozhong; Ru, Kun; Qiu, Lugui; An, Gang] Chinese Acad Med Sci, Inst Hematol, State Key Lab Expt Hematol, Tianjin, Peoples R China. [Shi, Lihui; Qin, Xiaoqi; Wang, Huijun; Xia, Yonghui; Li, Yuanyuan; Chen, Xuejing; Shang, Lei; Feng, Xiaoyan; Xu, Yan; Deng, Shuhui; Hao, Mu; Zou, Dehui; Zhao, Yaozhong; Ru, Kun; Qiu, Lugui; An, Gang] Chinese Acad Med Sci, Blood Dis Hosp, Tianjin, Peoples R China. [Shi, Lihui; Qin, Xiaoqi; Wang, Huijun; Xia, Yonghui; Li, Yuanyuan; Chen, Xuejing; Shang, Lei; Feng, Xiaoyan; Xu, Yan; Deng, Shuhui; Hao, Mu; Zou, Dehui; Zhao, Yaozhong; Ru, Kun; Qiu, Lugui; An, Gang] Peking Union Med Coll, Tianjin, Peoples R China. [Qin, Xiaoqi] Shanxi Med Univ, Dept Hematol, Hosp 2, Taiyuan, Peoples R China. [Tai, Yu-Tzu; Acharya, Chirag] Harvard Med Sch, Dana Farber Canc Inst, LeBow Inst Myeloma Therapeut, Boston, MA USA. [Tai, Yu-Tzu; Acharya, Chirag] Harvard Med Sch, Dana Farber Canc Inst, Jerome Lipper Ctr Multiple Myeloma Ctr, Boston, MA USA. [Acharya, Prakrati] Harvard Med Sch, Mt Auburn Hosp, Cambridge, MA USA. RP Ru, K; An, G (reprint author), Chinese Acad Med Sci, Inst Hematol, State Key Lab Expt Hematol, Tianjin, Peoples R China.; Ru, K; An, G (reprint author), Chinese Acad Med Sci, Blood Dis Hosp, Tianjin, Peoples R China.; Ru, K; An, G (reprint author), Peking Union Med Coll, Tianjin, Peoples R China. EM kunru@yahoo.com; angang@ihcams.ac.cn FU National Natural Science Foundation of China [81670202, 81400175, 81370632]; Special Key Anticancer Research and Development Program of Tianjin Municipality [12ZCDZSY17600] FX The present study was financially supported by the National Natural Science Foundation of China (81670202, 81400175 and 81370632), and the Special Key Anticancer Research and Development Program of Tianjin Municipality (12ZCDZSY17600). NR 34 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 12 BP 18792 EP 18801 PG 10 WC Oncology; Cell Biology SC Oncology; Cell Biology GA EO7OE UT WOS:000396879200017 ER PT J AU Thong, P Lee, K Toh, HJ Dong, J Tee, CS Low, KP Chang, PH Bhuvaneswari, R Tan, NC Soo, KC AF Thong, Patricia Lee, Kijoon Toh, Hui-Jin Dong, Jing Tee, Chuan-Sia Low, Kar-Perng Chang, Pui-Haan Bhuvaneswari, Ramaswamy Tan, Ngian-Chye Soo, Khee-Chee TI Early assessment of tumor response to photodynamic therapy using combined diffuse optical and diffuse correlation spectroscopy to predict treatment outcome SO ONCOTARGET LA English DT Article DE photodynamic therapy; treatment response monitoring; optical spectroscopy; tissue oxygenation; relative blood flow ID ANTITUMOR IMMUNITY; FLUENCE RATE; BLOOD-FLOW; REFLECTANCE SPECTROSCOPY; COHERENCE TOMOGRAPHY; CELL-DEATH; EFFICACY; CANCER; MODEL; PDT AB Photodynamic therapy (PDT) of cancer involves the use of a photosensitizer that can be light-activated to eradicate tumors via direct cytotoxicity, damage to tumor vasculature and stimulating the body's immune system. Treatment outcome may vary between individuals even under the same regime; therefore a non-invasive tumor response monitoring system will be useful for personalization of the treatment protocol. We present the combined use of diffuse optical spectroscopy (DOS) and diffuse correlation spectroscopy (DCS) to provide early assessment of tumor response. The relative tissue oxygen saturation (rStO2) and relative blood flow (rBF) in tumors were measured using DOS and DCS respectively before and after PDT with reference to baseline values in a mouse model. In complete responders, PDT-induced decreases in both rStO2 and rBF levels were observed at 3 h post-PDT and the rBF remained low until 48 h post-PDT. Recovery of these parameters to baseline values was observed around 2 weeks after PDT. In partial responders, the rStO2 and rBF levels also decreased at 3 h post PDT, however the rBF values returned toward baseline values earlier at 24 h post-PDT. In contrast, the rStO2 and rBF readings in control tumors showed fluctuations above the baseline values within the first 48 h. Therefore tumor response can be predicted at 3 to 48 h post-PDT. Recovery or sustained decreases in the rBF at 48 h post-PDT corresponded to long-term tumor control. Diffuse optical measurements can thus facilitate early assessment of tumor response. This approach can enable physicians to personalize PDT treatment regimens for best outcomes. C1 [Thong, Patricia; Toh, Hui-Jin; Tee, Chuan-Sia; Low, Kar-Perng; Chang, Pui-Haan; Bhuvaneswari, Ramaswamy; Soo, Khee-Chee] Natl Canc Ctr, Div Med Sci, Singapore, Singapore. [Lee, Kijoon; Dong, Jing] Nanyang Technol Univ, Sch Chem & Biomed Engn, Div Bioengn, Singapore, Singapore. [Tan, Ngian-Chye] Natl Canc Ctr, Div Surg Oncol, Singapore, Singapore. [Lee, Kijoon; Dong, Jing] Nanyang Technol Univ, Singapore, Singapore. [Dong, Jing] Massachusetts Gen Hosp, Harvard Med Sch, Boston, MA 02114 USA. [Dong, Jing] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. [Lee, Kijoon] Daegu Gyeongbuk Inst Sci & Technol, Daegu, South Korea. RP Soo, KC (reprint author), Natl Canc Ctr, Div Med Sci, Singapore, Singapore. EM admskc@nccs.com.sg FU SingHealth Foundation Grant [SHF/FG431P/2010]; Ministry of Education, Singapore [RG37/07]; APOCARE Pharma GmBH (Germany) FX This work was supported by a SingHealth Foundation Grant (SHF/FG431P/2010) and an Academic Research Fund Tier 1 Grant (RG37/07) from the Ministry of Education, Singapore. Chlorin-e6 was sponsored by APOCARE Pharma GmBH (Germany). NR 56 TC 0 Z9 0 U1 1 U2 1 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 12 BP 19902 EP 19913 DI 10.18632/oncotarget.15720 PG 12 WC Oncology; Cell Biology SC Oncology; Cell Biology GA EO7OE UT WOS:000396879200102 ER PT J AU Armstrong, RA McKee, AC Cairns, NJ AF Armstrong, Richard A. McKee, Ann C. Cairns, Nigel J. TI Pathology of the Superior Colliculus in Chronic Traumatic Encephalopathy SO OPTOMETRY AND VISION SCIENCE LA English DT Article DE chronic traumatic encephalopathy (CTE); superior colliculus; neurofibrillary tangles (NFT); neuronal loss; laminar distribution ID PROGRESSIVE SUPRANUCLEAR PALSY; CREUTZFELDT-JAKOB-DISEASE; ALZHEIMERS-DISEASE; BRAIN-STEM; CORTICOBASAL DEGENERATION; HEAD-INJURY; NEUROPATHOLOGY; DEMENTIA; SPECTRUM; DEPOSITS AB Purpose. To investigate neuropathological changes in the superior colliculus in chronic traumatic encephalopathy. Methods. The densities of the tau-immunoreactive neurofibrillary tangles, neuropil threads, dot-like grains, astrocytic tangles, and neuritic plaques, together with abnormally enlarged neurons, typical neurons, vacuolation, and frequency of contacts with blood vessels, were studied across the superior colliculus from pia mater to the periaqueductal gray in eight chronic traumatic encephalopathy and six control cases. Results. Tau-immunoreactive pathology was absent in the superior colliculus of controls but present in varying degrees in all chronic traumatic encephalopathy cases, significant densities of tau-immunoreactive neurofibrillary tangles, NT, or dot-like grains being present in three cases. No significant differences in overall density of the tau-immunoreactive neurofibrillary tangles, neuropil threads, dot-like grains, enlarged neurons, vacuoles, or contacts with blood vessels were observed in control and chronic traumatic encephalopathy cases, but chronic traumatic encephalopathy cases had significantly lower mean densities of neurons. The distribution of surviving neurons across the superior colliculus suggested greater neuronal loss in intermediate and lower laminae in chronic traumatic encephalopathy. Changes in density of the tauimmunoreactive pathology across the laminae were variable, but in six chronic traumatic encephalopathy cases, densities of tau-immunoreactive neurofibrillary tangles, neuropil threads, or dot-like grains were significantly greater in intermediate and lower laminae. Pathological changes were not correlated with the distribution of blood vessels. Conclusions. The data suggest significant pathology affecting the superior colliculus in a proportion of chronic traumatic encephalopathy cases with a laminar distribution which could compromise motor function rather than sensory analysis. C1 [Armstrong, Richard A.] Aston Univ, Vis Sci, Birmingham B4 7ET, W Midlands, England. [McKee, Ann C.] VA Boston Healthcare Syst, Dept Pathol & Lab Med, Boston, MA USA. [McKee, Ann C.] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [McKee, Ann C.] Boston Univ, Sch Med, Dept Pathol, Boston, MA 02118 USA. [Cairns, Nigel J.] Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63110 USA. [Cairns, Nigel J.] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO USA. RP Armstrong, RA (reprint author), Aston Univ, Vis Sci, Birmingham B4 7ET, W Midlands, England. EM R.A.Armstrong@aston.ac.uk RI Armstrong, Richard/H-4557-2012 OI Armstrong, Richard/0000-0002-5046-3199 FU National Institute of Neurological Disorders and Stroke [1UO1NS086659-01]; Department of Veterans Affairs; Veterans Affairs Biorepository [CSP 501]; Translational Research Center for Traumatic Brain Injury and Stress Disorders (TRACTS); Veterans Affairs Rehabilitation Research and Development Traumatic Brain Injury Center of Excellence [B6796-C]; National Institute of Aging Boston University Alzheimer's Disease Center [P30AG13846, 0572063345-5]; Charles F. and Joanne Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO from the National Institute on Aging [P50 AG05681, P01 AG03991] FX The authors thank the use of the resources and facilities at the Edith Nourse Rogers Memorial Veterans Hospital (Bedford, MA). We also gratefully acknowledge the help of all members of the chronic traumatic encephalopathy center at Boston University School of Medicine, VA Boston, and the Bedford VA and the individuals and families whose participation and contributions made this work possible. This work was supported by the National Institute of Neurological Disorders and Stroke (1UO1NS086659-01), Department of Veterans Affairs, the Veterans Affairs Biorepository (CSP 501), the Translational Research Center for Traumatic Brain Injury and Stress Disorders (TRACTS), Veterans Affairs Rehabilitation Research and Development Traumatic Brain Injury Center of Excellence (B6796-C), and the National Institute of Aging Boston University Alzheimer's Disease Center (P30AG13846; supplement 0572063345-5). This work was supported by the Charles F. and Joanne Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO (P50 AG05681 and P01 AG03991 from the National Institute on Aging). The authors have no associations, stock ownership, equity interests, patents, or licenses that could be perceived as a conflict of interest. NR 44 TC 1 Z9 1 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1040-5488 EI 1538-9235 J9 OPTOMETRY VISION SCI JI Optom. Vis. Sci. PD JAN PY 2017 VL 94 IS 1 BP 33 EP 42 PG 10 WC Ophthalmology SC Ophthalmology GA EM5ZZ UT WOS:000395393900006 PM 27391531 ER PT J AU Houston, KE Barrett, AM AF Houston, Kevin E. Barrett, A. M. TI Patching for Diplopia Contraindicated in Patients with Brain Injury? SO OPTOMETRY AND VISION SCIENCE LA English DT Article DE strabismus; patching; monocular occlusion; hemispatial neglect; spatial neglect ID RIGHT-HEMISPHERE STROKE; UNILATERAL SPATIAL NEGLECT; HEMISPATIAL NEGLECT; VISUAL NEGLECT; SPONTANEOUS-RECOVERY; SUPERIOR COLLICULUS; REHABILITATION; DISORDERS; ATTENTION; DEFICITS AB Purpose. Patching for double vision is a common palliative treatment for head-trauma patients with acquired strabismus when prisms are not feasible. Methods. We review literature on spatial neglect and discuss possible effects of monocular occlusion on spatial attention. Results. Patching the left eye has been shown to worsen spatial judgments in some brain-injured patients with left neglect by inhibiting the right superior colliculus further impairing contralateral leftward orienting (the Sprague Effect). Conclusions. Because more peripheral parts of the visual field increasingly project to the contralateral superior colliculus with the temporal crescent being entirely contralateral, avoiding patching of the temporal crescent was advised, and in most cases can be achieved by taping off the spectacle lens and avoiding an elastic eye patch. C1 [Houston, Kevin E.] Spaulding Rehabil Hosp, Boston, MA USA. [Houston, Kevin E.] Harvard Med Sch, Dept Ophthalmol, Boston, MA USA. [Houston, Kevin E.] Massachusetts Eye & Ear, Boston, MA USA. [Barrett, A. M.] Kessler Fdn, W Orange, NJ USA. RP Houston, KE (reprint author), Massachusetts Eye & Ear Infirm, Dept Ophthalmol, 243 Charles St, Boston, MA 02114 USA. EM kevin_houston@meei.harvard.edu FU NEI NIH HHS [K12 EY016335]; NICHD NIH HHS [K24 HD062647] NR 44 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 1040-5488 EI 1538-9235 J9 OPTOMETRY VISION SCI JI Optom. Vis. Sci. PD JAN PY 2017 VL 94 IS 1 BP 120 EP 124 PG 5 WC Ophthalmology SC Ophthalmology GA EM5ZZ UT WOS:000395393900017 PM 27575993 ER PT J AU Talaei-Khoei, M Fischerauer, SF Lee, SG Ring, D Vranceanu, AM AF Talaei-Khoei, Mojtaba Fischerauer, Stefan F. Lee, Sang-Gil Ring, David Vranceanu, Ana-Maria TI Pain Catastrophizing Mediates the Effect of Psychological Inflexibility on Pain Intensity and Upper Extremity Physical Function in Patients with Upper Extremity Illness SO PAIN PRACTICE LA English DT Article DE pain; physical function; psychological inflexibility; pain catastrophizing; depression; anxiety ID MEASUREMENT INFORMATION-SYSTEM; ITEM RESPONSE THEORY; TRIPARTITE MODEL; OUTCOMES; ACCEPTANCE; DEPRESSION; ANXIETY; PROMIS; VALIDATION; PROGRESS AB BackgroundPsychological inflexibilitythe inability to take value-based actions in the presence of unwanted thoughts, feelings, or bodily symptomsis associated with negative health outcomes including depression and anxiety. ObjectiveWe aimed to determine the association between the general construct of psychological inflexibility and pain intensity, and upper extremity physical function in patients with musculoskeletal illness in an orthopedics practice. We also set out to test multiple-mediator models proposing that psychological inflexibility affects pain intensity and upper extremity physical function directly, as well as indirectly through depression, anxiety, and pain catastrophizing. MethodsOne hundred and eight patients with upper extremity illness completed self-report measures of pain intensity, upper extremity physical function, psychological inflexibility, pain catastrophizing, depression, and anxiety in this cross-sectional study. ResultsWe found that psychological inflexibility affected pain intensity and upper extremity physical function directly and indirectly. Pain catastrophizing but not depression or anxiety mediated the association of psychological inflexibility to pain intensity and upper extremity physical function. ConclusionsPsychological inflexibility plays an important role in understanding the increased pain and decreased upper extremity physical function in patients with musculoskeletal pain. It also suggests that the cognitive error of pain catastrophizing is one of the mechanisms through which the general construct of psychological inflexibility may influence pain intensity and upper extremity physical function. Psychological treatments aimed at decreasing pain and increasing upper extremity physical function should target both pain catastrophizing and psychological inflexibility. C1 [Talaei-Khoei, Mojtaba; Fischerauer, Stefan F.; Lee, Sang-Gil; Ring, David] Harvard Med Sch, Massachusetts Gen Hosp, Orthopaed Hand & Upper Extrem Serv, Boston, MA USA. [Fischerauer, Stefan F.] Med Univ Graz, Univ Hosp Graz, Dept Orthopaed & Traumatol, Graz, Austria. [Vranceanu, Ana-Maria] Harvard Med Sch, Massachusetts Gen Hosp, Dept Psychiat, Boston, MA USA. RP Vranceanu, AM (reprint author), Massachusetts Gen Hosp, Behav Med Serv, One Bowdoin Sq,7th Floor, Boston, MA 02114 USA. EM avranceanu@partners.org NR 46 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1530-7085 EI 1533-2500 J9 PAIN PRACT JI Pain Pract. PD JAN PY 2017 VL 17 IS 1 BP 129 EP 140 DI 10.1111/papr.12494 PG 12 WC Anesthesiology; Clinical Neurology SC Anesthesiology; Neurosciences & Neurology GA EL2DP UT WOS:000394430600013 PM 27739246 ER PT J AU Chen, C Carlberg, V Kroshinsky, D AF Chen, Chen (Amy) Carlberg, Valerie Kroshinsky, Daniela TI Angioedema After Squaric Acid Treatment in a 6-Year-Old Girl SO PEDIATRIC DERMATOLOGY LA English DT Article ID ALOPECIA-AREATA; DIBUTYLESTER AB Alopecia areata (AA) involves the immune-related destruction of hair follicles, resulting in patches of complete hair loss, most often on the scalp. The topical sensitizer squaric acid dibutylester (SADBE) is a popular treatment option given its low side-effect profile, hair regrowth potential, and lack of cross-reactivity with other chemicals. We describe a unique case of a 6-year-old girl who developed angioedema after SADBE treatment for AA. C1 [Chen, Chen (Amy); Carlberg, Valerie; Kroshinsky, Daniela] Harvard Med Sch, Boston, MA USA. [Carlberg, Valerie; Kroshinsky, Daniela] Massachusetts Gen Hosp, Dept Dermatol, 55 Fruit St, Boston, MA 02114 USA. RP Kroshinsky, D (reprint author), Massachusetts Gen Hosp, Dept Dermatol, 55 Fruit St, Boston, MA 02114 USA. EM dkroshinsky@mgh.harvard.edu NR 9 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0736-8046 EI 1525-1470 J9 PEDIATR DERMATOL JI Pediatr. Dermatol. PD JAN-FEB PY 2017 VL 34 IS 1 BP E44 EP E46 DI 10.1111/pde.12993 PG 3 WC Dermatology; Pediatrics SC Dermatology; Pediatrics GA EK5GT UT WOS:000393955600012 PM 27699860 ER PT J AU Barber, C Gagnon, D Fonda, J Cho, K Hermos, J Miller, M AF Barber, Catherine Gagnon, David Fonda, Jennifer Cho, Kelly Hermos, John Miller, Matthew TI Assessing the impact of prescribing directives on opioid prescribing practices among Veterans Health Administration providers SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Article DE opioid analgesics; prescribing patterns; physicians; poisoning; pharmacoepidemiology ID UNITED-STATES; OVERDOSE DEATHS; PRESCRIPTION OPIOIDS; DRUG OVERDOSE; ABUSE; ANALGESICS; EPIDEMIC; PAIN; FORMULATIONS; PATTERNS AB Purpose The study aimed to test whether directives on opioid prescribing released by the Veterans Health Administration (VHA) or the Food and Drug Administration (FDA) had an impact on prescribing among VHA providers. Methods We used the VHA's linked pharmacy and patient medical records database to identify new prescriptions written for propoxyphene, fentanyl, and controlled release (CR) oxycodone between 1/1/2000 and 12/31/2009. We plotted the monthly proportion of these prescriptions that complied with components of four specific safety alerts or directives for these substances issued by the VHA or FDA between 1/1/2001 and 12/31/2008. We modeled compliance using interrupted time series analysis and a generalized additive model with the addition of an indicator variable to flag prescriptions that followed the directive's release date. Results A total of 32.2 million new prescriptions for fentanyl, oxycodone CR, and propoxyphene were written for VHA patients meeting inclusion criteria. Compliance with guidelines in the directives increased steadily throughout the entire study period, with no clinically meaningful inflection point near the date of each directive's release. Generalized additive modeling and interrupted time series analysis found that the indicator flag slightly improved the fit of the data, but visual inspection of the plots revealed no change at a level of practical significance. Conclusions While prescribing compliance increased throughout the period, release of FDA and VHA alerts and guidelines did not appear to contribute to this change. Given the fivefold increase in the rate of drug-related overdose deaths since 1990, identifying effective methods to communicate safety messages and change prescriber behavior remains a priority for future work. Copyright (C) 2016 John Wiley & Sons, Ltd. C1 [Barber, Catherine; Miller, Matthew] Harvard Sch Publ Hlth, Harvard Injury Control Res Ctr, 677 Huntington Ave,3rd Floor, Boston, MA 02115 USA. [Gagnon, David; Fonda, Jennifer; Cho, Kelly; Hermos, John] VA Boston Healthcare Syst, Massachusetts Area Vet Res & Informat Ctr MAVERIC, Boston, MA USA. [Miller, Matthew] Northeastern Univ, Dept Hlth Sci, Boston, MA 02115 USA. RP Barber, C (reprint author), Harvard Sch Publ Hlth, Harvard Injury Control Res Ctr, 677 Huntington Ave,3rd Floor, Boston, MA 02115 USA. EM cbarber@hsph.harvard.edu FU CDC's National Center for Injury Prevention and Control [R21CE001605] FX Submitted to Pharmacoepidemiology and Drug Safety on 09 March 2015. All authors report no financial interests in the findings. This work was supported by a grant from the CDC's National Center for Injury Prevention and Control (grant no. R21CE001605, "Unintentional Poisoning from Prescription Drug Overdoses among Veterans"). The material presented herein has not previously been published or submitted for publication. NR 43 TC 0 Z9 0 U1 0 U2 0 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD JAN PY 2017 VL 26 IS 1 BP 40 EP 46 DI 10.1002/pds.4066 PG 7 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA EO0QS UT WOS:000396403600006 PM 27530106 ER PT J AU Kang, UB Marto, JA AF Kang, Un-Beom Marto, Jarrod A. TI Leucine-rich repeat kinase 2 and Parkinson's disease SO PROTEOMICS LA English DT Review DE Biomedicine; LRRK2; Parkinson's disease ID ACTIVATED PROTEIN-KINASE; FOCAL ADHESION KINASE; LRRK2 G2019S MUTATION; MITOCHONDRIAL FISSION; DOPAMINERGIC-NEURONS; SUBSTANTIA-NIGRA; BRAIN PENETRANT; GTP-BINDING; EXPRESSION; INHIBITOR AB Leucine-rich repeat kinase 2 (LRRK2) is a large multidomain protein that is expressed in many tissues and participates in numerous biological pathways. Mutations in LRRK2 are recognized as genetic risk factors for familial Parkinson's disease (PD) and may also represent causal factors in the more common sporadic form of PD. The structure of LRRK2 comprises a combination of GTPase, kinase, and scaffolding domains. This functional diversity, combined with a potentially central role in genetic and idiopathic PD motivates significant effort to further credential LRRK2 as a therapeutic target. Here, we review the current understanding for LRRK2 function in normal physiology and PD, with emphasis on insight gained from proteomic approaches. C1 Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. Dana Farber Canc Inst, Blais Prote Ctr, Boston, MA 02115 USA. Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA USA. RP Marto, JA (reprint author), Dana Farber Canc Inst, Dept Canc Biol, Longwood Ctr 2208, 450 Brookline Ave, Boston, MA 02115 USA. EM jarrod_marto@dfci.harvard.edu FU Michael J. Fox Foundation LEAPS Research Program FX The authors acknowledge generous support from the Michael J. Fox Foundation LEAPS Research Program. NR 111 TC 3 Z9 3 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1615-9853 EI 1615-9861 J9 PROTEOMICS JI Proteomics PD JAN PY 2017 VL 17 IS 1-2 AR UNSP 1600092 DI 10.1002/pmic.201600092 PG 9 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EL2EM UT WOS:000394432900001 ER PT J AU Cuevas, AG O'Brien, K Saha, S AF Cuevas, Adolfo G. O'Brien, Kerth Saha, Somnath TI What is the key to culturally competent care: Reducing bias or cultural tailoring? SO PSYCHOLOGY & HEALTH LA English DT Article DE clinician-patient relationships; patient-centred care; cultural competency; health care disparities; ethnic minorities; focus groups ID PATIENT-CENTERED CARE; HEALTH-CARE; LANGUAGE BARRIERS; DISPARITIES; QUALITY; CLINICIAN; LATINOS; ACCESS; COMMUNICATION; PERCEPTIONS AB Objective: To gain a better understanding as to whether disparities in patient-provider relationships arise from ethnic minority patients being treated differently than European American patients while they would prefer to be treated the same, or whether disparities arise when ethnic minority patients are treated the same as European American patients while they would prefer to be treated differently. Method: African-American, Latina/Latino and European American community members were recruited to participate in one of 27 focus group discussions. Topics included what made a good or bad relationship with a doctor and what led one to trust a doctor. A thematic analysis was conducted using NVivo 10. Results: Patients of all groups described experiences that reflected the concepts of patient-centred care, such as wanting a clinician who is attentive to patients' needs. African-American patients reported experiences they viewed as discriminatory. Some African-American patients felt it was appropriate to racially/ethnically contextualise their care, and most Latina/Latino patients preferred language/culturally concordant clinicians. Conclusion: Health care disparities might be reduced through a patientcentred approach to cultural competency training, general knowledge of the cultural context of clinicians' patient population, and attention to the effects of racial bias and discrimination among both clinicians and non-clinical staff. C1 [Cuevas, Adolfo G.; O'Brien, Kerth] Portland State Univ, Dept Psychol, Portland, OR 97207 USA. [Saha, Somnath] Oregon Hlth & Sci Univ, Portland Vet Affairs Med Ctr, Publ Hlth & Prevent Med, Med Informat & Clin Epidemiol, Portland, OR 97201 USA. [Cuevas, Adolfo G.] Harvard TH Chan Sch Publ Hlth, Dept Social & Behav Sci, Boston, MA 02215 USA. RP Cuevas, AG (reprint author), Portland State Univ, Dept Psychol, Portland, OR 97207 USA.; Cuevas, AG (reprint author), Harvard TH Chan Sch Publ Hlth, Dept Social & Behav Sci, Boston, MA 02215 USA. EM acuevas@hsph.harvard.edu OI O'Brien, Kerth/0000-0002-1566-7364 FU Robert Wood Johnson Foundation; National Institute of Health [3R25CA057711] FX Project EQUALED was funded by a grant from the Robert Wood Johnson Foundation. The preparation of this article was supported by the National Institute of Health 3R25CA057711. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. NR 40 TC 0 Z9 0 U1 1 U2 1 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND SN 0887-0446 EI 1476-8321 J9 PSYCHOL HEALTH JI Psychol. Health PY 2017 VL 32 IS 4 BP 493 EP 507 DI 10.1080/08870446.2017.1284221 PG 15 WC Public, Environmental & Occupational Health; Psychology, Multidisciplinary SC Public, Environmental & Occupational Health; Psychology GA EO5VU UT WOS:000396761800007 PM 28165767 ER PT J AU O'Neill, AC Somarouthu, B Tirumani, SH Braschi-Amirfarzan, M Van den Abbeele, AD Ramaiya, NH Shinagare, AB AF O'Neill, Ailbhe C. Somarouthu, Bhanusupriya Tirumani, Sree Harsha Braschi-Amirfarzan, Marta Van den Abbeele, Annick D. Ramaiya, Nikhil H. Shinagare, Atul B. TI Patterns and Prognostic Importance of Hepatic Involvement in Patients with Serous Ovarian Cancer: A SingleInstitution Experience with 244 Patients SO RADIOLOGY LA English DT Article ID CYTOREDUCTIVE SURGERY; SURVIVAL IMPACT; FALLOPIAN-TUBE; CT; METASTASES; CARCINOMA; METAANALYSIS; DEBULKING AB Purpose: To evaluate the frequency, patterns, and prognostic importance of metastatic hepatic involvement in serous ovarian cancer. Materials and Methods: This institutional review board-approved retrospective study, with waived informed consent, included 244 patients with pathologically proven serous ovarian cancer (mean age +/- standard deviation, 59 years +/- 10.7; range 1993 years). Electronic medical records and all available imaging studies over a median follow-up of 44 months (interquartile range [IQR], 2770) were reviewed to identify the frequency of liver parenchymal invasion (LPI) from perihepatic peritoneal metastasis and hematogenous liver metastases. The associations and prognostic importance of LPI and hematogenous metastases were studied by using univariate and multivariate Cox proportional analysis. Results: Eighty-four of 244 patients (34%) developed perihepatic metastases, of whom 55 (23%) developed LPI after median of 43 months (IQR, 2563). Hematogenous hepatic metastases developed in 38 of 244 patients (16%) after median of 42 months (IQR, 2664). At multivariate analysis, age (P = .008; hazard ratio [HR]: 1.03; 95% confidence interval [CI]: 1.009, 1.07) and suboptimal cytoreduction (P = .03; HR, 2.13; 95% CI: 1.12, 4.07) were associated with LPI. Increasing age (P = .01; HR, 1.04; 95% CI: 1.008, 1.08), high-grade tumor (P = .01; HR, 6.75; 95% CI: 1.44, 120.5), and advanced stage (P = .03; HR, 3.16; 95% CI: 1.94, 4.56) were associated with hematogenous metastases. Overall survival with and without LPI was similar (median, 80 months; IQR, 50not reached vs 123 months; IQR, 49279; P = .6). Hematogenous metastases were associated with significantly shorter survival at univariate (median 63 months, IQR 43139 vs 145 months, IQR 50not reached; P = .006) and multivariate analyses (P = .03; HR, 1.88; 95% CI: 1.14, 3.28). Conclusion: Differentiating hematogenous metastases and LPI is important for radiologists; hematogenous metastases are associated with shorter survival, while LPI does not adversely affect survival and prognostically behaves like peritoneal disease. (C) RSNA, 2016 C1 [O'Neill, Ailbhe C.; Somarouthu, Bhanusupriya; Tirumani, Sree Harsha; Braschi-Amirfarzan, Marta; Van den Abbeele, Annick D.; Ramaiya, Nikhil H.; Shinagare, Atul B.] Dana Farber Canc Inst, Dept Imaging, 450 Brookline Ave, Boston, MA 02115 USA. RP Shinagare, AB (reprint author), Dana Farber Canc Inst, Dept Imaging, 450 Brookline Ave, Boston, MA 02115 USA. EM ashinagare@partners.org FU Radiological Society of North America [RSCH1422] FX A. B. S. supported by the Radiological Society of North America (RSCH1422). NR 28 TC 0 Z9 0 U1 0 U2 0 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD JAN PY 2017 VL 282 IS 1 BP 160 EP 170 DI 10.1148/radiol.2016152595 PG 11 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA EM7VG UT WOS:000395519800018 PM 27479640 ER PT J AU Albadawi, H Chen, JW Oklu, R Wu, Y Wojtkiewicz, G Pulli, B Milner, JD Cambria, RP Watkins, MT AF Albadawi, Hassan Chen, John W. Oklu, Rahmi Wu, Yue Wojtkiewicz, Gregory Pulli, Benjamin Milner, John D. Cambria, Richard P. Watkins, Michael T. TI Spinal Cord Inflammation: Molecular Imaging after Thoracic Aortic Ischemia Reperfusion Injury SO RADIOLOGY LA English DT Article ID THERAPEUTIC TARGET; LIPID-PEROXIDATION; SECONDARY INJURY; MYELOPEROXIDASE; INFARCTION; MODEL; ACTIVATION; INHIBITION; EVOLUTION; SURGERY AB Purpose: To evaluate whether noninvasive molecular imaging technologies targeting myeloperoxidase (MPO) can reveal early inflammation associated with spinal cord injury after thoracic aortic ischemia-reperfusion (TAR) in mice. Materials and Methods: The study was approved by the institutional animal care and use committee. C57BL6 mice that were 8-10 weeks old underwent TAR (n = 55) or sham (n = 26) surgery. Magnetic resonance (MR) imaging (n = 6) or single photon emission computed tomography (SPECT)/computed tomography (CT) (n = 15) studies targeting MPO activity were performed after intravenous injection of MPO sensors (bis-5-hydroxytryptamide-tetraazacyclododecane [HT]-diethyneletriaminepentaacetic acid [DTPA]-gadolinium or indium 111-bis-5-HT-DTPA, respectively). Immunohistochemistry and flow cytometry were used to identify myeloid cells and neuronal loss. Proinflammatory cytokines, keratinocyte chemoattractant (KC), and interleukin 6 (IL-6) were measured with enzyme-linked immunosorbent assay. Statistical analyses were performed by using nonparametric tests and the Pearson correlation coefficient. P < .05 was considered to indicate a significant difference. Results: Myeloid cells infiltrated into the injured cord at 6 and 24 hours after TAR. MR imaging confirmed the presence of ischemic lesions associated with mild MPO-mediated enhancement in the thoracolumbar spine at 24 hours compared with the sham procedure. SPECT/CT imaging of MPO activity showed marked MPO-sensor retention at 6 hours (P = .003) that continued to increase at 24 hours after TAR (P = .0001). The number of motor neurons decreased substantially at 24 hours after TAR (P < .01), which correlated inversely with in vivo inflammatory changes detected at molecular imaging (r = 0.64, P = .0099). MPO was primarily secreted by neutrophils, followed by lymphocyte antigen 6 complexhigh monocytes and/or macrophages. There were corresponding increased levels of proinflammatory cytokines KC (P = .0001) and IL-6 (P = .0001) that mirrored changes in MPO activity. Conclusion: MPO is a suitable imaging biomarker for identifying and tracking inflammatory damage in the spinal cord after TAR in a mouse model. (C) RSNA, 2016 C1 [Albadawi, Hassan; Milner, John D.; Cambria, Richard P.; Watkins, Michael T.] Massachusetts Gen Hosp, Harvard Med Sch, Dept Surg, Div Vasc & Endovasc Surg, 70 Blossom St,Edwards 301, Boston, MA 02114 USA. [Chen, John W.; Wu, Yue; Wojtkiewicz, Gregory; Pulli, Benjamin] Massachusetts Gen Hosp, Ctr Syst Biol, Harvard Med Sch, 70 Blossom St,Edwards 301, Boston, MA 02114 USA. [Chen, John W.; Wu, Yue; Wojtkiewicz, Gregory; Pulli, Benjamin] Massachusetts Gen Hosp, Harvard Med Sch, Inst Innovat Imaging, Dept Radiol, 70 Blossom St,Edwards 301, Boston, MA 02114 USA. [Oklu, Rahmi] Mayo Clin, Dept Radiol, Div Vasc & Intervent Radiol, Scottsdale, AZ USA. RP Albadawi, H (reprint author), Massachusetts Gen Hosp, Harvard Med Sch, Dept Surg, Div Vasc & Endovasc Surg, 70 Blossom St,Edwards 301, Boston, MA 02114 USA. EM halbadawi@mgh.harvard.edu FU National Institutes of Health [R01NS070835, R01-NS072167]; Massachusetts General Hospital (Division of Vascular and Endovascular Surgery, Henry and Nod Meyer Sundry Fund) FX Supported by the National Institutes of Health (R01NS070835, R01-NS072167) and by Massachusetts General Hospital (Division of Vascular and Endovascular Surgery, Henry and Nod Meyer Sundry Fund). NR 38 TC 0 Z9 0 U1 0 U2 0 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD JAN PY 2017 VL 282 IS 1 BP 202 EP 211 DI 10.1148/radiol.2016152222 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA EM7VG UT WOS:000395519800022 PM 27509542 ER PT J AU Bukhari, SIA Vasudevan, S AF Bukhari, Syed I. A. Vasudevan, Shobha TI FXR1a-associated microRNP: A driver of specialized non-canonical translation in quiescent conditions SO RNA BIOLOGY LA English DT Editorial Material DE 4EBP dephosphorylation; DAP5; FXR1a; low mTOR activity; microRNA; mRNA cap binding; non-canonical translation; PARN; poly(A) shortening; quiescence ID INITIATION-FACTOR 4G; MESSENGER-RNA CAP; CELL-CYCLE ARREST; SITE-MEDIATED TRANSLATION; EMBRYONIC STEM-CELLS; CARCINOMA IN-SITU; C VIRUS-RNA; POLY(A)-SPECIFIC RIBONUCLEASE; EUKARYOTIC TRANSLATION; BINDING-PROTEIN AB Eukaryotic protein synthesis is a multifaceted process that requires coordination of a set of translation factors in a particular cellular state. During normal growth and proliferation, cells generally make their proteome via conventional translation that utilizes canonical translation factors. When faced with environmental stress such as growth factor deprivation, or in response to biological cues such as developmental signals, cells can reduce canonical translation. In this situation, cells adapt alternative modes of translation to make specific proteins necessary for required biological functions under these distinct conditions. To date, a number of alternative translation mechanisms have been reported, which include non-canonical, cap dependent translation and cap independent translation such as IRES mediated translation. Here, we discuss one of the alternative modes of translation mediated by a specialized microRNA complex, FXR1a-microRNP that promotes non-canonical, cap dependent translation in quiescent conditions, where canonical translation is reduced due to low mTOR activity. C1 [Bukhari, Syed I. A.; Vasudevan, Shobha] Harvard Med Sch, Massachusetts Gen Hosp, Ctr Canc Res, 185 Cambridge St,CPZN 4202, Boston, MA 02114 USA. RP Vasudevan, S (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Ctr Canc Res, 185 Cambridge St,CPZN 4202, Boston, MA 02114 USA. EM vasudevan.shobha@mgh.harvard.edu FU NIGMS [GM100202] FX SV is funded by NIGMS grant GM100202. NR 143 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 1547-6286 EI 1555-8584 J9 RNA BIOL JI RNA Biol. PY 2017 VL 14 IS 2 BP 137 EP 145 DI 10.1080/15476286.2016.1265197 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EM3HD UT WOS:000395204200001 PM 27911187 ER PT J AU Schachter, SC AF Schachter, Steven C. TI Successful health communication in epileptology SO SEIZURE-EUROPEAN JOURNAL OF EPILEPSY LA English DT Review DE Communication; Doctor-patient relationship; Patient education; Epilepsy; Stigma; Seizure detection ID EPILEPSY; ADULTS; MANAGEMENT; SEIZURE; NEEDS; CARE; SATISFACTION; ADHERENCE; QUALITY; INTERVENTION AB Advances in communication technologies have had an impact on virtually every aspect of daily life and have shaped the ways that persons with epilepsy learn about their disorder; communicate with their care providers, families and friends; and are viewed by society. This paper discusses drivers of changing communication patterns in epileptology and barriers that remain, available tools to enhance communication among and between all stakeholders, and potential future developments. (C) 2016 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved. C1 [Schachter, Steven C.] Massachusetts Gen Hosp, Beth Israel Deaconess Med Ctr, Dept Neurol, Boston, MA 02114 USA. [Schachter, Steven C.] Harvard Med Sch, Boston, MA USA. RP Schachter, SC (reprint author), 125 Nashua St,Room 328, Boston, MA 02114 USA. EM sschacht@bidmc.harvard.edu NR 36 TC 1 Z9 1 U1 0 U2 0 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 1059-1311 EI 1532-2688 J9 SEIZURE-EUR J EPILEP JI Seizure PD JAN PY 2017 VL 44 BP 7 EP 10 DI 10.1016/j.seizure.2016.10.005 PG 4 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA EL2TJ UT WOS:000394472800004 PM 27780659 ER PT J AU Batchelder, AW Safren, S Mitchell, AD Ivardic, I O'Cleirigh, C AF Batchelder, Abigail W. Safren, Steven Mitchell, Avery D. Ivardic, Ivan O'Cleirigh, Conall TI Mental health in 2020 for men who have sex with men in the United States SO SEXUAL HEALTH LA English DT Review ID HIV PREEXPOSURE PROPHYLAXIS; RANDOMIZED CONTROLLED-TRIAL; POSTTRAUMATIC-STRESS-DISORDER; COGNITIVE-BEHAVIORAL THERAPY; INJECTION-DRUG USE; TRANSMISSION RISK BEHAVIOR; DEPRESSION CBT-AD; NEW-YORK-CITY; SUBSTANCE USE; BLACK-MEN AB Despite continued advances in HIV prevention and treatment, gay and bisexual men and other men who have sex with men (MSM) remain the population most impacted by HIV/AIDS in the US and many other Western countries. Additionally, MSM are disproportionately affected by various psychological problems, including depression, distress, trauma and substance use. These challenges frequently co-occur, and are associated with higher rates of behaviours related to HIV acquisition and transmission, HIV infection, and, for those living with HIV/AIDS, lower levels of treatment engagement. Moreover, racial disparities exist among MSM in the US; for example, young African American MSM bear a disproportionate burden of the continuing HIV epidemic, likely related to disparate HIV prevalence in partner pools as well as long-standing structural inequities. In this review, the mental health challenges facing MSM primarily in the US, related to HIV and STI prevention and across the HIV care cascade, including HIV diagnosis, engagement and retention in care, and antiretroviral adherence, are illustrated. Disparities among MSM including racial and ethnic, age-related and structural barriers associated with HIV prevention and treatment, as well as current interventions, are also described. Moving forward towards 2020, resources will be needed to assess and implement scalable intervention strategies to address psychological and social barriers to HIV and STI risk reduction and treatment for MSM, with a particular focus on the most vulnerable subpopulations. As access to prevention and treatment strategies expand, and new breakthroughs continue to emerge, behavioural strategies will continue to be needed to reduce risk and increase uptake and engagement among MSM most at risk through 2020 and beyond. C1 [Batchelder, Abigail W.; O'Cleirigh, Conall] Harvard Med Sch, Dept Psychiat, Massachusetts Gen Hosp, One Bowdoin Sq,7th Floor, Boston, MA 02114 USA. [Batchelder, Abigail W.; Mitchell, Avery D.; O'Cleirigh, Conall] Fenway Hlth, Fenway Inst, 1340 Boylston St, Boston, MA 02215 USA. [Safren, Steven; Ivardic, Ivan] Univ Miami, Dept Psychol, POB 248185, Coral Gables, FL 33124 USA. [Mitchell, Avery D.] Univ N Carolina, Dept Psychol & Neurosci, 235 E Cameron Ave, Chapel Hill, NC 27599 USA. RP Batchelder, AW (reprint author), Harvard Med Sch, Dept Psychiat, Massachusetts Gen Hosp, One Bowdoin Sq,7th Floor, Boston, MA 02114 USA.; Batchelder, AW (reprint author), Fenway Hlth, Fenway Inst, 1340 Boylston St, Boston, MA 02215 USA. EM abatchelder@mgh.harvard.edu FU NIDA [9K24DA040489] FX Dr O'Cleirigh's time on this manuscript was supported by the NIMH (HIV Prevention and Trauma Treatment for MSM with Childhood Sexual Abuse Histories, R01MH095624, PIO'Cleirigh) and by NIAID (Harvard University Center for AIDS Research, 5P30AI060354-12 PI Walker). Dr Safren's time was supported by grant from NIDA (Addressing Psychosocial Comorbidities in HIV Treatment and Prevention, 9K24DA040489, PI Safren). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Mental Health (NIMH), The National Institute for Drug Abuse (NIDA) or the National Institutes of Health (NIH). NR 151 TC 1 Z9 1 U1 1 U2 1 PU CSIRO PUBLISHING PI CLAYTON PA UNIPARK, BLDG 1, LEVEL 1, 195 WELLINGTON RD, LOCKED BAG 10, CLAYTON, VIC 3168, AUSTRALIA SN 1448-5028 EI 1449-8987 J9 SEX HEALTH JI Sex Health PY 2017 VL 14 IS 1 SI SI BP 59 EP 71 DI 10.1071/SH16083 PG 13 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA EM8PF UT WOS:000395572700007 ER PT J AU Demanuele, C Bartsch, U Baran, B Khan, S Vangel, MG Cox, R Hamalainen, M Jones, MW Stickgold, R Manoach, DS AF Demanuele, Charmaine Bartsch, Ullrich Baran, Bengi Khan, Sheraz Vangel, Mark G. Cox, Roy Hamalainen, Matti Jones, Matthew W. Stickgold, Robert Manoach, Dara S. TI Coordination of Slow Waves With Sleep Spindles Predicts Sleep-Dependent Memory Consolidation in Schizophrenia SO SLEEP LA English DT Article DE sleep spindles; slow waves; schizophrenia; motor; procedural learning; memory consolidation ID EYE-MOVEMENT SLEEP; DIRECT-CURRENT STIMULATION; PLACEBO-CONTROLLED TRIAL; CORTICOTHALAMIC FEEDBACK; OSCILLATIONS; RIPPLES; PERFORMANCE; COHERENCE; DEFICITS; HUMANS AB Study Objectives: Schizophrenia patients have correlated deficits in sleep spindle density and sleep-dependent memory consolidation. In addition to spindle density, memory consolidation is thought to rely on the precise temporal coordination of spindles with slow waves (SWs). We investigated whether this coordination is intact in schizophrenia and its relation to motor procedural memory consolidation. Methods: Twenty-one chronic medicated schizophrenia patients and 17 demographically matched healthy controls underwent two nights of polysomnography, with training on the finger tapping motor sequence task (MST) on the second night and testing the following morning. We detected SWs (0.5-4 Hz) and spindles during non-rapid eye movement (NREM) sleep. We measured SW-spindle phase-amplitude coupling and its relation with overnight improvement in MST performance. Results: Patients did not differ from controls in the timing of SW-spindle coupling. In both the groups, spindles peaked during the SW upstate. For patients alone, the later in the SW upstate that spindles peaked and the more reliable this phase relationship, the greater the overnight MST improvement. Regression models that included both spindle density and SW-spindle coordination predicted overnight improvement significantly better than either parameter alone, suggesting that both contribute to memory consolidation. Conclusion: Schizophrenia patients show intact spindle-SW temporal coordination, and these timing relationships, together with spindle density, predict sleep-dependent memory consolidation. These relations were seen only in patients suggesting that their memory is more dependent on optimal spindle-SW timing, possibly due to reduced spindle density. Interventions to improve memory may need to increase spindle density while preserving or enhancing the coordination of NREM oscillations. C1 [Demanuele, Charmaine; Baran, Bengi; Vangel, Mark G.; Manoach, Dara S.] Massachusetts Gen Hosp, Dept Psychiat, Charlestown Navy Yard 149,13th St,Room 1-111, Charlestown, MA 02129 USA. [Demanuele, Charmaine; Baran, Bengi; Khan, Sheraz; Vangel, Mark G.; Hamalainen, Matti; Manoach, Dara S.] Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Demanuele, Charmaine; Baran, Bengi; Khan, Sheraz; Vangel, Mark G.; Cox, Roy; Hamalainen, Matti; Stickgold, Robert; Manoach, Dara S.] Harvard Med Sch, Boston, MA USA. [Bartsch, Ullrich; Jones, Matthew W.] Univ Bristol, Sch Physiol & Pharmacol, Bristol, Avon, England. [Cox, Roy; Stickgold, Robert] Beth Israel Deaconess Med Ctr, Dept Psychiat, Boston, MA 02215 USA. RP Manoach, DS (reprint author), Massachusetts Gen Hosp, Dept Psychiat, Charlestown Navy Yard 149,13th St,Room 1-111, Charlestown, MA 02129 USA. EM Dara.Manoach@mgh.harvard.edu FU National Institutes of Health [R01 MH092638, R01 MH048832, 1UL1TR001102-01]; Sunovion Pharmaceuticals, Inc. [30675]; NARSAD Young Investigator Award from the Brain and Behavior Research Foundation; Medical Research Council [G1002064]; Rubicon grant from The Netherlands Organization for Scientific Research; Eli Lilly Co. FX This work was supported by the National Institutes of Health R01 MH092638 to DSM and RS; R01 MH048832 to RS; 1UL1TR001102-01 to Harvard Catalyst; Grant # 30675 from Sunovion Pharmaceuticals, Inc. (formerly Sepracor, Inc.) to DSM; an NARSAD Young Investigator Award from the Brain and Behavior Research Foundation to CD; Medical Research Council grant G1002064 for support of MWJ and UB; and Rubicon grant from The Netherlands Organization for Scientific Research to RC. MWJ received research support from Eli Lilly & Co. NR 79 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 0161-8105 EI 1550-9109 J9 SLEEP JI Sleep PD JAN 1 PY 2017 VL 40 IS 1 AR PII zsw013 DI 10.1093/sleep/zsw013 PG 10 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA EK7SO UT WOS:000394125700013 ER PT J AU Richards, A Inslicht, SS Metzler, TJ Mohlenhoff, BS Rao, MN O'Donovan, A Neylan, TC AF Richards, Anne Inslicht, Sabra S. Metzler, Thomas J. Mohlenhoff, Brian S. Rao, Madhu N. O'Donovan, Aoife Neylan, Thomas C. TI Sleep and Cognitive Performance From Teens To Old Age: More Is Not Better SO SLEEP LA English DT Article DE Sleep duration; cognitive performance; aging; adolescence ID ADULT LIFE-SPAN; WORKING-MEMORY; VISUAL MEMORY; UNITED-STATES; DURATION; ADOLESCENTS; HEALTH; ASSOCIATION; SCHEDULES; BEHAVIORS AB Objectives: To determine the interaction of age and habitual sleep duration in predicting cognitive performance in a large sample of participants aged 15 to 89 years. Methods: This study is a cross-sectional analysis of performance data gathered between January 2012 and September 2013. First-time players ( N = 512 823) of three internet cognitive training games measuring processing speed, working memory, visuospatial memory, and arithmetic participated in the study. Results: Performance was based on a measure of speed and accuracy for each game. The relationship between performance and self-reported habitual sleep duration was examined in the sample as a whole and across 10-year age groups starting at age 15 and ending at 75 and older. Performance peaked at 7 h of sleep duration for all three games in the sample as a whole, and the decrements in performance for sleep durations greater than 7 h were either comparable or greater in the youngest as compared to the oldest age groups. Conclusions: These findings challenge the hypothesis that deteriorating cognitive performance with long sleep duration is driven by medical comorbidities associated with aging. Further, these data are consistent with an optimal dose model of sleep and suggest that the model for the homeostatic recovery of cognitive function as a function of sleep duration should incorporate a curvilinear decline with longer duration sleep, indicating that there may be a cost to increased sleep. Replication and further research is essential for clarifying the sleep duration-cognition relationship in youth and adults of all ages. C1 [Richards, Anne; Inslicht, Sabra S.; Mohlenhoff, Brian S.; Rao, Madhu N.; O'Donovan, Aoife; Neylan, Thomas C.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Richards, Anne; Inslicht, Sabra S.; Metzler, Thomas J.; Mohlenhoff, Brian S.; O'Donovan, Aoife; Neylan, Thomas C.] San Francisco VA Med Ctr, 4150 Clement St, San Francisco, CA 94121 USA. RP Richards, A (reprint author), San Francisco VA Med Ctr, 4150 Clement St, San Francisco, CA 94121 USA. EM anne.richards@ucsf.edu FU U.S. Department of Veteran Affairs [1IK2CX000871-01A2]; U.S. Department of Defense [W81XWH-16-1-0259] FX Work on this project was funded in part by grants to Dr. Richards from the U.S. Department of Veteran Affairs (1IK2CX000871-01A2) and the U.S. Department of Defense (W81XWH-16-1-0259). NR 51 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 0161-8105 EI 1550-9109 J9 SLEEP JI Sleep PD JAN 1 PY 2017 VL 40 IS 1 AR PII zsw029 DI 10.1093/sleep/zsw029 PG 9 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA EK7SO UT WOS:000394125700029 ER PT J AU Swetz, KM Barnett, MD Kamal, AH Mansel, JK AF Swetz, Keith M. Barnett, Michael D. Kamal, Arif H. Mansel, J. Keith TI Physician Aid in Dying in the US South: What Does the Future Hold? SO SOUTHERN MEDICAL JOURNAL LA English DT Editorial Material C1 Univ Alabama Birmingham, Ctr Palliat & Support Care, Birmingham Vet Affairs Med Ctr, 1720 2nd Ave S,BDB 650, Birmingham, AL 35294 USA. Duke Univ, Duke Canc Inst, Durham, NC USA. Mayo Clin, Div Gen Internal Med, Sect Palliat Med, Rochester, MN USA. Univ Mississippi, Med Ctr, Dept Med, Jackson, MS 39216 USA. RP Swetz, KM (reprint author), Univ Alabama Birmingham, Ctr Palliat & Support Care, 1720 2nd Ave S,BDB 650, Birmingham, AL 35294 USA. EM kswetz@uabmc.edu NR 6 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 0038-4348 EI 1541-8243 J9 SOUTH MED J JI South.Med.J. PD JAN PY 2017 VL 110 IS 1 BP 9 EP 10 DI 10.14423/SMJ.0000000000000582 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA EL1KS UT WOS:000394379900003 PM 28052167 ER PT J AU Vachhani, R Patel, T Centor, RM Estrada, CA AF Vachhani, Raj Patel, Toral Centor, Robert M. Estrada, Carlos A. TI Sensitivity for Diagnosing Group A Streptococcal Pharyngitis from Manufacturers is 10% Higher than Reported in Peer-Reviewed Publications SO SOUTHERN MEDICAL JOURNAL LA English DT Article DE diagnostic test approval; pharyngitis; diagnosis; sensitivity and specificity; streptococcal infections; diagnosis; microbiology; techniques and procedures ID ANTIGEN-DETECTION TESTS; TEST ACCURACY; SORE THROAT; METAANALYSIS; REGRESSION AB Objectives Meta-analyses based on peer-reviewed publications report a sensitivity of approximately 85% for rapid antigen streptococcus tests to diagnose group A streptococcal (GAS) pharyngitis. Because these meta-analyses excluded package inserts, we examined the test characteristics of rapid antigen streptococcal tests and molecular methods that manufacturers report in their package inserts. Methods We included tests available in the US market (Food and Drug Administration, period searched 1993-2015) and used package insert data to calculate pooled sensitivity and specificity. To examine quality, we used the Quality Assessment of Diagnostic Accuracy Studies-2. We excluded 26 tests having different trade names but identical methods and data. Results The study design was prospective in 41.7% (10 of 24). The pooled sensitivity of the most commonly used method, lateral flow/immunochromatographic, was 95% (95% confidence interval [CI] 94-96) and the pooled specificity was 98% (96-98); 7108 patients. The pooled sensitivity of the polymerase chain reaction or molecular methods was 98% (95% CI 96-98) and the pooled specificity was 96% (95% CI 95-97); 5685 patients. Conclusions Package inserts include sponsored studies that overestimate the sensitivity of rapid tests to diagnose GAS pharyngitis by approximately 10%. Physicians should understand that package inserts overestimate diagnostic test utility; a negative test cannot be used to exclude GAS pharyngitis. C1 [Estrada, Carlos A.] Univ Alabama Birmingham, Div Gen Internal Med, 732 FOT,510 20th St S, Birmingham, AL 35294 USA. Case Western Reserve Univ, Dept Med, Cleveland, OH 44106 USA. Birmingham Vet Affairs Med Ctr, Birmingham, AL USA. RP Estrada, CA (reprint author), Univ Alabama Birmingham, Div Gen Internal Med, 732 FOT,510 20th St S, Birmingham, AL 35294 USA. EM cestrada@uabmc.edu FU Justin E. Rodgers Foundation FX R.M.C. received funding from the Justin E. Rodgers Foundation. The remaining authors did not report any financial relationships or conflicts of interest. NR 19 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 0038-4348 EI 1541-8243 J9 SOUTH MED J JI South.Med.J. PD JAN PY 2017 VL 110 IS 1 BP 59 EP 64 DI 10.14423/SMJ.0000000000000597 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA EL1KS UT WOS:000394379900015 PM 28052179 ER PT J AU Suri, P Boyko, EJ Smith, NL Jarvik, JG Williams, FMK Jarvik, GP Goldberg, J AF Suri, Pradeep Boyko, Edward J. Smith, Nicholas L. Jarvik, Jeffrey G. Williams, Frances M. K. Jarvik, Gail P. Goldberg, Jack TI Modifiable risk factors for chronic back pain: insights using the co-twin control design SO SPINE JOURNAL LA English DT Article DE Activity; Alcohol; Depression; Low back pain; Musculoskeletal diseases; Obesity; Sleep; Smoking; Stress disorders; Twins ID ERA TWIN REGISTRY; POPULATION-BASED SAMPLE; LIFE-STYLE-FACTORS; PHYSICAL-ACTIVITY; PTSD CHECKLIST; PSYCHOMETRIC PROPERTIES; PSYCHIATRIC-DISORDERS; OBESITY; METAANALYSIS; HERITABILITY AB BACKGROUND: Inconsistent associations between modifiable risk factors and chronic back pain (CBP) may be due to the inability of traditional epidemiologic study designs to properly account for an array of potential genetic and environmental confounding factors. The co-twin control research design, comparing modifiable risk factors in twins discordant for CBP, offers a unique way to remove numerous confounding factors. PURPOSE: The study aimed to examine the association of modifiable lifestyle and psychological factors with lifetime CBP. STUDY DESIGN/SETTING: This is a cross-sectional co-twin control study in a nationwide sample of male twin members of the Vietnam Era Twin Registry. PATIENT SAMPLE: The sample is composed of 7,108 participants, including 1,308 monozygotic (MZ) pairs and 793 dizygotic pairs. OUTCOME MEASURE: The outcome measure is the self-reported lifetime history of CBP. METHODS: Lifestyle factors included body mass index (BMI), smoking history, alcohol consumption, habitual physical activity, and typical sleep duration. Psychological factors included depression (Patient Health Questionnaire-9) and posttraumatic stress disorder (PTSD) symptoms (PTSD Checklist). Covariates included age, race, education, and income. Odds ratios (ORs) and 95% confidence intervals (CI) were estimated for the association of risk factors with lifetime CBP when considering twins as individuals, and a within-pair co-twin control analysis that accounted for familial and genetic factors. Funding was through VA Grant 5IK2RX001515; there were no study-specific conflicts of interest. RESULTS: The mean age of respondents was 62 years and the prevalence of lifetime CBP was 28%. All lifestyle factors were associated with CBP in the individual level analysis. However, none of these persisted in the within-pair analyses, except for severe obesity (BMI >= 35.0), which was associated with lifetime CBP in both individual-level (OR=1.6, 95% CI: 1.3-1.9) and within-pair analyses (MZ analysis: OR=3.7, 95% CI: 1.2-11.4). Symptoms of PTSD and depression were strongly associated with lifetime CBP in both the individual-level (moderate or severe depression: OR=4.2, 95% CI: 3.6-4.9, and severe PTSD: OR=4.8, 95% CI: 4.0-5.7) and within-pair (MZ) analyses (moderate or severe depression: OR=4.6, 95% CI: 2.4-8.7, and severe PTSD: OR=3.2, 95% CI: 1.6-6.5). CONCLUSIONS: Many associations between modifiable lifestyle risk factors and CBP are due to confounding by familial and genetic factors. Severe obesity, depression, and PTSD should be considered in the development of intervention strategies to reduce the prevalence of CBP. Published by Elsevier Inc. C1 [Suri, Pradeep; Boyko, Edward J.; Smith, Nicholas L.; Goldberg, Jack] VA Puget Sound Hlth Care Syst, Seattle Epidemiol Res & Informat Ctr, S-152 ERIC,1660 S Columbian Way, Seattle, WA 98108 USA. [Suri, Pradeep] Div Rehabil Care Serv, 1660 S Columbian Way, Seattle, WA 98108 USA. [Suri, Pradeep] Univ Washington, Dept Rehabil Med, 325 Ninth Ave,Box 359612, Seattle, WA 98104 USA. [Boyko, Edward J.] VA Puget Sound Hlth Care Syst, Gen Med Serv, 1660 S Columbian Way, Seattle, WA 98108 USA. [Smith, Nicholas L.; Goldberg, Jack] Univ Washington, Dept Epidemiol, 1959 NE Pacific St Hlth Sci Bldg,Box 357236, Seattle, WA 98195 USA. [Jarvik, Jeffrey G.] Univ Washington, Comparat Effectiveness Cost & Outcomes Res Ctr, 4333 Brooklyn Ave NE,Box 359455, Seattle, WA 98195 USA. [Jarvik, Jeffrey G.] Univ Washington, Dept Radiol, 325 9th Ave, Seattle, WA 98104 USA. [Jarvik, Jeffrey G.] Univ Washington, Dept Neurol Surg, 325 9th Ave, Seattle, WA 98104 USA. [Jarvik, Jeffrey G.] Univ Washington, Dept Hlth Serv, 325 9th Ave, Seattle, WA 98104 USA. [Williams, Frances M. K.] Kings Coll London, Dept Twin Res & Genet Epidemiol, London WC2R 2LS, England. [Jarvik, Gail P.] Dept Med Med Genet, 3720 15th Ave NE, Seattle, WA 98105 USA. [Jarvik, Gail P.] Univ Washington, Dept Genome Sci, 3720 15th Ave NE, Seattle, WA 98105 USA. RP Suri, P (reprint author), VA Puget Sound Hlth Care Syst, Seattle Epidemiol Res & Informat Ctr, S-152 ERIC,1660 S Columbian Way, Seattle, WA 98108 USA. EM pradeep.suri@va.gov FU VA Career Development Award from the US Department of Veterans Affairs Rehabilitation Research and Development Service [1IK2RX001515]; Cooperative Studies Program [569]; VA Puget Sound Health Care System FX This work was supported by VA Career Development Award #1IK2RX001515 from the US Department of Veterans Affairs Rehabilitation Research and Development Service. Funding for this study was also provided by Cooperative Studies Program #569. Dr Suri and Dr Boyko are staff physicians at the VA Puget Sound Health Care System in Seattle, Washington. Dr Goldberg and Dr Smith are research scientists at the VA Puget Sound Health Care System. The participation of Dr Suri, Dr Boyko, Dr Smith, and Dr Goldberg in this study was funded by the VA Puget Sound Health Care System. The contents of this work do not represent the views of the US Department of Veterans Affairs or the US Government. NR 67 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 1529-9430 EI 1878-1632 J9 SPINE J JI Spine Journal PD JAN PY 2017 VL 17 IS 1 BP 4 EP 14 DI 10.1016/j.spinee.2016.07.533 PG 11 WC Clinical Neurology; Orthopedics SC Neurosciences & Neurology; Orthopedics GA EO1IL UT WOS:000396451800003 PM 27794503 ER PT J AU Marjoua, Y Xiao, R Waites, C Yang, BW Harris, MB Schoenfeld, AJ AF Marjoua, Youssra Xiao, Ryan Waites, Cameron Yang, Brian W. Harris, Mitchel B. Schoenfeld, Andrew J. TI A systematic review of spinal research conducted using the National Surgical Quality Improvement Program SO SPINE JOURNAL LA English DT Review DE Academic influence; Citation analysis; h-index; Impact factor; National Surgical Quality Improvement Program; Systematic review ID ORTHOPEDIC-SURGERY; KNEE ARTHROPLASTY; RISK-FACTORS; BIG DATA; COMPLICATIONS; MORTALITY; PRODUCTIVITY; DATABASE; FACULTY; TRAUMA AB BACKGROUND CONTEXT: Over the course of the last decade, interest in the use of large data repositories for clinical research in orthopedic and spine surgery has grown substantially. Detractors maintain that the clinical relevance of research conducted using large registries is limited, and that the academic influence of such studies is minimal. Such contentions have not been empirically evaluated. PURPOSE: This study sought to perform a systematic review of spinal research conducted using the National Surgical Quality Improvement Program (NSQIP). STUDY DESIGN: This is a systematic review. OUTCOME MEASURES: Impact factor (IF) of the journal of publication and number of citations of published articles conducted using the NSQIP. METHODS: Orthopedic and spine-specific NSQIP articles published from January 1, 2007 to July 31, 2015, were identified through a query of PubMed or Medline, Embase, Web of Science, and Scopus. Articles were classified by journal of publication, year of publication, study topic, study purpose, and method of statistical analysis. Spine surgical publications were compared with other orthopedic research conducted using the NSQIP. The primary dependent variables for the purposes of statistical testing were IF of the journal in which the article was published and the number of citations for each publication. Negative binomial regression was used to evaluate the characteristics of papers associated with increased IF and number of citations. RESULTS: Of the 1,525 articles identified in the initial search, 114 studies were considered eligible for inclusion in the systematic review. The average IF for the journals publishing orthopedic NSQIP articles was 2.75 (standard deviation [SD] 1.22, range 0-5.28), whereas it was 2.52 (SD 0.81, range 1.38-5.28) for spinal research. The average number of citations per article was 6.08 (SD 10.9, range 0-69) and 6.4 (SD 12.0, range 0-69) for spine-specific studies. Following negative binomial regression, only IF (regression coefficients [RC] 0.31; 95% confidence intervals [CI] 0.08, 0.55) and the year of publication (RC-1.29; 9% CI-1.64, -0.95) were found to have a statistically significant association with number of citations. Among spine-specific research articles, only the year of publication was found to influence the number of citations (RC-1.29; 95% CI-1.94, -0.64). CONCLUSIONS: Our findings indicate that the academic impact of orthopedic and spine surgical research conducted using NSQIP is highly variable, with most publications found to have relativelylow impact. As our evaluation of study characteristics associated with high-impact publications and increased citations were unable to uncover factors that are likely translatable, we suggest following research design guidelines that highlight best practices when using large datasets for orthopedic research. (C) 2016 Elsevier Inc. All rights reserved. C1 [Marjoua, Youssra] Massachusetts Gen Hosp, Harvard Combined Orthopaed Residency Program, 55 Fruit St, Boston, MA 02114 USA. [Xiao, Ryan; Waites, Cameron; Yang, Brian W.] Harvard Med Sch, 25 Shattuck St, Boston, MA 02115 USA. [Harris, Mitchel B.; Schoenfeld, Andrew J.] Harvard Med Sch, Brigham & Womens Hosp, Dept Orthopaed Surg, 75 Francis St, Boston, MA 02115 USA. RP Schoenfeld, AJ (reprint author), Harvard Med Sch, Brigham & Womens Hosp, Dept Orthopaed Surg, 75 Francis St, Boston, MA 02115 USA. EM ajschoen@neomed.edu OI Waites, Cameron/0000-0001-6926-4643; Yang, Brian/0000-0002-4580-4438 NR 19 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 1529-9430 EI 1878-1632 J9 SPINE J JI Spine Journal PD JAN PY 2017 VL 17 IS 1 BP 88 EP 95 DI 10.1016/j.spinee.2016.08.013 PG 8 WC Clinical Neurology; Orthopedics SC Neurosciences & Neurology; Orthopedics GA EO1IL UT WOS:000396451800014 PM 27520079 ER PT J AU Gordon, AJ AF Gordon, Adam J. TI The 40th annual meeting of AMERSA: Highlights, abstracts, and awards SO SUBSTANCE ABUSE LA English DT Editorial Material C1 [Gordon, Adam J.] Univ Pittsburgh, Sch Med, Pittsburgh, PA 15240 USA. [Gordon, Adam J.] VA Pittsburgh Healthcare Syst, Pittsburgh, PA 15240 USA. RP Gordon, AJ (reprint author), Univ Pittsburgh, Sch Med, Pittsburgh, PA 15240 USA.; Gordon, AJ (reprint author), VA Pittsburgh Healthcare Syst, Pittsburgh, PA 15240 USA. EM gordona@medschool.pitt.edu NR 2 TC 0 Z9 0 U1 0 U2 0 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 0889-7077 EI 1547-0164 J9 SUBST ABUS JI Subst. Abus. PY 2017 VL 38 IS 1 BP 1 EP 1 DI 10.1080/08897077.2017.1281646 PG 1 WC Substance Abuse SC Substance Abuse GA EO3NN UT WOS:000396601600001 PM 28080324 ER PT J AU Gordon, AJ AF Gordon, Adam J. TI Abstracts of the 18th Annual Meeting of the International Society of Addiction Medicine (ISAM)-2016 SO SUBSTANCE ABUSE LA English DT Editorial Material C1 [Gordon, Adam J.] Univ Pittsburgh, Sch Med, Pittsburgh, PA 15240 USA. [Gordon, Adam J.] VA Pittsburgh Healthcare Syst, Pittsburgh, PA 15240 USA. RP Gordon, AJ (reprint author), Univ Pittsburgh, Sch Med, Pittsburgh, PA 15240 USA.; Gordon, AJ (reprint author), VA Pittsburgh Healthcare Syst, Pittsburgh, PA 15240 USA. EM gordona@medschool.pitt.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 0889-7077 EI 1547-0164 J9 SUBST ABUS JI Subst. Abus. PY 2017 VL 38 IS 1 BP 2 EP 2 DI 10.1080/08897077.2017.1281044 PG 1 WC Substance Abuse SC Substance Abuse GA EO3NN UT WOS:000396601600002 PM 28075715 ER PT J AU Kertesz, SG AF Kertesz, Stefan G. TI Turning the tide or riptide? The changing opioid epidemic SO SUBSTANCE ABUSE LA English DT Editorial Material DE Opioids; opioid use disorder; overdose; pain; prescriptions; primary care; treatment access ID UNITED-STATES; CHRONIC PAIN; ASSOCIATION; ADDICTION; THERAPY AB The US opioid epidemic has changed profoundly in the last 3 years, in ways that require substantial recalibration of the US policy response. This report summarizes the changing nature of overdose deaths in Jefferson County (home to Birmingham, Alabama) using data updated through June 30, 2016. Heroin and fentanyl have come to dominate an escalating epidemic of lethal opioid overdose, whereas opioids commonly obtained by prescription play a minor role, accounting for no more than 15% of reported deaths in 2015. Such local data, along with similar reports from other localities, augment the insights available from the Centers for Disease Control and Prevention's current overdose summary, which lacks data from 2015-2016 and lacks information regarding fentanyl in particular. The observed changes in the opioid epidemic are particularly remarkable because they have emerged despite sustained reductions in opioid prescribing and sustained reductions in prescription opioid misuse. Among US adults, past-year prescription opioid misuse is at its lowest level since 2002. Among 12th graders it is at its lowest level in 20 years. A credible epidemiologic account of the opioid epidemic is as follows: although opioid prescribing by physicians appears to have unleashed the epidemic prior to 2012, physician prescribing no longer plays a major role in sustaining it. The accelerating pace of the opioid epidemic in 2015-2016 requires a serious reconsideration of governmental policy initiatives that continue to focus on reductions in opioid prescribing. The dominant priority should be the assurance of subsidized access to evidencebased medication-assisted treatment for opioid use disorder. Such treatment is lacking across much of the United States at this time. Further aggressive focus on prescription reduction is likely to obtain diminishing returns while creating significant risks for patients. C1 [Kertesz, Stefan G.] Univ Alabama Birmingham, Sch Med, Birmingham VA Med Ctr, 700 19th St South Mailstop 151, Birmingham, AL 35233 USA. RP Kertesz, SG (reprint author), Univ Alabama Birmingham, Sch Med, Birmingham VA Med Ctr, 700 19th St South Mailstop 151, Birmingham, AL 35233 USA. EM skertesz@uabmc.edu NR 50 TC 0 Z9 0 U1 0 U2 0 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 0889-7077 EI 1547-0164 J9 SUBST ABUS JI Subst. Abus. PY 2017 VL 38 IS 1 BP 3 EP 8 DI 10.1080/08897077.2016.1261070 PG 6 WC Substance Abuse SC Substance Abuse GA EO3NN UT WOS:000396601600003 PM 27858590 ER PT J AU Das, S Shah, N Ghadiali, M AF Das, Smita Shah, Nina Ghadiali, Murtuza TI Intravenous use of intranasal naloxone: A case of overdose reversal SO SUBSTANCE ABUSE LA English DT Editorial Material DE Drug overdose; harm reduction; naloxone; opiate dependence ID OPIOID OVERDOSE; HEROIN OVERDOSE; DRUG-USERS; PARTICIPANTS; PREVENTION; MORTALITY; KNOWLEDGE; EDUCATION; EFFICACY; ACCESS AB Background: Opioid overdose is a growing concern in the United States and internationally. Prehospital or pre-medical personnel (layperson) administration of naloxone, an opioid antagonist, to reverse overdose, is an expanding mode of harm reduction. Recently, community clinics, methadone clinics, needle exchanges, some pharmacies, and other health care facilities have made naloxone available to the community. Case: This case describes heroin overdose reversal of a 28-year-old male who had been using about a gram of heroin intravenously for 3 years but recently reduced frequency of use in an attempt to stop. He was seen initially 1 week prior to a buprenorphine induction in our clinic. After the initial intake, he used intravenous heroin, a larger amount than over the past several weeks in anticipation of abstinence, lost consciousness, and was difficult to arouse. A friend with him noted the patient's respirations to become shallow and administered naloxone nasal spray that the patient had obtained from a needle exchange, but did so intravenously by attaching an unused drug needle to the syringe barrel in place of the nasal atomizer. The patient's overdose was reversed and he recovered. Discussion: This is the first known published case of a community-distributed naloxone nasal spray being used intravenously by a layperson (bystander). The case emphasizes the efficacy of naloxone in overdose reversal and also the need for education or instructions on naloxone use by others (not just the user). Finally, it highlights the risk of overdose in those entering treatment, seeking intoxication one last time. C1 [Das, Smita; Ghadiali, Murtuza] Univ Calif San Francisco, Dept Addict Psychiat, San Francisco, CA 94143 USA. [Das, Smita] Stanford Univ, Sch Med, Dept Psychiat & Behav Sci, Palo Alto, CA 94304 USA. [Das, Smita] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA. [Das, Smita] San Francisco VA Med Ctr, San Francisco, CA USA. [Shah, Nina] Kaiser Permanente San Francisco Med Ctr, Chem Dependency Recovery Program, San Francisco, CA USA. [Ghadiali, Murtuza] Kaiser Permanente San Francisco Med Ctr, Dept Addict Med, San Francisco, CA USA. RP Das, S (reprint author), Univ Calif San Francisco, Addict Psychiat, 4150 Clement St, San Francisco, CA 94121 USA. EM smidas@stanford.edu NR 27 TC 0 Z9 0 U1 1 U2 1 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 0889-7077 EI 1547-0164 J9 SUBST ABUS JI Subst. Abus. PY 2017 VL 38 IS 1 BP 18 EP 21 DI 10.1080/08897077.2016.1267686 PG 4 WC Substance Abuse SC Substance Abuse GA EO3NN UT WOS:000396601600006 PM 27925864 ER PT J AU Gellad, WF Zhao, XH Thorpe, CT Thorpe, JM Sileanu, FE Cashy, JP Mor, M Hale, JA Radomski, T Hausmann, LRM Fine, MJ Good, CB AF Gellad, Walid F. Zhao, Xinhua Thorpe, Carolyn T. Thorpe, Joshua M. Sileanu, Florentina E. Cashy, John P. Mor, Maria Hale, Jennifer A. Radomski, Thomas Hausmann, Leslie R. M. Fine, Michael J. Good, Chester B. TI Overlapping buprenorphine, opioid, and benzodiazepine prescriptions among veterans dually enrolled in Department of Veterans Affairs and Medicare Part D SO SUBSTANCE ABUSE LA English DT Editorial Material DE Buprenorphine; opiate substitution treatment; opioid; veterans ID METHADONE; PROGRAMS; EPIDEMIC AB Background: Buprenorphine is a key tool in the management of opioid use disorder, but there are growing concerns about abuse, diversion, and safety. These concerns are amplified for the Department of Veterans Affairs (VA), whose patients may receive care concurrently from multiple prescribers within and outside VA. To illustrate the extent of this challenge, we examined overlapping prescriptions for buprenorphine, opioids, and benzodiazepines among veterans dually enrolled in VA and Medicare Part D. Methods: We constructed a cohort of all veterans dually enrolled in VA and Part D who filled an opioid prescription in 2012. We identified patients who received tablet or film buprenorphine products from either source. We calculated the proportion of buprenorphine recipients with any overlapping prescription (based on days supply) for a nonbuprenorphine opioid or benzodiazepine, focusing on veterans who received overlapping prescriptions from a different system than their buprenorphine prescription (Part D buprenorphine recipients receiving overlapping opioids or benzodiazepines from VA and vice versa). Results: There were 1790 dually enrolled veterans with buprenorphine prescriptions, including 760 (43%) from VA and 1091 (61%) from Part D (61 veterans with buprenorphine from both systems were included in each group). Among VA buprenorphine recipients, 199 (26%) received an overlapping opioid prescription and 11 (1%) received an overlapping benzodiazepine prescription from Part D. Among Part D buprenorphine recipients, 208 (19%) received an overlapping opioid prescription and 178 (16%) received an overlapping benzodiazepine prescription from VA. Among VA and Part D buprenorphine recipients with cross-system opioid overlap, 25% (49/199) and 35% (72/208), respectively, had > 90 days of overlap. Conclusions: Many buprenorphine recipients receive overlapping prescriptions for opioids and benzodiazepines from a different health care system than the one in which their buprenorphine was filled. These findings highlight a previously undocumented safety risk for veterans dually enrolled in VA and Medicare. C1 [Gellad, Walid F.; Zhao, Xinhua; Thorpe, Carolyn T.; Thorpe, Joshua M.; Sileanu, Florentina E.; Cashy, John P.; Mor, Maria; Hale, Jennifer A.; Radomski, Thomas; Hausmann, Leslie R. M.; Fine, Michael J.; Good, Chester B.] VA Pittsburgh Healthcare Syst, Ctr Hlth Equ Res & Promot, Univ Dr 151C, Pittsburgh, PA 15240 USA. [Gellad, Walid F.; Radomski, Thomas; Hausmann, Leslie R. M.; Fine, Michael J.; Good, Chester B.] Univ Pittsburgh, Sch Med, Div Gen Internal Med, Pittsburgh, PA USA. [Thorpe, Carolyn T.; Thorpe, Joshua M.] Univ Pittsburgh, Sch Pharm, Dept Pharm & Therapeut, Pittsburgh, PA 15261 USA. RP Gellad, WF (reprint author), VA Pittsburgh Healthcare Syst, Ctr Hlth Equ Res & Promot, Univ Dr 151C, Pittsburgh, PA 15240 USA. EM walid.gellad@va.gov FU VA Health Services Research & Development (HSRD) [I01 HX001765-01]; Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Health Services Research and Development, VA Information Resource Center Affairs [SDR 02-237, 98-004] FX This work was supported by VA Health Services Research & Development (HSR&D) I01 HX001765-01. Support for VA/CMS data is provided by the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Health Services Research and Development, VA Information Resource Center (project numbers SDR 02-237 and 98-004). The funder had no role in the design and conduct of the study, collection, management, analysis, and interpretation of data, or preparation of the manuscript. This work represents the opinions of the authors alone and does not necessarily represent the views of the Department of Veterans Affairs or the United States Government. The authors declare they have no conflicts of interest. NR 19 TC 0 Z9 0 U1 0 U2 0 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 0889-7077 EI 1547-0164 J9 SUBST ABUS JI Subst. Abus. PY 2017 VL 38 IS 1 BP 22 EP 25 DI 10.1080/08897077.2016.1267071 PG 4 WC Substance Abuse SC Substance Abuse GA EO3NN UT WOS:000396601600007 PM 27925868 ER PT J AU Mitchell, MA Broyles, LM Pringle, JL Kraemer, KL Childers, JW Buranosky, RA Gordon, AJ AF Mitchell, Michael A. Broyles, Lauren M. Pringle, Janice L. Kraemer, Kevin L. Childers, Julie W. Buranosky, Raquel A. Gordon, Adam J. TI Education for the mind and the heart? Changing residents' attitudes about addressing unhealthy alcohol use SO SUBSTANCE ABUSE LA English DT Editorial Material DE education; internship and residency; professional role; screening; unhealthy alcohol use ID STUDENTS-ATTITUDES; DISORDERS; PROGRAM AB Background: Screening and brief intervention counseling for unhealthy alcohol use are among the top 10 recommended clinical preventive services for US adults. Although federally funded training programs in alcohol screening, brief intervention, and referral to treatment (SBIRT) have focused on increasing physicians' professional readiness to address drinking with their patients, programs typically focus on knowledge and skill acquisition, with less attention to attitudinal change. The purpose of this study was to assess the impact of a multicomponent SBIRT training program on changes in internal medical residents' professional readiness for working with patients with unhealthy alcohol use. Methods: Between 2011 and 2013, first-year internal medicine residents (n = 80) at a large academic medical center participated in a 16-hour SBIRT training program, consisting of two 3-hour didactic sessions, online modules, and a half-day clinical experience, during the Ambulatory Care month of the residency training year. Residents completed a modified Alcohol and Problems Perceptions Questionnaire (AAPPQ) at the beginning and end of the residency year to assess changes in professional readiness to work with adults with unhealthy alcohol use across 6 domains: Role Adequacy, Role Legitimacy, Role Support, Motivation, Task-Specific Self-esteem, and Satisfaction. Wilcoxon signed-rank tests were used to evaluate changes in the 6 AAPPQ subscale scores over time. Results: Residents reported significant increases in Role Adequacy (alcoholrelated knowledge/skills; pre: 34 and post: 39.5; P <.0001) and Role Support (professional support; pre: 16 and post: 18; P D.005) scores. No significant differences in the remaining AAPPQ subscales were detected. Conclusions: Residents in the SBIRT training program indicated improvements in knowledge, skills, and professional role support but not in motivation, task-specific self-esteem, or satisfaction for working with patients with unhealthy alcohol use. Explicit curricular attention to these domains may be required to facilitate SBIRT skills application and sustained practice change. C1 [Mitchell, Michael A.; Gordon, Adam J.] VA Pittsburgh Healthcare Syst, Dept Vet Affairs, Adv Fellowship VA Interdisciplinary Addict Progra, Pittsburgh, PA USA. [Mitchell, Michael A.; Broyles, Lauren M.; Gordon, Adam J.] VA Pittsburgh Healthcare Syst, Ctr Hlth Equ Res & Promot, Pittsburgh, PA USA. [Broyles, Lauren M.; Gordon, Adam J.] VA Pittsburgh Healthcare Syst, VISN Mental Illness Res Educ & Clin Ctr 4, Pittsburgh, PA USA. [Broyles, Lauren M.; Kraemer, Kevin L.; Childers, Julie W.; Buranosky, Raquel A.; Gordon, Adam J.] Univ Pittsburgh, Sch Med, Dept Med, Div Gen Internal Med, Pittsburgh, PA 15213 USA. [Broyles, Lauren M.; Kraemer, Kevin L.; Gordon, Adam J.] Univ Pittsburgh, Ctr Res Healthcare, Pittsburgh, PA USA. [Pringle, Janice L.] Univ Pittsburgh, Sch Pharm, Program Evaluat & Res Unit, Pittsburgh, PA USA. RP Mitchell, MA (reprint author), Allegheny Cty Human Serv, Off Data Anal Res & Evaluat, One Smithfield St,Suite 400, Pittsburgh, PA 15222 USA. EM mike.mitchell@alleghenycounty.us FU Substance Abuse and Mental Health Service Administration (SAMHSA); Center for Substance Abuse Treatment (CSAT) [1TI020263-01]; US Department of Veterans Affairs Office of Academic Affiliations Advanced Fellowship Program in Addiction Treatment; Health Services Research and Development Service of the US Department of Veterans Affairs [CDA 10-014] FX The SMaRT project was originally funded through the Substance Abuse and Mental Health Service Administration (SAMHSA) and the Center for Substance Abuse Treatment (CSAT) (Award No. 1TI020263-01; Principal Investigator: J. Pringle). The funding agency was not involved in the work reported in the manuscript or in the composition of the submission. At the time this work was completed, Michael Mitchell was supported by the US Department of Veterans Affairs Office of Academic Affiliations Advanced Fellowship Program in Addiction Treatment. Dr. Broyles was supported by a Career Development Award (CDA 10-014) from the Health Services Research and Development Service of the US Department of Veterans Affairs. The material is the result of work supported with resources and the use of facilities at the VA Pittsburgh Healthcare System, Pittsburgh, Pennsylvania. The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs or the United States government. NR 9 TC 0 Z9 0 U1 0 U2 0 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 0889-7077 EI 1547-0164 J9 SUBST ABUS JI Subst. Abus. PY 2017 VL 38 IS 1 BP 40 EP 42 DI 10.1080/08897077.2016.1185076 PG 3 WC Substance Abuse SC Substance Abuse GA EO3NN UT WOS:000396601600011 PM 27163655 ER PT J AU Chung, T Ye, FF Hipwell, AE Stepp, SD Miller, E Borrero, S Hawk, M AF Chung, Tammy Ye, Feifei Hipwell, Alison E. Stepp, Stephanie D. Miller, Elizabeth Borrero, Sonya Hawk, Mary TI Alcohol and marijuana use in pathways of risk for sexually transmitted infection in white and black adolescent females SO SUBSTANCE ABUSE LA English DT Article DE Adolescent; alcohol; female; marijuana; risky sexual behavior; sexually transmitted infection ID BEHAVIOR; TRAJECTORIES; METAANALYSIS; INTERCOURSE; GROWTH; GIRLS; AGE AB Background: Some types of sexually transmitted infection (STI) have higher prevalence in females than males, and among black, relative to white, females. Identifying mechanisms of STI risk is critical to effective intervention. The authors tested a model in which alcohol and marijuana use serve as mediating factors in the associations between depression and conduct problems with sexual risk behavior (SRB) and STI in adolescent females. Methods: The Pittsburgh Girls Study is a longitudinal observational study of females who have been followed annually to track the course of mental and physical health conditions. The 3 oldest cohorts (N = 1750; 56.8% black, 43.2% white) provided self-reports of substance use, depression and conduct problems, SRB, and STI at ages 16-18. A path model tested alcohol and marijuana use at age 17 as mechanisms that mediate the associations of depression and conduct problems at age 16 with SRB and STI at age 18. Results: Race was involved in 2 risk pathways. In one pathway, white females reported greater alcohol use, which was associated with greater SRB. In another pathway, black females reported earlier sexual onset, which was associated with subsequent SRB. Public assistance use was independently associated with early sexual onset and STI. SRB, but not substance use, mediated the association of depression and conduct problems with STI. Conclusions: Differences by race in pathways of risk for SRB and STI, involving, for example, alcohol use and early sexual onset, were identified for young white and black females, respectively. Depression and conduct problems may signal risk for SRB and STI in young females, and warrant attention to improve health outcomes. C1 [Chung, Tammy; Hipwell, Alison E.; Stepp, Stephanie D.] Univ Pittsburgh, Western Psychiat Inst & Clin, Med Ctr, 3811 Ohara St, Pittsburgh, PA 15213 USA. [Ye, Feifei] Univ Pittsburgh, Sch Educ, Pittsburgh, PA 15260 USA. [Hipwell, Alison E.; Stepp, Stephanie D.] Univ Pittsburgh, Dept Psychol, Pittsburgh, PA 15260 USA. [Miller, Elizabeth] Univ Pittsburgh, Sch Med, Div Adolescent & Young Adult Med, Childrens Hosp Pittsburgh UPMC, Pittsburgh, PA USA. [Borrero, Sonya] Univ Pittsburgh, Div Gen Internal Med, Pittsburgh, PA USA. [Borrero, Sonya] VA Pittsburgh Healthcare Syst, VA Ctr Hlth Equ & Promot, Pittsburgh, PA USA. [Hawk, Mary] Univ Pittsburgh, Grad Sch Publ Hlth, Pittsburgh, PA USA. RP Chung, T (reprint author), Univ Pittsburgh, Med Ctr, Pittsburgh Adolescent Alcohol Res Ctr, Western Psychiat Inst & Clin, 3811 OHara St, Pittsburgh, PA 15213 USA. EM chungta@upmc.edu RI Chung, Tammy/B-9712-2017 OI Chung, Tammy/0000-0002-1527-2792 FU NIDA [R01 DA012237]; NIMH [R01 MH056630]; Office of Juvenile Justice and Delinquency Prevention [2013-JF-FX-0058]; FISA Foundation; Falk Fund FX This work was supported by NIDA R01 DA012237, NIMH R01 MH056630, The Office of Juvenile Justice and Delinquency Prevention (2013-JF-FX-0058), the FISA Foundation, and the Falk Fund. The funders had no role in design and conduct of the study; collection, management, analysis, or interpretation of the data; or review or approval of the manuscript. The authors have no conflicts of interest to declare. NR 24 TC 0 Z9 0 U1 1 U2 1 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 0889-7077 EI 1547-0164 J9 SUBST ABUS JI Subst. Abus. PY 2017 VL 38 IS 1 BP 77 EP 81 DI 10.1080/08897077.2016.1263591 PG 5 WC Substance Abuse SC Substance Abuse GA EO3NN UT WOS:000396601600017 PM 27897467 ER PT J AU Ailawadhi, S Akard, LP Miller, CB Jillella, A DeAngelo, DJ Ericson, SG Lin, F Warsi, G Radich, J AF Ailawadhi, Sikander Akard, Luke P. Miller, Carole B. Jillella, Anand DeAngelo, Daniel J. Ericson, Solveig G. Lin, Felice Warsi, Ghulam Radich, Jerald TI Exploratory study on the impact of switching to nilotinib in 18 patients with chronic myeloid leukemia in chronic phase with suboptimal response to imatinib SO THERAPEUTIC ADVANCES IN HEMATOLOGY LA English DT Article DE CML-CP; ENABL; imatinib; nilotinib; suboptimal response; switch; tyrosine kinase inhibitor ID COMPLETE CYTOGENETIC RESPONSE; EARLY MOLECULAR RESPONSE; BCR-ABL RNA; TREATED PATIENTS; PREDICTS; CML; INTERFERON; DURATION; TIME AB Background: The phase II, exploratory, open-label Exploring Nilotinib BCR-ABL Effects (ENABL) study [ClinicalTrials.gov identifier: NCT00644878] assessed the impact of switching to nilotinib therapy in patients with chronic myeloid leukemia in chronic phase (CML-CP) who had a suboptimal molecular response with imatinib. Methods: Patients with CML-CP who had previously achieved a complete cytogenetic response (CCyR), but had a suboptimal molecular response, with frontline imatinib therapy (N = 18) were assigned to receive nilotinib 300 mg twice daily. The primary endpoint was the change in BCR-ABL1 transcript levels from baseline after 12 months; rates of major molecular response (MMR) and safety were also assessed. Results: At 3 months after switching to nilotinib, 10 of 17 (59%) evaluable patients had achieved MMR. At 12 months, 9 of 12 (75%) evaluable patients had achieved MMR, and the median BCR-ABL1 level among all patients remaining in the study was 0.020% on the International Scale (IS), equivalent to a 3.7-log reduction from the standardized IS baseline (primary endpoint). Adverse events (AEs) were typically grade 1/2 and manageable with dose interruptions. A total of three patients experienced serious study drug-related AEs, including pancreatitis, bradycardia, and vertigo. No deaths were reported. Conclusions: Overall, results from this exploratory study suggest that switching to nilotinib due to suboptimal molecular response with imatinib can result in improved molecular response for patients with CML-CP. C1 [Ailawadhi, Sikander] Mayo Clin, Div Hematol & Oncol, 4500 San Pablo Rd, Jacksonville, FL 32224 USA. [Akard, Luke P.] Indiana Blood & Marrow Transplantat, Dept Hematol, Indianapolis, IN USA. [Miller, Carole B.] St Agnes Hosp, Dept Internal Med, Baltimore, MD USA. [Miller, Carole B.] St Agnes Hosp, Dept Med Oncol, Baltimore, MD USA. [Jillella, Anand] Georgia Regents Univ, Dept Med, Augusta, GA USA. [DeAngelo, Daniel J.] Dana Farber Canc Inst, Hematol Oncol, Boston, MA 02115 USA. [Ericson, Solveig G.; Lin, Felice; Warsi, Ghulam] Novartis Pharmaceut, E Hanover, NJ USA. [Radich, Jerald] Fred Hutchinson Canc Res Ctr, Clin Canc Div, 1124 Columbia St, Seattle, WA 98104 USA. RP Ailawadhi, S (reprint author), Mayo Clin, Div Hematol & Oncol, 4500 San Pablo Rd, Jacksonville, FL 32224 USA. EM ailawadhi.sikander@mayo.edu FU Novartis Pharmaceuticals Corporation (East Hanover, NJ, USA) FX This work was supported by Novartis Pharmaceuticals Corporation (East Hanover, NJ, USA). NR 22 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 2040-6207 EI 2040-6215 J9 THER ADV HEMATOL JI Ther. Adv. Hematol. PD JAN PY 2017 VL 8 IS 1 BP 3 EP 12 DI 10.1177/2040620716678118 PG 10 WC Hematology SC Hematology GA EL5NP UT WOS:000394668100001 PM 28042454 ER PT J AU Hoover, EL Caplan, DN Waters, GS Carney, A AF Hoover, Elizabeth L. Caplan, David N. Waters, Gloria S. Carney, Anne TI Communication and quality of life outcomes from an interprofessional intensive, comprehensive, aphasia program (ICAP) SO TOPICS IN STROKE REHABILITATION LA English DT Article ID THERAPY; STROKE; IMPACT; RELIABILITY; LANGUAGE; VALIDITY AB Background: Intensive Comprehensive Aphasia Programs (ICAPs) have developed in response to a growing need for treatments which produce changes in language function in people with aphasia, especially in the chronic phase of recovery. ICAPs are growing in number and several papers have presented preliminary results of their use, but little data exist about their efficacy or effectiveness. Objective: This paper explores the communication effects of an ICAP program that incorporated evidence-dbased individual and group treatment in an interprofessional program. Method: Twenty-seven individuals with chronic aphasia were provided with 30 h of interprofessional treatment a week for a four-week period in both individual and group formats. A delayed treatment, within-participant research protocol was used. Language measures were taken at two intervals pre-and two intervals post treatment. Functional, narrative, and quality of life measures were taken once pre and once post treatment. Results: Significant change was observed on targeted language functions post treatment. Significant treatment effects were also observed on functional and quality of life measures as well as on all impairment-based language measures for the group. Conclusion: The results provide evidence of linguistic and quality of life change in individuals with chronic aphasia who were treated in an interprofessional ICAP. C1 [Hoover, Elizabeth L.; Waters, Gloria S.; Carney, Anne] Boston Univ, Coll Hlth & Rehabil Sci, Sargent Coll, Dept Speech Language & Hearing Sci, 635 Commonwealth Ave, Boston, MA 02215 USA. [Caplan, David N.] Massachusetts Gen Hosp, Neuropsychol Lab, Boston, MA 02114 USA. RP Hoover, EL (reprint author), Boston Univ, Coll Hlth & Rehabil Sci, Sargent Coll, Dept Speech Language & Hearing Sci, 635 Commonwealth Ave, Boston, MA 02215 USA. EM ehoover@bu.edu NR 44 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 1074-9357 EI 1945-5119 J9 TOP STROKE REHABIL JI Top. Stroke Rehabil. PY 2017 VL 24 IS 2 BP 82 EP 90 DI 10.1080/10749357.2016.1207147 PG 9 WC Rehabilitation SC Rehabilitation GA EO6SS UT WOS:000396823400002 PM 27456043 ER PT J AU Wiederhold, NP Patterson, TF Srinivasan, A Chaturvedi, AK Fothergill, AW Wormley, FL Ramasubramanian, AK Lopez-Ribot, JL AF Wiederhold, Nathan P. Patterson, Thomas F. Srinivasan, Anand Chaturvedi, Ashok K. Fothergill, Annette W. Wormley, Floyd L. Ramasubramanian, Anand K. Lopez-Ribot, Jose L. TI Repurposing auranofin as an antifungal: In vitro activity against a variety of medically important fungi SO VIRULENCE LA English DT Article DE antifungal susceptibility; auranofin; repurposing; spectrum of action ID DRUG; INHIBITORS; BACTERIAL; AGENTS AB Repositioning old drugs can significantly decrease the time and effort that it takes to develop novel antifungal therapeutics, which represents a pressing and unmet clinical need due to the devastating nature of fungal infections. We have previously described the activity of auranofin, a gold thiol compound used to treat rheumatoid arthritis, against Candida albicans biofilms. Here we evaluate its antifungal spectrum of action and describe its activity against a variety of medically important fungi. C1 [Wiederhold, Nathan P.; Fothergill, Annette W.] Univ Texas Hlth Sci Ctr San Antonio, Dept Pathol, San Antonio, TX 78229 USA. [Wiederhold, Nathan P.; Patterson, Thomas F.] Univ Texas Hlth Sci Ctr San Antonio, Div Infect Dis, Dept Med, San Antonio, TX 78229 USA. [Patterson, Thomas F.] South Texas Vet Hlth Care Syst, San Antonio, TX USA. [Srinivasan, Anand; Ramasubramanian, Anand K.] Univ Texas Hlth Sci Ctr San Antonio, Dept Biomed Engn, San Antonio, TX 78229 USA. [Srinivasan, Anand; Chaturvedi, Ashok K.; Wormley, Floyd L.; Ramasubramanian, Anand K.; Lopez-Ribot, Jose L.] Univ Texas San Antonio, South Texas Ctr Emerging Infect Dis, San Antonio, TX USA. [Chaturvedi, Ashok K.; Wormley, Floyd L.; Lopez-Ribot, Jose L.] Univ Texas Hlth Sci Ctr San Antonio, Dept Biol, San Antonio, TX 78229 USA. RP Lopez-Ribot, JL (reprint author), Univ Texas San Antonio, Dept Biol, MBT Room 1-242,One UTSA Circle, San Antonio, TX 78249 USA. EM jose.lopezribot@utsa.edu FU National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services [HHS272201000018I, A06]; Army Research Office of the Department of Defense [W911NF-11-1-0136]; Clusters in Research Excellence grant from the San Antonio Life Science Institute (SALSI); Margaret Batts Tobin Foundation, San Antonio, TX FX This project utilized preclinical services funded by the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, under Contract Nos. HHS272201000018I, Task Order A06. Additional support was provided by the Army Research Office of the Department of Defense under Contract No. W911NF-11-1-0136, by a Clusters in Research Excellence grant from the San Antonio Life Science Institute (SALSI) and by the Margaret Batts Tobin Foundation, San Antonio, TX. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript, and the content is solely the responsibility of the authors. NR 21 TC 1 Z9 1 U1 0 U2 0 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 2150-5594 EI 2150-5608 J9 VIRULENCE JI Virulence PY 2017 VL 8 IS 2 BP 138 EP 142 DI 10.1080/21505594.2016.1196301 PG 5 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA EM5TY UT WOS:000395377700004 PM 27268469 ER PT J AU Mifflin, J AF Mifflin, Jeffrey TI Jungle of Stone: The True Story of Two Men, their Extraordinary Journey, and the Discovery of the Lost Civilization of the Maya SO VISUAL ANTHROPOLOGY LA English DT Book Review C1 [Mifflin, Jeffrey] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Mifflin, J (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. EM jmifflin@mgh.harvard.edu NR 1 TC 0 Z9 0 U1 0 U2 0 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 0894-9468 EI 1545-5920 J9 VIS ANTHROPOL JI Vis. Anthropol. PY 2017 VL 30 IS 2 BP 174 EP 176 DI 10.1080/08949468.2017.1277114 PG 3 WC Anthropology SC Anthropology GA EM2BI UT WOS:000395121000006 ER PT J AU Kurz, FT Kembro, JM Flesia, AG Armoundas, AA Cortassa, S Aon, MA Lloyd, D AF Kurz, Felix T. Kembro, Jackelyn M. Flesia, Ana G. Armoundas, Antonis A. Cortassa, Sonia Aon, Miguel A. Lloyd, David TI Network dynamics: quantitative analysis of complex behavior in metabolism, organelles, and cells, from experiments to models and back SO WILEY INTERDISCIPLINARY REVIEWS-SYSTEMS BIOLOGY AND MEDICINE LA English DT Review ID DETRENDED FLUCTUATION ANALYSIS; NONSTATIONARY TIME-SERIES; SMALL-WORLD NETWORKS; STOCHASTIC RESONANCE; CIRCADIAN-RHYTHMS; CARDIAC MYOCYTES; SYSTEMS BIOLOGY; MITOCHONDRIAL-FUNCTION; INDIVIDUAL MITOCHONDRIA; REGULATORY NETWORKS AB Advancing from two core traits of biological systems: multilevel network organization and nonlinearity, we review a host of novel and readily available techniques to explore and analyze their complex dynamic behavior within the framework of experimental-computational synergy. In the context of concrete biological examples, analytical methods such as wavelet, power spectra, and metabolomics-fluxomics analyses, are presented, discussed, and their strengths and limitations highlighted. Further shown is how time series from stationary and nonstationary biological variables and signals, such as membrane potential, high-throughput metabolomics, O-2 and CO2 levels, bird locomotion, at the molecular, (sub) cellular, tissue, and whole organ and animal levels, can reveal important information on the properties of the underlying biological networks. Systems biology-inspired computational methods start to pave the way for addressing the integrated functional dynamics of metabolic, organelle and organ networks. As our capacity to unravel the control and regulatory properties of these networks and their dynamics under normal or pathological conditions broadens, so is our ability to address endogenous rhythms and clocks to improve health-span in human aging, and to manage complex metabolic disorders, neurodegeneration, and cancer. (C) 2016 Wiley Periodicals, Inc. C1 [Cortassa, Sonia; Aon, Miguel A.] NIA, NIH, BRC BG Rm 09B119,251 Bayview Blvd, Baltimore, MD 21224 USA. [Kurz, Felix T.; Armoundas, Antonis A.] Harvard Med Sch, Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charlestown, MA USA. [Kurz, Felix T.] Univ Heidelberg Hosp, Dept Neuroradiol, Heidelberg, Germany. [Kembro, Jackelyn M.] Univ Nacl Cordoba, CONICET, IIByT, Cordoba, Argentina. [Kembro, Jackelyn M.] Univ Nacl Cordoba, Fac Ciencias Exactas Fis & Nat, Inst Ciencia & Tecnol Alimentos, Catedra Quim Biol, Cordoba, Argentina. [Flesia, Ana G.] Univ Nacl Cordoba, CONICET, CIEM, Cordoba, Argentina. [Flesia, Ana G.] Univ Nacl Cordoba, Fac Matemat Astron & Fis FAMAF, Cordoba, Argentina. [Cortassa, Sonia; Aon, Miguel A.] Johns Hopkins Univ, Dept Med, Div Cardiol, Baltimore, MD USA. [Lloyd, David] Cardiff Univ, Sch Biosci, Cardiff, S Glam, Wales. RP Aon, MA (reprint author), NIA, NIH, BRC BG Rm 09B119,251 Bayview Blvd, Baltimore, MD 21224 USA.; Aon, MA (reprint author), Johns Hopkins Univ, Dept Med, Div Cardiol, Baltimore, MD USA. EM maon1@jhu.edu FU Medical Faculty, Heidelberg University; Hoffmann-Klose Foundation (Heidelberg University) FX F.T.K. was supported by a physician-scientist postdoctoral fellowship of the Medical Faculty, Heidelberg University, and by the Hoffmann-Klose Foundation (Heidelberg University). J.M.K. and A.G.F. are career members of the National Research Council (CONICET, Argentina). We would like to thank Prof. Marc R. Roussel (Univ. Lethbridge, Canada) for valuable feedback and permission to reproduce Figure 10. This manuscript, or part of it, has neither been published nor is currently under consideration for publication by any other journal. NR 192 TC 0 Z9 0 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1939-5094 EI 1939-005X J9 WIRES SYST BIOL MED JI Wiley Interdiscip. Rev.-Syst. Biol PD JAN-FEB PY 2017 VL 9 IS 1 DI 10.1002/wsbm.1352 PG 30 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EL8VP UT WOS:000394898700003 ER PT J AU Arias, OE Umukoro, PE Stoffel, SD Hopcia, K Sorensen, G Dennerlein, JT AF Arias, Oscar E. Umukoro, Peter E. Stoffel, Sonja D. Hopcia, Karen Sorensen, Glorian Dennerlein, Jack T. TI Associations between trunk flexion and physical activity of patient care workers for a single shift: A pilot study SO WORK-A JOURNAL OF PREVENTION ASSESSMENT & REHABILITATION LA English DT Article DE Posture; workload; ergonomics; and bending ID ISCHEMIC-HEART-DISEASE; ALL-CAUSE MORTALITY; ENERGY-EXPENDITURE; BACK DISORDERS; LIFTING TASKS; POSTURE; NURSES; RISK; EXERTION; EXPOSURE AB BACKGROUND: Trunk flexion and occupational physical activity are parameters that have been used to assess and characterize jobs with high physical demands. OBJECTIVE: Characterize the physical load of trunk flexion and physical activity of patient care unit (PCU) workers during a single work shift. METHODS: Participants wore an accelerometer to measure physical activity and an inclinometer to assess trunk flexion during a single work shift, which was compared using correlation and linear regression analyses. RESULTS: Participants spent 74% of their work time upright between -10 degrees to 20 degrees and 19% of their time flexed between 20 degrees to 45 degrees On average workers spent 3% and 5% of their time, in the extreme postures of less than -10 degrees and greater than 45 degrees, respectively. Participants spent 99% of their shift below moderate and vigorous activity. The largest correlation found was between the number of forward trunk flexions to 20 degrees degrees per shift and minutes in lifestyle activity (r = 0.6, p < 0.001). No correlations between minutes of moderate or vigorous physical activity and trunk flexion were observed. CONCLUSIONS: This study suggests that the physical demands of patient care unit workers as measured through trunk flexion are associated with lifestyle and light levels of physical activity. C1 [Arias, Oscar E.; Umukoro, Peter E.; Dennerlein, Jack T.] Harvard Sch Publ Hlth, Ctr Work Hlth & Wellbeing, Boston, MA USA. [Stoffel, Sonja D.] Camosun Coll, Ctr Sport & Exercise Educ, Victoria, BC, Canada. [Stoffel, Sonja D.; Sorensen, Glorian] Harvard Sch Publ Hlth, Dept Social & Behav Sci, Boston, MA USA. [Hopcia, Karen] Partners HealthCare Inc, Dept Occupat Hlth, Boston, MA USA. [Hopcia, Karen] Univ Illinois, Dept Hlth Syst Sci, Chicago, IL USA. [Sorensen, Glorian] Dana Faber Canc Inst, Ctr Community Based Res, Boston, MA USA. [Dennerlein, Jack T.] Northeastern Univ, Bouve Coll Hlth Sci, Dept Phys Therapy Movement & Rehabil Sci, Boston, MA 02115 USA. [Arias, Oscar E.] Univ Calif Los Angeles, Dept Environm Hlth Sci, Los Angeles, CA USA. RP Arias, OE (reprint author), Univ Calif Los Angeles, 650 Charles E Young Dr S,56-071C Box 951772, Los Angeles, CA 90095 USA. EM oea936@mail.harvard.edu FU Harvard School of Public Health Center for Work, Health and Wellbeing, a National Institute for Occupational Safety and Health Total Worker Health(TM) Center of Excellence [U19 OH008861] FX This work was partially supported by a pilot study grant from the Harvard School of Public Health Center for Work, Health and Wellbeing, a National Institute for Occupational Safety and Health Total Worker Health (TM) Center of Excellence (grant U19 OH008861). This study would not have been accomplished without the participation of Partners HealthCare System and leadership from Dennis Colling and KurtWesterman. The authors would like thank Alberto Caban-Martinez, Sarah Oppenheimer, Chelsea Cote, Danielle Touhey, and Courtney Cullen who helped us in participant recruitment and data collection. In addition, the authors thank David Lombardi and Paul Catalano for their assistance with the research methods. NR 50 TC 0 Z9 0 U1 0 U2 0 PU IOS PRESS PI AMSTERDAM PA NIEUWE HEMWEG 6B, 1013 BG AMSTERDAM, NETHERLANDS SN 1051-9815 EI 1875-9270 J9 WORK JI Work PY 2017 VL 56 IS 2 BP 247 EP 255 DI 10.3233/WOR-172481 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA EO2TN UT WOS:000396548900008 PM 28211832 ER PT J AU Lin, BM White, M Glover, A Wamah, GP Trotti, DL Randall, K Alkire, BC Cheney, ML Parker, G Shrime, MG AF Lin, Brian M. White, Michelle Glover, Ana Wamah, Greta Peterson Trotti, Davi L. Randall, Kirstie Alkire, Blake C. Cheney, Mack L. Parker, Gary Shrime, Mark G. TI Barriers to Surgical Care and Health Outcomes: A Prospective Study on the Relation Between Wealth, Sex, and Postoperative Complications in the Republic of Congo SO WORLD JOURNAL OF SURGERY LA English DT Article ID SUB-SAHARAN AFRICA; UNMET NEED; USER FEES; SURGERY; DISTANCE; CAPACITY; UGANDA; DETERMINANTS; ASSOCIATION; FACILITIES AB Approximately thirty percent of the global burden of disease is comprised of surgical conditions. However, five billion people lack access to surgery, with complex factors acting as barriers. We examined whether patient demographics predict barriers to care, and the relation between these factors and postoperative complications in a prospective cohort. Participants included people presenting to a global charity in Republic of Congo with a surgical condition between August 2013 and May 2014. The outcomes were self-reported barrier to care and postoperative complications documented by medical record. Logistic regression was used to adjust for covariates. Of 1237 patients in our study, 1190 (96.2 %) experienced a barrier to care and 126 (10.2 %) experienced a postoperative complication. The most frequently reported barrier was cost (73 %), followed by lack of provider (8.2 %). Greater wealth was associated with decreased odds of cost as a barrier (OR 0.72 [0.57, 0.90]). Greater wealth (OR 1.52 [1.03, 2.25]) and rural home location (OR 3.35 [1.16, 9.62]) were associated with increased odds of no surgeon being available. Cost as a barrier (OR 2.82 [1.02, 7.77]), female sex (OR 3.45 [1.62, 7.33]), and lack of surgeon (OR 5.62 [1.68, 18.77]) were associated with increased odds of postoperative complication. Patient wealth was not associated with odds of postoperative complication. Barriers to surgery were common in Republic of Congo. Patient wealth and home location may predict barriers to surgery. Addressing gender disparities, access to providers, and patient perception of barriers in addition to removal of barriers may help maximize patient health benefits. C1 [Lin, Brian M.; Alkire, Blake C.; Cheney, Mack L.; Shrime, Mark G.] Harvard Med Sch, Dept Otolaryngol, Massachusetts Eye & Ear Infirm, 243 Charles St, Boston, MA 02114 USA. [White, Michelle; Glover, Ana; Wamah, Greta Peterson; Trotti, Davi L.; Randall, Kirstie; Parker, Gary; Shrime, Mark G.] Mercy Ships, Tyler, TX 75704 USA. [White, Michelle; Glover, Ana; Wamah, Greta Peterson; Trotti, Davi L.; Randall, Kirstie; Parker, Gary; Shrime, Mark G.] Mercy Ships, Toamasina, Madagascar. [Shrime, Mark G.] Harvard Med Sch, Dept Global Hlth & Social Med, Program Global Surg & Social Change, Boston, MA 02115 USA. RP Lin, BM (reprint author), Harvard Med Sch, Dept Otolaryngol, Massachusetts Eye & Ear Infirm, 243 Charles St, Boston, MA 02114 USA. EM brian_lin@meei.harvard.edu NR 51 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0364-2313 EI 1432-2323 J9 WORLD J SURG JI World J.Surg. PD JAN PY 2017 VL 41 IS 1 BP 14 EP 23 DI 10.1007/s00268-016-3676-x PG 10 WC Surgery SC Surgery GA EI0EY UT WOS:000392147000005 PM 27473131 ER PT J AU Spence, RT Chang, DC Chu, K Panieri, E Mueller, JL Hutter, MM AF Spence, Richard T. Chang, David C. Chu, Kathryn Panieri, Eugenio Mueller, Jessica L. Hutter, Matthew M. TI An Online Tool for Global Benchmarking of Risk-Adjusted Surgical Outcomes SO WORLD JOURNAL OF SURGERY LA English DT Article ID QUALITY IMPROVEMENT PROGRAM; TRAUMA DATA-BANK; AMERICAN-COLLEGE; INFORMED-CONSENT; SURGERY; CALCULATOR; MORTALITY; HOSPITALS; VARIABLES; RESOURCE AB Increasing evidence demonstrates significant variation in adverse outcomes following surgery between countries. In order to better quantify these variations, we hypothesize that freely available online risk calculators can be used as a tool to generate global benchmarking of risk-adjusted surgical outcomes. This is a prospective cohort study conducted at an academic teaching hospital in South Africa (GSH). Consecutive adult patients undergoing major general or vascular surgery who met the ACS-NSQIP inclusion criteria for a 3-month period were included. Data variables required by the ACS risk calculator were prospectively collected, and patients were followed for 30 days post-surgery for the occurrence of endpoints. Calculating observed-to-expected ratios for ten outcome measures of interest generated risk-adjusted outcomes benchmarked against the ACS-NSQIP consortium. A total of 373 major general and vascular surgery procedures met the inclusion criteria. The GSH operative cohort varied significantly compared to the 2012 ACS-NSQIP database. The risk-adjusted O/E ratios were significant for any complication O/E 1.91 (95 % CI 1.57-2.31), surgical site infections O/E 4.76 (95 % CI 3.71-6.01), renal failure O/E 3.29 (95 % CI 1.50-6.24), death O/E 3.43 (95 % CI 2.19-5.11), and total length of stay (LOS) O/E 3.43 (95 % CI 2.19-5.11). Freely available online risk calculators can be utilized as tools for global benchmarking of risk-adjusted surgical outcomes. C1 [Spence, Richard T.; Chang, David C.; Mueller, Jessica L.; Hutter, Matthew M.] Massachusetts Gen Hosp, Dept Gen Surg, Codman Ctr Clin Effectiveness Surg, Boston, MA 02114 USA. [Spence, Richard T.; Chu, Kathryn; Panieri, Eugenio] Univ Cape Town, Dept Surg, Rondebosch Oaks Albion Rd, ZA-7700 Rondebosch, Cape Town, South Africa. [Chang, David C.; Mueller, Jessica L.; Hutter, Matthew M.] Harvard Med Sch, Boston, MA USA. RP Spence, RT (reprint author), Massachusetts Gen Hosp, Dept Gen Surg, Codman Ctr Clin Effectiveness Surg, Boston, MA 02114 USA.; Spence, RT (reprint author), Univ Cape Town, Dept Surg, Rondebosch Oaks Albion Rd, ZA-7700 Rondebosch, Cape Town, South Africa. EM spnric004@myuct.ac.za NR 28 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0364-2313 EI 1432-2323 J9 WORLD J SURG JI World J.Surg. PD JAN PY 2017 VL 41 IS 1 BP 24 EP 30 DI 10.1007/s00268-016-3668-x PG 7 WC Surgery SC Surgery GA EI0EY UT WOS:000392147000006 PM 27468741 ER PT J AU Crowley, ST Belcher, J Choudhury, D Griffin, C Pichler, R Robey, B Rohatgi, R Mielcarek, B AF Crowley, Susan T. Belcher, Justin Choudhury, Devasmita Griffin, Cassandra Pichler, Raymond Robey, Brooks Rohatgi, Rajeev Mielcarek, Bessie TI Targeting Access to Kidney Care Via Telehealth: The VA Experience SO ADVANCES IN CHRONIC KIDNEY DISEASE LA English DT Article DE Telemedicine; Health services; Access to health care; Kidney disease; Patient education as topic ID PREDIALYSIS NEPHROLOGY CARE; LIMITED HEALTH LITERACY; OF-VETERANS-AFFAIRS; PERITONEAL-DIALYSIS; UNITED-STATES; OUTCOMES; DISEASE; CKD; ASSOCIATIONS; TECHNOLOGY AB The Veterans Affairs (VA) is the largest integrated health care system in the United States and is responsible for the care of a population with a disproportionately high rate of CKD. As such, ensuring access to kidney health services is a VA imperative. One facet of the VA's strategy to reduce CKD is to leverage the use of teletechnology to expand the VA's outreach to Veterans with kidney disease. A wide array of teletechnology services have been deployed to both pull in Veterans and push out kidney health services to Veterans in their preferred health care venue. Teletechnology, thus, expands Veteran choice, facilitates their access to care, and furthers the goal of delivering patient-centered kidney specialty care. The VA has demonstrated the feasibility of virtual delivery of kidney specialty care services and education via synchronous and asynchronous approaches. The challenges ahead include determining the relative health care value of kidney telehealth services, identifying Veterans most likely to benefit from specific technologies and optimizing the adoption of effective kidney telehealth services by both providers and patients alike to ensure optimal and timely kidney health care delivery. C1 VA Connecticut Healthcare Syst, Dept Med, Nephrol Sect, West Haven, CT 06516 USA. Yale Univ, Dept Med, Nephrol Sect, New Haven, CT 06511 USA. Salem VA Med Ctr, Dept Med, Nephrol Sect, Salem, VA USA. Virginia Tech Caril Sch Med, Dept Med, Nephrol Sect, Roanoke, VA USA. VA Puget Sound Healthcare Syst, Dept Med, Nephrol Sect, Seattle, WA USA. Univ Washington, Sch Med, Div Nephrol, Seattle, WA 98195 USA. VA White River Junct VAMC, Dept Med, Nephrol Sect, White River Jct, VT USA. Dartmouth Med Sch, Dept Med, Nephrol Sect, Hanover, NH USA. VA Northport Healthcare Syst, Dept Med, Nephrol Sect, Northport, NY USA. SUNY Stony Brook, Sch Med, Dept Med, Nephrol Sect, Stony Brook, NY USA. RP Crowley, ST (reprint author), VA Connecticut Healthcare Syst 111F, VA Kidney Dis Natl Program, Renal Sect VA CT HCS, 950 Campbell Ave, West Haven, CT 06516 USA. EM susan.crowley@va.gov FU VA Puget Sound Health Care System; VA Office of Specialty Care; VA Office of Rural Health FX Support: Drs Pichler and Young received funding through the VA Puget Sound Health Care System and are supported by clinical grants from the VA Office of Specialty Care and the VA Office of Rural Health. The opinions expressed here are those of the authors and do not constitute policy of the US government. NR 36 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 1548-5595 EI 1548-5609 J9 ADV CHRONIC KIDNEY D JI Adv. Chronic Kidney Dis. PD JAN PY 2017 VL 24 IS 1 BP 22 EP 30 DI 10.1053/j.ackd.2016.11.005 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA EN0UI UT WOS:000395725600006 PM 28224939 ER PT J AU Chang, TS Teng, E Elashoff, D Grill, JD AF Chang, Timothy S. Teng, Edmond Elashoff, David Grill, Joshua D. CA Alzheimer's Dis Neuroimaging TI Optimizing Effect Sizes With Imaging Enrichment and Outcome Choices for Mild Alzheimer Disease Clinical Trials SO ALZHEIMER DISEASE & ASSOCIATED DISORDERS LA English DT Article DE Alzheimer disease; cognitive decline; clinical trial; enrichment; ADAS-Cog ID POSITRON-EMISSION-TOMOGRAPHY; PITTSBURGH COMPOUND-B; FLORBETAPIR F 18; COGNITIVE IMPAIRMENT; ASSESSMENT SCALE; AMYLOID-BETA; PET; ASSOCIATION; DIAGNOSIS; DEMENTIA AB Recent clinical trials in mild Alzheimer disease (AD) have enriched for amyloid-specific positron emission tomography (PET) imaging and used extended versions of the AD Assessment Scale-Cognitive Subscale (ADAS-Cog) in an effort to increase the sensitivity to detect treatment effects. We used data from mild AD participants in the AD Neuroimaging Initiative to model trial effect sizes for 12- and 24-month trials using 3 versions of the ADAS-Cog and increased standardized uptake value ratio (SUVR) cutoffs for amyloid imaging inclusion criteria. For 12-month trials, extended ADAS-Cog versions improved effect sizes. The ADAS-Cog11 elicited larger effect sizes when enriching for SUVR 1.1 only, whereas the ADAS-Cog12 and ADAS-Cog13 were associated with larger effect sizes with higher SUVR thresholds. For 24-month trials, extended ADAS-Cog versions increased effect sizes for trials not enriched for amyloid and trials enriched for SUVR 1.1. Only enriching for higher SUVR thresholds (1.3 and 1.4, not 1.1) increased trial power. We conclude that extended versions of the ADAS-Cog improve mild AD trial effect sizes for both 12- and 24-month long studies, whereas amyloid imaging criteria may be most valuable for 12-month trials. C1 [Chang, Timothy S.; Teng, Edmond] Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurol, Los Angeles, CA 90095 USA. [Elashoff, David] Univ Calif Los Angeles, David Geffen Sch Med, Dept Biostat, Los Angeles, CA 90095 USA. [Teng, Edmond] Vet Affairs Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. [Grill, Joshua D.] Univ Calif Irvine, Inst Memory Impairments & Neurol Disorders, 3206 Biol Sci 3, Irvine, CA 92697 USA. RP Grill, JD (reprint author), Univ Calif Irvine, Inst Memory Impairments & Neurol Disorders, 3206 Biol Sci 3, Irvine, CA 92697 USA. EM jgrill@uci.edu FU NIA [AG016570, AG016573]; Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health) [U01 AG024904]; DOD ADNI (Department of Defense) [W81XWH-12-2-0012]; National Institute on Aging; National Institute of Biomedical Imaging and Bioengineering; Canadian Institutes of Health Research FX J.D.G. and E.T. were supported by NIA AG016570. J.D.G. is currently supported by NIA AG016573. Data collection and sharing for this project was funded by the Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: Alzheimer's Association; Alzheimer's Drug Discovery Foundation; Araclon Biotech; BioClinica Inc.; Biogen Idec Inc.; Bristol-Myers Squibb Company; Eisai Inc.; Elan Pharmaceuticals Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd and its affiliated company Genentech Inc.; Fujirebio; GE Healthcare; IXICO Ltd; Janssen Alzheimer Immunotherapy Research & Development, LLC; Johnson & Johnson Pharmaceutical Research & Development, LLC; Medpace Inc.; Merck & Co. Inc.; Meso Scale Diagnostics, LLC; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Synarc Inc.; and Takeda Pharmaceutical Company. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (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 Disease Cooperative Study at the University of California, San Diego. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California. NR 30 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 0893-0341 J9 ALZ DIS ASSOC DIS JI Alzheimer Dis. Assoc. Dis. PD JAN-MAR PY 2017 VL 31 IS 1 BP 19 EP 26 DI 10.1097/WAD.0000000000000150 PG 8 WC Clinical Neurology; Pathology SC Neurosciences & Neurology; Pathology GA EM8JH UT WOS:000395556900004 PM 27196535 ER PT J AU Pruzin, JJ Schneider, JA Capuano, AW Leurgans, SE Barnes, LL Ahima, RS Arnold, SE Bennett, DA Arvanitakis, Z AF Pruzin, Jeremy J. Schneider, Julie A. Capuano, Ana W. Leurgans, Sue E. Barnes, Lisa L. Ahima, Rexford S. Arnold, Steven E. Bennett, David A. Arvanitakis, Zoe TI Diabetes, Hemoglobin A1C, and Regional Alzheimer Disease and Infarct Pathology SO ALZHEIMER DISEASE & ASSOCIATED DISORDERS LA English DT Article DE Alzheimer disease; neuritic plaques; tangles; cerebrovascular disease; infarction; pathology; diabetes; hemoglobin A1C; epidemiology ID GLYCATION END-PRODUCTS; COGNITIVE FUNCTION; OLDER PERSONS; INSULIN-RESISTANCE; INCREASED RISK; DEMENTIA; BRAIN; MELLITUS; NEUROPATHOLOGY; BETA AB We examined the relationship of diabetes and hemoglobin A1C (A1C) to 2 common causes of dementia. The study included 1228 subjects who underwent annual clinical evaluations and a brain autopsy at death, as part of a Rush longitudinal cohort study of aging. A total of 433 subjects had A1C data available. Neuropathologic evaluations documented the size and location of infarcts. Modified silver stain-based Alzheimer disease (AD) measures included global and regional scores. We used regression analyses to examine associations of diabetes and A1C with overall and regional neuropathology. Diabetes [odds ratio (OR)=0.94; 95% confidence interval (CI), 0.73-1.20) and A1C (OR=0.83; 95% CI, 0.62-1.10) were not associated with global AD pathology across the brain, nor with overall or individual measures of neuropathology in mesial temporal or neocortical regions separately (all P>0.05). Diabetes was associated with a higher odds of any infarct (OR=1.43; 95% CI, 1.07-1.90), and particularly with gross (OR=1.53; 95% CI, 1.14-2.06) but not microinfarcts (P=0.06), and subcortical (OR=1.79; 95% CI, 1.34-2.39) but not cortical infarcts (P=0.83). In summary, we found no relationship of diabetes or A1C with global or regional AD pathology, including in the mesial temporal lobe. Diabetes is associated with gross subcortical infarcts. Our results suggest that the diabetes-dementia link is based on subcortical vascular pathology and not on regional AD pathology. C1 [Pruzin, Jeremy J.; Schneider, Julie A.; Capuano, Ana W.; Leurgans, Sue E.; Barnes, Lisa L.; Bennett, David A.; Arvanitakis, Zoe] Rush Alzheimers Dis Ctr, 600S Paulina Ave,Suite 1020, Chicago, IL 60612 USA. [Pruzin, Jeremy J.; Schneider, Julie A.; Capuano, Ana W.; Leurgans, Sue E.; Barnes, Lisa L.; Bennett, David A.; Arvanitakis, Zoe] Rush Univ, Med Ctr, Dept Neurol Sci, 600S Paulina Ave,Suite 1020, Chicago, IL 60612 USA. [Schneider, Julie A.] Rush Univ, Med Ctr, Dept Pathol, Chicago, IL 60612 USA. [Barnes, Lisa L.] Rush Univ, Med Ctr, Dept Behav Sci, Chicago, IL 60612 USA. [Ahima, Rexford S.] Johns Hopkins Univ, Dept Med, Div Endocrinol Diabet & Metab, Baltimore, MD USA. [Arnold, Steven E.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Neurol, Interdisciplinary Brain Ctr, Boston, MA USA. RP Arvanitakis, Z (reprint author), Rush Alzheimers Dis Ctr, 600S Paulina Ave,Suite 1020, Chicago, IL 60612 USA.; Arvanitakis, Z (reprint author), Rush Univ, Med Ctr, Dept Neurol Sci, 600S Paulina Ave,Suite 1020, Chicago, IL 60612 USA. FU National Institutes of Health [P30 AG10161, RF1 AG15819, R01 AG17917, RF1 AG022018, R01 AG40039, R01 NS084965] FX Supported by the National Institutes of Health grants P30 AG10161, RF1 AG15819, R01 AG17917, RF1 AG022018, R01 AG40039, and R01 NS084965. NR 56 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 0893-0341 J9 ALZ DIS ASSOC DIS JI Alzheimer Dis. Assoc. Dis. PD JAN-MAR PY 2017 VL 31 IS 1 BP 41 EP 47 DI 10.1097/WAD.0000000000000172 PG 7 WC Clinical Neurology; Pathology SC Neurosciences & Neurology; Pathology GA EM8JH UT WOS:000395556900007 PM 27755004 ER PT J AU Brook, CD Maxfield, AZ Ahmed, H Sedaghat, AR Holbrook, EH Gray, ST AF Brook, Christopher D. Maxfield, Alice Z. Ahmed, Hena Sedaghat, Ahmad R. Holbrook, Eric H. Gray, Stacey T. TI Factors influencing the need for endoscopic sinus surgery in adult patients with cystic fibrosis SO AMERICAN JOURNAL OF RHINOLOGY & ALLERGY LA English DT Article ID CHRONIC RHINOSINUSITIS; GENOTYPE; MANAGEMENT; SECRETION; PHENOTYPE; SNOT-22; NASAL AB Background: Risk factors in adult patients with cystic fibrosis (CF) associated with surgical intervention have not been delineated. Objective: To identify characteristics of adult patients with CF and with chronic rhinosinusitis that predict surgical intervention with endoscopic sinus surgery (ESS). Methods: Patients were identified in a tertiary sinus center by the International Classification of Diseases, Ninth Revision codes 277.00 -277.03, which represent CF. Charts were reviewed for the CF transmembrane conductance regulator (CFTR) gene mutation, Lund-Mackay score (LMS), the 22-item Sino-Nasal Outcome Test (SNOT-22) score, previous ESS, and occurrence of ESS after presentation. The Fisher exact test was used to test frequency of events between the groups, and the Mann Whitney U test and the t-test were used to compare means among LMS, SNOT-22, and age. The Cox proportional hazard analysis was used to calculate hazard ratios (HR) for the impact of LMS, SNOT-22 score, previous ESS, and CFTR gene mutation status on the occurrence of ESS after presentation. Results: One hundred and fifteen patients met the inclusion criteria for the study. Patients with a history of surgery more often underwent ESS after presentation (p <= 0.01). The LMS and the SNOT-22 score were not significantly different between the groups of previous ESS and no previous ESS (p = 0.23 and p = 0.28, respectively). A severe mutation genotype was predictive of ESS after presentation (p = 0.03). SNOT-22 scores did not differ between the severe and mild groups (36.0 and 32.4, respectively; p = 0.57), but the mean LMS was significantly higher in the severe mutation group (12.5 and 9.7; p <= 0.01). Univariate Cox proportional hazard analysis revealed an increased occurrence of ESS for patients with severe mutations (HR, 3.6; p <= 0.01) or a history of ESS (HR, 2.3; p <= 0.01). Conclusion: The occurrence of ESS in adult patients with CF was predicted by previous ESS intervention as well as the severity of CFTR mutation. C1 [Brook, Christopher D.; Maxfield, Alice Z.; Ahmed, Hena; Sedaghat, Ahmad R.; Holbrook, Eric H.; Gray, Stacey T.] Harvard Med Sch, Dept Otolaryngol, Boston, MA USA. [Brook, Christopher D.; Maxfield, Alice Z.; Sedaghat, Ahmad R.; Holbrook, Eric H.; Gray, Stacey T.] Massachusetts Eye & Ear Infirm, Dept Otolaryngol, 243 Charles St, Boston, MA 02114 USA. RP Brook, CD (reprint author), Boston Med Ctr, 1 Boston Med Ctr Pl,FGH Bldg,4th Floor, Boston, MA 02118 USA. EM Chris.brook@bmc.org NR 27 TC 1 Z9 1 U1 0 U2 0 PU OCEAN SIDE PUBLICATIONS INC PI PROVIDENCE PA 95 PITMAN ST, PROVIDENCE, RI 02906 USA SN 1945-8924 EI 1945-8932 J9 AM J RHINOL ALLERGY JI Am. J. Rhinol. Allergy PD JAN-FEB PY 2017 VL 31 IS 1 BP 44 EP 47 DI 10.2500/ajra.2017.31.4385 PG 4 WC Otorhinolaryngology SC Otorhinolaryngology GA EO1PV UT WOS:000396471300019 PM 28234153 ER PT J AU Scangas, GA Bleier, BS AF Scangas, George A. Bleier, Benjamin S. TI Anosmia: Differential diagnosis, evaluation, and management SO AMERICAN JOURNAL OF RHINOLOGY & ALLERGY LA English DT Article ID ENDOSCOPIC SINUS SURGERY; EXPERIMENTAL DIABETIC-NEUROPATHY; AGING OLFACTORY EPITHELIUM; UPPER RESPIRATORY-TRACT; ALPHA-LIPOIC ACID; TERM-FOLLOW-UP; CHRONIC RHINOSINUSITIS; SMELL DYSFUNCTION; NERVE CONDUCTION; OXIDATIVE STRESS AB The ability to scrutinize our surroundings remains heavily dependent on the sense of smell. From the ability to detect dangerous situations such as fires to the recollection of a fond memory triggered by an odor, the advantages of an intact olfactory system cannot be overstated. Outcomes studies have highlighted the profound negative impact of anosmia and parosmia on the overall quality of life. The National Institute on Deafness and Other Communication Disorders estimates that similar to 1.4% of the United States population experiences chronic olfactory dysfunction and smell loss. Efforts have focused on improving both the diagnosis of olfactory dysfunction through olfactory testing and improved reporting of treatment outcomes of olfactory training. The purpose of this article was to review the differential diagnosis, workup, and current treatment strategies of anosmia and smell disorders. C1 [Scangas, George A.; Bleier, Benjamin S.] Harvard Med Sch, Massachusetts Eye & Ear Infirm, Dept Otolaryngol, 243 Charles St, Boston, MA 02114 USA. RP Scangas, GA (reprint author), Harvard Med Sch, Massachusetts Eye & Ear Infirm, Dept Otolaryngol, 243 Charles St, Boston, MA 02114 USA. EM George_scangas@meei.harvard.edu NR 87 TC 1 Z9 1 U1 2 U2 2 PU OCEAN SIDE PUBLICATIONS INC PI PROVIDENCE PA 95 PITMAN ST, PROVIDENCE, RI 02906 USA SN 1945-8924 EI 1945-8932 J9 AM J RHINOL ALLERGY JI Am. J. Rhinol. Allergy PD JAN-FEB PY 2017 VL 31 IS 1 BP E3 EP E7 DI 10.2500/ajra.2017.31.4403 PG 5 WC Otorhinolaryngology SC Otorhinolaryngology GA EO1PV UT WOS:000396471300005 ER PT J AU Calio, A Bria, E Pilotto, S Gilioli, E Nottegar, A Eccher, A Cima, L Santo, A Pedron, S Turri, G Knuutila, S Chilosi, M Vanzo, F Bogina, G Terzi, A Tortora, G Scarpa, A Loda, M Martignoni, G Brunelli, M AF Calio, Anna Bria, Emilio Pilotto, Sara Gilioli, Eliana Nottegar, Alessia Eccher, Albino Cima, Luca Santo, Antonio Pedron, Serena Turri, Giona Knuutila, Sakari Chilosi, Marco Vanzo, Francesca Bogina, Giuseppe Terzi, Alberto Tortora, Giampaolo Scarpa, Aldo Loda, Massimo Martignoni, Guido Brunelli, Matteo TI ALK gene copy number in lung cancer: Unspecific polyploidy versus specific amplification visible as double minutes SO CANCER BIOMARKERS LA English DT Article DE ALK gene copy number; gains; polyploidy; amplification; double minutes ID CRIZOTINIB RESISTANCE; INHIBITOR THERAPY; HYBRIDIZATION; CARCINOMA; CELLS; CHROMOSOMES AB BACKGROUND: Gains of a gene due to DNA polyploidy versus amplification of the specific locus are distinct molecular alterations in tumors. OBJECTIVE: We quantified copy number gains of ALK gene due to unspecific polyploidy versus amplifications of the specific locus in a series of non-small cell lung cancers. METHODS: The locus specific ALK copy (LSI) number status was evaluated in 205 cases by FISH. Ratio LSI ALK copy number corrected for control probes CEP2, CEP3 and CEP17 (CEPs) was scored. Amplification of the specific ALK locus was defined when ratio set to >= 2 while polyploidy was interpreted when the increase in gene copy resulted < 2 in ratio (LSI/ control CEPs). RESULTS: Twenty one cases (10.2%) showed >= 8 ALK signals, 68 cases (33.2%) 3-7 signals and 116 cases (56.6%) a mean of 2 signals. Only 2/ 21 cases of the cohort harboring >= 8 signals showed a ratio >= 2 after CEPs correction interpretable as amplified, showing numerous doubled fluorescent spots. All the remaining cases showed a mirrored number of fluorescent spots per each CEPs, interpretable as polyploidy. CONCLUSION: We detected a high prevalence of ALK gene copy number usually due to polyploidy rather than ALK locus amplification, the latter visible prevalently as double minutes. C1 [Calio, Anna; Gilioli, Eliana; Nottegar, Alessia; Eccher, Albino; Cima, Luca; Pedron, Serena; Turri, Giona; Chilosi, Marco; Scarpa, Aldo; Martignoni, Guido; Brunelli, Matteo] Univ & Hosp Trust, Dept Diagnost & Publ Hlth, Anat Pathol, Verona, Italy. [Bria, Emilio; Pilotto, Sara; Santo, Antonio; Tortora, Giampaolo] Univ & Hosp Trust, Med Oncol, Verona, Italy. [Knuutila, Sakari] Univ Helsinki, Lab Mol Cytogenet, Dept Pathol, Helsinki, Finland. [Vanzo, Francesca] Venetos Res Ctr eHlth Innovat, Arsenal, Veneto, Italy. [Bogina, Giuseppe] SacroCuore Hosp, Anat Pathol, Negrar, Italy. [Terzi, Alberto] SacroCuore Hosp, Thorac Surg, Negrar, Italy. [Loda, Massimo] Harvard Med Sch, Dana Farber Canc Inst, Brigham & Womens Hosp, Boston, MA USA. [Martignoni, Guido] Pederzoli Hosp, Anat Pathol, Verona, Italy. RP Brunelli, M (reprint author), Univ Verona, Dept Diagnost & Publ Hlth, Ple L Scuro 10, I-37134 Verona, Italy. EM matteo.brunelli@univr.it NR 24 TC 0 Z9 0 U1 0 U2 0 PU IOS PRESS PI AMSTERDAM PA NIEUWE HEMWEG 6B, 1013 BG AMSTERDAM, NETHERLANDS SN 1574-0153 EI 1875-8592 J9 CANCER BIOMARK JI Cancer Biomark. PY 2017 VL 18 IS 2 BP 215 EP 220 DI 10.3233/CBM-161680 PG 6 WC Oncology SC Oncology GA EN6JA UT WOS:000396109100015 PM 28009326 ER PT J AU Bao, K Lee, JH Kang, H Park, GK El Fakhri, G Choi, HS AF Bao, Kai Lee, Jeong Heon Kang, Homan Park, G. Kate El Fakhri, Georges Choi, Hak Soo TI PSMA-targeted contrast agents for intraoperative imaging of prostate cancer SO CHEMICAL COMMUNICATIONS LA English DT Article ID NEAR-INFRARED FLUOROPHORES; MEMBRANE ANTIGEN PSMA; PRECLINICAL EVALUATION; GUIDED SURGERY; INHIBITORS AB Prostate-specific membrane antigen (PSMA) can serve as a molecular cell surface target for the detection and treatment of prostate cancer. Near-infrared (NIR) fluorescence imaging enables highly sensitive, rapid, and non-radioactive imaging of PSMA, though specific targeting still remains a challenge because no optimized contrast agents exist. C1 [Bao, Kai; Lee, Jeong Heon; Kang, Homan; Park, G. Kate; El Fakhri, Georges; Choi, Hak Soo] Massachusetts Gen Hosp, Gordon Ctr Med Imaging, Dept Radiol, Boston, MA 02114 USA. [Bao, Kai; Lee, Jeong Heon; Kang, Homan; Park, G. Kate; El Fakhri, Georges; Choi, Hak Soo] Harvard Med Sch, Boston, MA 02114 USA. [Bao, Kai] Shenyang Pharmaceut Univ, Key Lab Struct Based Drug Design & Discovery, Minist Educ, Shenyang 110016, Peoples R China. RP Choi, HS (reprint author), Massachusetts Gen Hosp, Gordon Ctr Med Imaging, Dept Radiol, Boston, MA 02114 USA.; Choi, HS (reprint author), Harvard Med Sch, Boston, MA 02114 USA. EM hchoi12@mgh.harvard.edu FU NIBIB [R01-EB011523, R01-EB017699]; National Natural Science Foundation of China [81502932] FX We thank Ramsey El Fakhri for editing, and SooYoung Han, Christina Shambaugh, and Julia Scotton for administrative assistance. This study was supported by the following grants: NIBIB # R01-EB011523 (HSC), NIBIB # R01-EB017699 (HSC), and National Natural Science Foundation of China (Grant No. 81502932). NR 31 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 10 BP 1611 EP 1614 DI 10.1039/c6cc09781b PG 4 WC Chemistry, Multidisciplinary SC Chemistry GA EM6SC UT WOS:000395441400009 PM 28085163 ER PT J AU Steiner, J Wiafe, S Camuso, J Milley, K Wooster, LT Bailey, CS Thomas, SS D'Alessandro, DA Garcia, JP Lewis, GD AF Steiner, Johannes Wiafe, Stephanie Camuso, Janice Milley, Katherine Wooster, Luke T. Bailey, Cole S. Thomas, Sunu S. D'Alessandro, David A. Garcia, Jose P. Lewis, Gregory D. TI Predicting Success Left Ventricular Assist Device Explantation Evaluation Protocol Using Comprehensive Cardiopulmonary Exercise Testing SO CIRCULATION-HEART FAILURE LA English DT Editorial Material ID HEART-FAILURE C1 [Steiner, Johannes; Wooster, Luke T.; Bailey, Cole S.; Thomas, Sunu S.; Lewis, Gregory D.] Harvard Med Sch, Div Cardiovasc Med, Dept Med, Boston, MA 02114 USA. [Wiafe, Stephanie; Camuso, Janice; Milley, Katherine; D'Alessandro, David A.; Garcia, Jose P.] Harvard Med Sch, Div Cardiothorac Surg, Dept Surg, Boston, MA 02114 USA. RP Lewis, GD (reprint author), Harvard Med Sch, Dept Internal Med, Div Cardiovasc Med, Massachusetts Gen Hosp, 55 Fruit St, Boston, MA 02114 USA. EM glewis@partners.org FU National Health Institutes and National Heart, Lung, and Blood Institute [1R01HL131029] FX This article is supported by National Health Institutes and National Heart, Lung, and Blood Institute funding (1R01HL131029). NR 4 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 1941-3289 EI 1941-3297 J9 CIRC-HEART FAIL JI Circ.-Heart Fail. PD JAN PY 2017 VL 10 IS 1 AR e003694 DI 10.1161/CIRCHEARTFAILURE.116.003694 PG 4 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EL1NQ UT WOS:000394387500007 ER PT J AU Streng, KW ter Maaten, JM Cleland, JG O'Connor, CM Davison, BA Metra, M Givertz, MM Teerlink, JR Ponikowski, P Bloomfield, DM Dittrich, HC Hillege, HL van Veldhuisen, DJ Voors, AA van der Meer, P AF Streng, Koen W. ter Maaten, Jozine M. Cleland, John G. O'Connor, Christopher M. Davison, Beth A. Metra, Marco Givertz, Michael M. Teerlink, John R. Ponikowski, Piotr Bloomfield, Daniel M. Dittrich, Howard C. Hillege, Hans L. van Veldhuisen, Dirk J. Voors, Adriaan A. van der Meer, Peter TI Associations of Body Mass Index With Laboratory and Biomarkers in Patients With Acute Heart Failure SO CIRCULATION-HEART FAILURE LA English DT Article DE biomarkers; heart failure; mortality; obesity; prognosis ID REGIONAL PRO-ADRENOMEDULLIN; GLYCATION END-PRODUCTS; NATRIURETIC PEPTIDES; SOLUBLE RECEPTOR; OBESITY PARADOX; URIC-ACID; MORTALITY; RISK; ROLOFYLLINE; POPULATION AB Background-Plasma concentrations of natriuretic peptides decline with obesity in patients with heart failure. Whether this is true for other biomarkers is unknown. We investigated a wide range of biomarker profiles in acute heart failure across the body mass index (BMI) spectrum. Methods and Results-A total of 48 biomarkers, assessing multiple pathophysiological pathways, were measured in 2033 patients included in PROTECT (Placebo-Controlled Randomized Study of the Selective A1 Adenosine Receptor Antagonist Rolofylline for Patients Hospitalized With Acute Decompensated Heart Failure and Volume Overload to Assess Treatment Effect on Congestion and Renal Function), a trial comparing the effects of rolofylline to placebo in patients with acute heart failure. Patients were classified into 4 groups according to BMI (<25, 25-30, 30-35, and >35 kg/m(2)). Of 2003 patients with known weight and height, mean age was 70 +/- 12 years and 67% were men. Patients with a higher BMI (> 35 kg/m2) had higher blood pressures, were younger, and were more often women. Median levels of brain natriuretic peptide were 550 pg/mL in patients with a BMI <25 kg/m(2) and 319 pg/mL in patients with a BMI >35 kg/m(2) (P<0.001). Multivariable regression revealed that brain natriuretic peptide (beta=-0.250; P<0.001) and receptor for advanced glycation endproducts (beta=-0.095; P<0.007) were inversely correlated to BMI, whereas higher levels of uric acid (beta=0.164; P<0.001), proadrenomedullin (beta=0.171; P<0.001), creatinine (beta=0.118; P=0.003), sodium (beta=0.101; P=0.006), and bicarbonate (beta=0.094; P=0.009) were associated with higher BMI. No significant interaction was seen between these 7 biomarkers and BMI on 180-day mortality. Conclusions-The plasma concentrations of several biomarkers are either positively or negatively influenced by BMI. These findings suggest that these markers should be interpreted with caution in patients with obesity. Although concentrations differ, their prognostic value for mortality up to 180 days did not differ. C1 [Streng, Koen W.; ter Maaten, Jozine M.; Hillege, Hans L.; van Veldhuisen, Dirk J.; Voors, Adriaan A.; van der Meer, Peter] Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, Groningen, Netherlands. [Cleland, John G.] Imperial Coll, Natl Heart & Lung Inst, Royal Brompton Hosp, London, England. [Cleland, John G.] Imperial Coll, Natl Heart & Lung Inst, Harefield Hosp, London, England. [O'Connor, Christopher M.] Inova Heart & Vasc Inst, Falls Church, VA USA. [Davison, Beth A.] Momentum Res, Durham, NC USA. [Metra, Marco] Univ Brescia, Brescia, Italy. [Givertz, Michael M.] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. [Teerlink, John R.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Teerlink, John R.] San Francisco VA Med Ctr, San Francisco, CA USA. [Ponikowski, Piotr] Med Univ, Clin Mil Hosp, Wroclaw, Poland. [Bloomfield, Daniel M.] Merck Res Labs, Rahway, NJ USA. [Dittrich, Howard C.] Univ Iowa, Carver Coll Med, Cardiovasc Res Ctr, Iowa City, IA 52242 USA. RP van der Meer, P (reprint author), Univ Med Ctr Groningen, Dept Cardiol, Hanzepl 1, NL-9713 GZ Groningen, Netherlands. EM p.van.der.meer@umcg.nl FU NovaCardia of Merck FX The PROTECT trial was supported by NovaCardia, a subsidiary of Merck. 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 1941-3289 EI 1941-3297 J9 CIRC-HEART FAIL JI Circ.-Heart Fail. PD JAN PY 2017 VL 10 IS 1 AR e003350 DI 10.1161/CIRCHEARTFAILURE.116.003350 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EL1NQ UT WOS:000394387500003 ER PT J AU Dichtel, LE Corey, KE Misdraji, J Bredella, MA Schorr, M Osganian, SA Young, BJ Sung, JC Miller, KK AF Dichtel, Laura E. Corey, Kathleen E. Misdraji, Joseph Bredella, Miriam A. Schorr, Melanie Osganian, Stephanie A. Young, Brian J. Sung, Joshua C. Miller, Karen K. TI The Association Between IGF-1 Levels and the Histologic Severity of Nonalcoholic Fatty Liver Disease SO CLINICAL AND TRANSLATIONAL GASTROENTEROLOGY LA English DT Article ID GROWTH-FACTOR-I; CARDIOVASCULAR RISK MARKERS; MORBIDLY OBESE-PATIENTS; HEPATIC STEATOSIS; HORMONE GH; REPLACEMENT THERAPY; BODY-COMPOSITION; CONTROLLED-TRIAL; UNITED-STATES; WEIGHT-LOSS AB OBJECTIVES: The mechanisms responsible for the development of nonalcoholic fatty liver disease (NAFLD) and progression to nonalcoholic steatohepatitis (NASH) are incompletely understood. Growing evidence suggests that growth hormone (GH) and insulin-like growth factor-1 (IGF-1) may have roles in the development and progression of NAFLD. We hypothesized that lower serum IGF-1 levels would be associated with increased liver fat accumulation, inflammation, and fibrosis in a group of meticulously phenotyped obese subjects with liver biopsies. METHODS: A retrospective, cross-sectional study was performed at Massachusetts General Hospital, Boston, MA, USA and St.Mary's Hospital, Richmond, VA,USA. Liver biopsies were performed in 142 subjects during NAFLD work-up or bariatric surgery and were graded by a single, blinded pathologist. Main outcome measures included liver histology and serum IGF-1. RESULTS: Mean age was 52 +/- 10 years and body mass index (BMI) was 43 +/- 9 kg/m(2). Mean serum IGF-1 was lower in subjects with lobular inflammation (112 +/- 47 vs. 136 +/- 57 ng/ml, P=0.01), hepatocyte ballooning (115 +/- 48 vs. 135 +/- 57 ng/ml, P=0.05), higher fibrosis stage (stage 2-4 vs. 0-1; 9640 vs. 125 +/- 51 ng/ml, P=0.005), and NASH (109 +/- 45 vs. 136 +/- 57 ng/ml, P=0.002). All results remained significant after controlling for age, BMI, and a diagnosis of diabetes, and all but hepatocyte ballooning (trend, P=0.06) remained significant after excluding individuals with cirrhosis. Steatosis was not significantly associated with mean serum IGF-1 levels. CONCLUSIONS: Low serum IGF-1 levels are associated with increased histologic severity of NAFLD when rigorously controlled for age, BMI, the presence of diabetes, and after the exclusion of subjects with cirrhosis. Further investigation is warranted to determine the differential effects of GH and IGF-1 on the development and progression of NAFLD, which could further elucidate pathophysiology and identify therapeutic targets. C1 [Dichtel, Laura E.; Schorr, Melanie; Miller, Karen K.] Harvard Med Sch, Massachusetts Gen Hosp, Neuroendocrine Unit, Boston, MA USA. [Corey, Kathleen E.] Harvard Med Sch, Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA USA. [Misdraji, Joseph] Harvard Med Sch, Massachusetts Gen Hosp, Dept Pathol, Boston, MA USA. [Bredella, Miriam A.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Radiol, Boston, MA USA. [Osganian, Stephanie A.] Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA. [Young, Brian J.; Sung, Joshua C.] Massachusetts Gen Hosp, Neuroendocrine Unit, Boston, MA 02114 USA. RP Dichtel, LE (reprint author), Massachusetts Gen Hosp, Dept Internal Med, Neuroendocrine Unit, BUL457B,55 Fruit St, Boston, MA 02114 USA. EM ldichtel@mgh.harvard.edu FU National Institutes of Health [R01 HL 077674, K24 HL092902, K23 RR023090, K23 DK099422, T32 DK007028]; Harvard Clinical and Translational Science Center (CTSC) [UL1 RR025758] FX This work was supported by National Institutes of Health grants R01 HL 077674, K24 HL092902, K23 RR023090, K23 DK099422, and T32 DK007028, as well as the Harvard Clinical and Translational Science Center (CTSC) grant UL1 RR025758. NR 64 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 2155-384X J9 CLIN TRANSL GASTROEN JI Clin. Transl. Gastroenterol. PD JAN PY 2017 VL 8 AR e217 DI 10.1038/ctg.2016.72 PG 9 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EN9YJ UT WOS:000396355200009 PM 28125073 ER PT J AU Saylor, PJ Lee, RJ Arora, KS Deshpande, V Hu, R Olivier, K Meneely, E Rivera, MN Ting, DT Wu, CL Miyamoto, DT AF Saylor, Philip J. Lee, Richard J. Arora, Kshitij S. Deshpande, Vikram Hu, Rong Olivier, Kara Meneely, Erika Rivera, Miguel N. Ting, David T. Wu, Chin-Lee Miyamoto, David T. TI Branched Chain RNA In Situ Hybridization for Androgen Receptor Splice Variant AR-V7 as a Prognostic Biomarker for Metastatic Castration-Sensitive Prostate Cancer SO CLINICAL CANCER RESEARCH LA English DT Article ID INCREASED SURVIVAL; ENZALUTAMIDE; RECOMMENDATION; CHEMOTHERAPY; ABIRATERONE; ALBUMIN AB Purpose: The androgen receptor (AR) mRNAsplice variant AR-V7 has emerged as a predictive biomarker for response to AR-targeted therapies. There are currently no commercially available assays to detect AR splice variants. The branched chain RNA in situ hybridization (ISH) platform enables the highly sensitive detection of RNA transcripts in formalin-fixed, paraffin-embedded (FFPE) tissues. Experimental design: We designed a branched chain RNA ISH probe to target the unique cryptic exon CE3 of AR-V7 using multiple tiling probes. This automated ISH assay was applied to tumor tissue from two distinct clinical cohorts that we hypothesized would differ in AR-V7 status. Results: We detected AR-V7 in all tumor samples from men with metastatic castration-resistant prostate cancer with tissue obtained after disease progression despite at least one subsequent line of hormonal therapy (abiraterone, enzalutamide, or bicalu-tamide; n = 12). We detected AR-V7 in just one tumor from men who had undergone prostatectomy for localized adenocarcinoma (n = 30; Gleason 4 + 5 = 9 in the AR-V7-positive sample). Given the apparent distinction between the above groups by AR-V7 signal, we analyzed pretreatment AR-V7 status as a predictive and prognostic biomarker in men with treatment-naive metastatic disease. Patients with metastases but without detectable AR-V7 RNA at baseline had significantly longer overall survival (log-rank P = 0.044) and a trend toward superior progression-free survival (log-rank P = 0.055). Conclusions: Within an institutional cohort, the RNA ISH assay identified AR-V7 within FFPE tissue and may have prognostic value in metastatic castration-sensitive prostate cancer. These preliminary findings warrant further study in larger cohorts. (C) 2016 AACR. C1 [Saylor, Philip J.; Lee, Richard J.; Arora, Kshitij S.; Deshpande, Vikram; Hu, Rong; Olivier, Kara; Meneely, Erika; Rivera, Miguel N.; Ting, David T.; Wu, Chin-Lee; Miyamoto, David T.] Harvard Med Sch, Massachusetts Gen Hosp, Canc Ctr, Boston, MA USA. [Saylor, Philip J.; Lee, Richard J.; Arora, Kshitij S.; Ting, David T.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Med, Boston, MA USA. [Arora, Kshitij S.; Deshpande, Vikram; Hu, Rong; Rivera, Miguel N.; Wu, Chin-Lee] Harvard Med Sch, Massachusetts Gen Hosp, Dept Pathol, Boston, MA USA. [Miyamoto, David T.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA USA. RP Miyamoto, DT (reprint author), Massachusetts Gen Hosp, 13th St,CNY Bldg 149, Charlestown, MA 02129 USA. EM dmiyamoto@mgh.harvard.edu OI Ting, David/0000-0002-3261-2322 FU Department of Defense; Prostate Cancer Foundation; Burroughs Wellcome Trust; NIH [4K12CA087723-14, P01CA120964] FX We thank K. Broderick for technical assistance. This work was partially supported by the Department of Defense (D.T. Miyamoto), Prostate Cancer Foundation (P.J. Saylor, R.J. Lee, D.T. Miyamoto), Burroughs Wellcome Trust (D.T. Ting), NIH 4K12CA087723-14 (D.T. Ting), and NIH P01CA120964 (C.-L. Wu). NR 20 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 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JAN PY 2017 VL 23 IS 2 BP 363 EP 369 DI 10.1158/1078-0432.CCR-16-0237 PG 7 WC Oncology SC Oncology GA EK4EQ UT WOS:000393880300006 PM 27440270 ER PT J AU Parsons, HA Beaver, JA Cimino-Mathews, A Ali, SM Axilbund, J Chu, D Connolly, RM Cochran, RL Croessmann, S Clark, TA Gocke, CD Jeter, SC Kennedy, MR Lauring, J Lee, J Lipson, D Miller, VA Otto, GA Rosner, GL Ross, JS Slater, S Stephens, PJ VanDenBerg, DA Wolff, AC Young, LE Zabransky, DJ Zhang, Z Zorzi, J Stearns, V Park, BH AF Parsons, Heather A. Beaver, Julia A. Cimino-Mathews, Ashley Ali, Siraj M. Axilbund, Jennifer Chu, David Connolly, Roisin M. Cochran, Rory L. Croessmann, Sarah Clark, Travis A. Gocke, Christopher D. Jeter, Stacie C. Kennedy, Mark R. Lauring, Josh Lee, Justin Lipson, Doron Miller, Vincent A. Otto, Geoff A. Rosner, Gary L. Ross, Jeffrey S. Slater, Shannon Stephens, Philip J. VanDenBerg, Dustin A. Wolff, Antonio C. Young, Lauren E. Zabransky, Daniel J. Zhang, Zhe Zorzi, Jane Stearns, Vered Park, Ben H. TI Individualized Molecular Analyses Guide Efforts (IMAGE): A Prospective Study of Molecular Profiling of Tissue and Blood in Metastatic Triple-Negative Breast Cancer SO CLINICAL CANCER RESEARCH LA English DT Article ID CIRCULATING TUMOR DNA; COLORECTAL-CANCER; ESR1 MUTATIONS; HETEROGENEITY; SUBTYPES; PLASMA AB Purpose: The clinical utility of next-generation sequencing (NGS) in breast cancer has not been demonstrated. We hypothesized that we could perform NGS of a new biopsy from patients with metastatic triple-negative breast cancer (TNBC) in a clinically actionable timeframe. Experimental Design: We planned to enroll 40 patients onto a prospective study, Individualized Molecular Analyses Guide Efforts (IMAGE), to evaluate the feasibility of obtaining a new biopsy of a metastatic site, perform NGS (FoundationOne), and convene a molecular tumor board to formulate treatment recommendations within 28 days. We collected blood at baseline and at time of restaging to assess cell-free circulating plasma tumorDNA(ptDNA). Results: We enrolled 26 women with metastatic TNBC who had received >= 1 line of prior chemotherapy, and 20 (77%) underwent NGS of a metastatic site biopsy. Twelve (60%) evaluable patients received treatment recommendations within 28 days of consent. The study closed after 20 patients underwent NGS, based on protocol-specified interim futility analysis. Three patients went on to receive genomically directed therapies. Twenty-four of 26 patients had genetic alterations successfully detected in ptDNA. Among 5 patients, 4 mutations found in tumor tissues were not identified in blood, and 4 mutations found in blood were not found in corresponding tumors. In 9 patients, NGS of follow-up blood samples showed 100% concordance with baseline blood samples. Conclusions: This study demonstrates challenges of performing NGS on prospective tissue biopsies in patients with metastatic TNBC within 28 days, while also highlighting the potential use of blood as a more time-efficient and less invasive method of mutational assessment. (C) 2016 AACR. C1 [Parsons, Heather A.; Beaver, Julia A.; Cimino-Mathews, Ashley; Axilbund, Jennifer; Chu, David; Connolly, Roisin M.; Cochran, Rory L.; Croessmann, Sarah; Gocke, Christopher D.; Jeter, Stacie C.; Lauring, Josh; Lee, Justin; Rosner, Gary L.; Slater, Shannon; VanDenBerg, Dustin A.; Wolff, Antonio C.; Zabransky, Daniel J.; Zhang, Zhe; Zorzi, Jane; Stearns, Vered; Park, Ben H.] Johns Hopkins Univ Hosp, Sidney Kimmel Comprehens Canc Ctr, Sch Med, 1650 Orleans St,CRBI,Rm 114, Baltimore, MD 21231 USA. [Ali, Siraj M.; Clark, Travis A.; Kennedy, Mark R.; Lipson, Doron; Miller, Vincent A.; Otto, Geoff A.; Ross, Jeffrey S.; Stephens, Philip J.; Young, Lauren E.] Fdn Med Inc, Cambridge, MA USA. [Parsons, Heather A.] Harvard Med Sch, Susan Smith Ctr Womens Canc Breast Oncol Program, Dana Farber Canc Inst, Boston, MA USA. RP Stearns, V; Park, BH (reprint author), Johns Hopkins Univ Hosp, Sidney Kimmel Comprehens Canc Ctr, Sch Med, 1650 Orleans St,CRBI,Rm 114, Baltimore, MD 21231 USA.; Park, BH (reprint author), Johns Hopkins Univ, CRB, Room 151,1650 Orleans St, Baltimore, MD 21287 USA. EM vstearn1@jhmi.edu; bpark2@jhmi.edu FU Conquer Cancer Foundation; NIH [CA088843, GM007309, CA168180, CA167939]; Pearl M. Stetler Research Fund; Avon Foundation; Commonwealth Foundation; Santa Fe Foundation; Canney Foundation; Cigarette Restitution Fund; Cindy Rosencrans Fund for Triple Negative Breast Cancer Research; Marcie and Ellen Foundation FX This work was supported by The Conquer Cancer Foundation's Young Investigator Award, The Pearl M. Stetler Research Fund, NIH (CA088843, GM007309, CA168180, CA167939), The Avon Foundation, Commonwealth Foundation, the Santa Fe Foundation, The Canney Foundation, Cigarette Restitution Fund, The Cindy Rosencrans Fund for Triple Negative Breast Cancer Research, and the Marcie and Ellen Foundation. Foundation Medicine analyzed samples free of charge. NR 32 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 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JAN PY 2017 VL 23 IS 2 BP 379 EP 386 DI 10.1158/1078-0432.CCR-16-1543 PG 8 WC Oncology SC Oncology GA EK4EQ UT WOS:000393880300008 PM 27489289 ER PT J AU Trinh, A Trumpi, K Melo, FDSE Wang, X de Jong, JH Fessler, E Kuppen, PJK Reimers, MS Swets, M Koopman, M Nagtegaal, ID Jansen, M Hooijer, GKJ Offerhaus, GJA Kranenburg, O Punt, CJ Medema, JP Markowetz, F Vermeulen, L AF Trinh, Anne Trumpi, Kari Melo, Felipe De Sousa E. Wang, Xin de Jong, Joan H. Fessler, Evelyn Kuppen, Peter J. K. Reimers, Marlies S. Swets, Marloes Koopman, Miriam Nagtegaal, Iris D. Jansen, Marnix Hooijer, Gerrit K. J. Offerhaus, George J. A. Kranenburg, Onno Punt, Cornelis J. Medema, Jan Paul Markowetz, Florian Vermeulen, Louis TI Practical and Robust Identification of Molecular Subtypes in Colorectal Cancer by Immunohistochemistry SO CLINICAL CANCER RESEARCH LA English DT Article ID EPITHELIAL-MESENCHYMAL TRANSITION; DEFICIENT MISMATCH REPAIR; GENE-EXPRESSION; MUTATION STATUS; CHEMOTHERAPY; CETUXIMAB; THERAPY; TISSUES; SYSTEM; LEVEL AB Purpose: Recent transcriptomic analyses have identified four distinct molecular subtypes of colorectal cancer with evident clinical relevance. However, the requirement for sufficient quantities of bulk tumor and difficulties in obtaining high-quality genome-wide transcriptome data from formalin-fixed paraffin-embedded tissue are obstacles toward widespread adoption of this taxonomy. Here, we develop an immunohistochemistry-based classifier to validate the prognostic and predictive value of molecular colorectal cancer subtyping in a multicenter study. Experimental Design: Tissue microarrays from 1,076 patients with colorectal cancer from four different cohorts were stained for five markers (CDX2, FRMD6, HTR2B, ZEB1, and KER) by immunohistochemistry and assessed for microsatellite instability. An automated classification system was trained on one cohort using quantitative image analysis or semiquantitative pathologist scoring of the cores as input and applied to three independent clinical cohorts. Results: This classifier demonstrated 87% concordance with the gold-standard transcriptome-based classification. Application to three validation datasets confirmed the poor prognosis of the mesenchymal-like molecular colorectal cancer subtype. In addition, retrospective analysis demonstrated the benefit of adding cetuximab to bevacizumab and chemotherapy in patients with RAS wild-type metastatic cancers of the canonical epithelial-like subtypes. Conclusions: This study shows that a practical and robust immunohistochemical assay can be employed to identify molecular colorectal cancer subtypes and uncover subtype-specific therapeutic benefit. Finally, the described tool is available online for rapid classification of colorectal cancer samples, both in the format of an automated image analysis pipeline to score tumor core staining, and as a classifier based on semiquantitative pathology scoring. (C) 2016 AACR. C1 [Trinh, Anne; Wang, Xin; Markowetz, Florian] Univ Cambridge, Canc Res UK Cambridge Inst, Cambridge, England. Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Trumpi, Kari; Koopman, Miriam; Offerhaus, George J. A.; Kranenburg, Onno] Univ Med Ctr Utrecht, Canc Ctr UMC Utrecht, Utrecht, Netherlands. [Melo, Felipe De Sousa E.; de Jong, Joan H.; Fessler, Evelyn; Medema, Jan Paul; Vermeulen, Louis] Univ Amsterdam, Acad Med Ctr, Ctr Expt Mol Med CEMM, Lab Expt Oncol & Radiobiol LEXOR, Amsterdam, Netherlands. [Melo, Felipe De Sousa E.] Genentech Inc, Dept Mol Oncol, San Francisco, CA 94080 USA. [Wang, Xin] City Univ Hong Kong, Dept Biomed Sci, Kowloon Tong, Hong Kong, Peoples R China. [Kuppen, Peter J. K.; Reimers, Marlies S.; Swets, Marloes] Leiden Univ Med Ctr, Dept Surg, Leiden, Netherlands. [Nagtegaal, Iris D.] Radboud Univ Nijmegen Med Ctr, Dept Pathol, Nijmegen, Netherlands. [Jansen, Marnix; Hooijer, Gerrit K. J.] Univ Amsterdam, Acad Med Ctr, Lymphoma & Myeloma Ctr Amsterdam, Dept Pathol, Amsterdam, Netherlands. [Jansen, Marnix] Queen Mary Univ London, Barts & London Sch Med & Dent, Barts Canc Inst, Ctr Tumour Biol, London, England. [Punt, Cornelis J.] Univ Amsterdam, Acad Med Ctr, Dept Med Oncol, Amsterdam, Netherlands. RP Vermeulen, L (reprint author), Univ Amsterdam, Acad Med Ctr, Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands. EM l.vermeulen@amc.uva.nl FU KWF [UVA2011-4969, UVA2014-7245]; Worldwide Cancer Research [14-1164]; Maag Lever Darm Stichting [MLDS-CDG 14-03]; European Research Council [ERG-StG 638193]; University of Cambridge; Cancer Research UK; Hutchison Whampoa Limited; CRUK [C14303/A17197, A19274] FX L. Vermeulen is supported by KWF grants (UVA2011-4969 and UVA2014-7245), Worldwide Cancer Research (14-1164), the Maag Lever Darm Stichting (MLDS-CDG 14-03), and the European Research Council (ERG-StG 638193). A. Trinh and F. Markowetz acknowledge the support of The University of Cambridge, Cancer Research UK, and Hutchison Whampoa Limited. Parts of this work were funded by CRUK core grant C14303/A17197 and A19274. NR 31 TC 1 Z9 1 U1 1 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JAN PY 2017 VL 23 IS 2 BP 387 EP 398 DI 10.1158/1078-0432.CCR-16-0680 PG 12 WC Oncology SC Oncology GA EK4EQ UT WOS:000393880300009 PM 27459899 ER PT J AU Zhu, XG Enomoto, K Zhao, L Zhu, YLJ Willingham, MC Meltzer, P Qi, J Cheng, SY AF Zhu, Xuguang Enomoto, Keisuke Zhao, Li Zhu, Yuelin J. Willingham, Mark C. Meltzer, Paul Qi, Jun Cheng, Sheue-yann TI Bromodomain and Extraterminal Protein Inhibitor JQ1 Suppresses Thyroid Tumor Growth in a Mouse Model SO CLINICAL CANCER RESEARCH LA English DT Article ID C-MYC; SELECTIVE-INHIBITION; BET BROMODOMAINS; CANCER; MUTATION; HORMONE; CELLS; TARGETS; FAMILY; MUTANT AB Purpose: New therapeutic approaches are needed for patients with thyroid cancer refractory to radioiodine treatment. An inhibitor of bromodomain and extraterminal domain (BET) proteins, JQ1, shows potent antitumor effects in hematological cancers and solid tumors. To evaluate whether JQ1 is effective against thyroid cancer, we examined antitumor efficacy of JQ1 using the Thrb(PV/PV) Kras(G12D) mouse, a model of anaplastic thyroid cancer. Experimental Design: We treated Thrb(PV/PV) Kras(G12D) mice with vehicle or JQ1 at a dose of 50 mg/kg body weight/day starting at the age of 8 weeks for a 10-week period and monitored thyroid tumor progression. Results: JQ1 markedly inhibited thyroid tumor growth and prolonged survival of these mice. Global differential gene expression analysis showed that JQ1 suppressed the cMyc (hereafter referred to as Myc) transcription program by inhibiting mRNA expression of Myc, ccnd1, and other related genes. JQ1-suppressed Myc expression was accompanied by chromatin remodeling as evidenced by increased expression of histones and hexamethylene bis-acetamide inducible 1, a suppressor of RNA polymerase II transcription elongation. Analyses showed that JQ1 decreased MYC abundance in thyroid tumors and attenuated the cyclin D1-CDK4-Rb-E2F3 signaling to decrease tumor growth. Further analysis indicated that JQ1 inhibited the recruitment of BDR4 to the promoter complex of the Myc and Ccnd1 genes in rat thyroid follicular PCCL3 cells, resulting in decreased MYC expression at the mRNA and protein levels to inhibit tumor cell proliferation. Conclusions: These preclinical findings suggest that BET inhibitors may be an effective agent to reduce thyroid tumor burden for the treatment of refractory thyroid cancer. (C) 2016 AACR. C1 [Zhu, Xuguang; Enomoto, Keisuke; Zhao, Li; Willingham, Mark C.; Cheng, Sheue-yann] NIH, Natl Canc Inst, Mol Biol Lab, Bethesda, MD USA. [Zhu, Yuelin J.; Meltzer, Paul] NIH, Ctr Canc Res, Natl Canc Inst, Lab Genet Branch, Bethesda, MD USA. [Qi, Jun] Dana Farber Canc Inst, Harvard Med Sch, Boston, MA USA. RP Cheng, SY (reprint author), Natl Canc Inst, Mol Biol Lab, 37 Convent Dr,Room 5128, Bethesda, MD USA. EM chengs@mail.nih.gov FU Intramural Research Program of the Center for Cancer Research, National Cancer Institute, NIH FX This research was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, NIH. NR 50 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 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JAN PY 2017 VL 23 IS 2 BP 430 EP 440 DI 10.1158/1078-0432.CCR-16-0914 PG 11 WC Oncology SC Oncology GA EK4EQ UT WOS:000393880300013 PM 27440272 ER PT J AU Chen, CE Chen, CT Hu, J Mehrota, A AF Chen, Connie E. Chen, Christopher T. Hu, Jia Mehrota, Ateev TI Walk-in clinics versus physician offices and emergency rooms for urgent care and chronic disease management SO COCHRANE DATABASE OF SYSTEMATIC REVIEWS LA English DT Review ID QUALITY-OF-CARE; RETAIL CLINICS; CENTERS; NHS; DEPARTMENTS; ILLNESSES; VISITS; TRIAL AB Background Walk-in clinics are growing in popularity around the world as a substitute for traditional medical care delivered in physician offices and emergency rooms, but their clinical efficacy is unclear. Objectives To assess the quality of care and patient satisfaction of walk-in clinics compared to that of traditional physician offices and emergency rooms for people who present with basic medical complaints for either acute or chronic issues. Search methods We searched CENTRAL, MEDLINE, Embase, six other databases, and two trials registers on 22 March 2016 together with reference checking, citation searching, and contact with study authors to identify additional studies. We applied no restrictions on language, publication type, or publication year. Selection criteria Study design: randomized trials, non-randomized trials, and controlled before-after studies. Population: standalone physical clinics not requiring advance appointments or registration, that provided basic medical care without expectation of follow-up. Comparisons: traditional primary care practices or emergency rooms. Data collection and analysis We used standard methodological procedures expected by Cochrane and the Cochrane Effective Practice and Organisation of Care (EPOC) Group. Main results The literature search identified 6587 citations, of which we considered 65 to be potentially relevant. We reviewed the abstracts of all 65 potentially relevant studies and retrieved the full texts of 12 articles thought to fit our study criteria. However, following independent author assessment of the full texts, we excluded all 12 articles. Authors' conclusions Controlled trial evidence about the mortality, morbidity, quality of care, and patient satisfaction of walk-in clinics is currently not available. C1 [Chen, Connie E.] Stanford Hlth Care, San Francisco, CA 94102 USA. [Chen, Christopher T.] Massachusetts Gen Hosp, Dept Med, Boston, MA USA. [Hu, Jia] Univ Toronto, Massachusetts Gen Hosp, Publ Hlth & Prevent Med, Toronto, ON, Canada. [Mehrota, Ateev] Harvard Med Sch, Dept Hlth Care Policy, Boston, MA USA. RP Chen, CE (reprint author), Stanford Hlth Care, San Francisco, CA 94102 USA. EM conn.chen@gmail.com FU Partners HealthCare, USA; Government of Ontario Ministry of Health and Long Term Care, Canada; Harvard Medical School, USA FX Internal sources; Partners HealthCare, USA.; Salary (CTC); Government of Ontario Ministry of Health and Long Term Care, Canada; Salary (JH); Harvard Medical School, USA; Salary (AM) NR 34 TC 0 Z9 0 U1 0 U2 0 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1469-493X EI 1361-6137 J9 COCHRANE DB SYST REV JI Cochrane Database Syst Rev. PY 2017 IS 2 AR CD011774 DI 10.1002/14651858.CD011774.pub2 PG 46 WC Medicine, General & Internal SC General & Internal Medicine GA EN6EG UT WOS:000396096700023 ER PT J AU Oaklander, AL Lunn, MPT Hughes, RAC van Schaik, IN Frost, C Chalk, CH AF Oaklander, Anne Louise Lunn, Michael P. T. Hughes, Richard A. C. van Schaik, Ivo N. Frost, Chris Chalk, Colin H. TI Treatments for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP): an overview of systematic reviews SO COCHRANE DATABASE OF SYSTEMATIC REVIEWS LA English DT Review ID RANDOMIZED CONTROLLED-TRIAL; INTRAVENOUS IMMUNOGLOBULIN TREATMENT; TECHNOLOGY-ASSESSMENT SUBCOMMITTEE; IMMUNE-MEDIATED POLYNEUROPATHIES; PLACEBO-CONTROLLED TRIAL; QUALITY-OF-LIFE; DOUBLE-BLIND; PLASMA-EXCHANGE; NEUROMUSCULAR DISORDERS; INTEROBSERVER AGREEMENT AB Background Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a chronic progressive or relapsing and remitting disease that usually causes weakness and sensory loss. The symptoms are due to autoimmune inflammation of peripheral nerves. CIPD affects about 2 to 3 per 100,000 of the population. More than half of affected people cannot walk unaided when symptoms are at their worst. CIDP usually responds to treatments that reduce inflammation, but there is disagreement about which treatment is most effective. Objectives To summarise the evidence fromCochrane systematic reviews (CSRs) and non-Cochrane systematic reviews of any treatment for CIDP and to compare the effects of treatments. Methods We considered all systematic reviews of randomised controlled trials (RCTs) of any treatment for any form of CIDP. We reported their primary outcomes, giving priority to change in disability after 12 months. Two overview authors independently identified published systematic reviews for inclusion and collected data. We reported the quality of evidence using GRADE criteria. Two other review authors independently checked review selection, data extraction and quality assessments. On 31 October 2016, we searched the Cochrane Database of Systematic Reviews, the Database of Abstracts of Reviews of Effects (in theCochrane Library), MEDLINE, Embase, and CINAHL Plus for systematic reviews of CIDP. We supplemented the RCTs in the existing CSRs by searching on the same date for RCTs of any treatment of CIDP (including treatment of fatigue or pain in CIDP), in the Cochrane Neuromuscular Specialised Register, CENTRAL, MEDLINE, Embase, and CINAHL Plus. Main results Five CSRs met our inclusion criteria. We identified 23 randomised trials, of which 15 had been included in these CSRs. We were unable to compare treatments as originally planned, because outcomes and outcome intervals differed. Corticosteroids It is uncertain whether daily oral prednisone improved impairment compared to no treatment because the quality of the evidence was very low (1 trial, 28 participants). According to moderate-quality evidence (1 trial, 41 participants), six months' treatment with high-dose monthly oral dexamethasone did not improve disability more than daily oral prednisolone. Observational studies tell us that prolonged use of corticosteroids sometimes causes serious side-effects. Plasma exchange According to moderate-quality evidence (2 trials, 59 participants), twice-weekly plasma exchange produced more short-term improvement in disability than sham exchange. In the largest observational study, 3.9% of plasma exchange procedures had complications. Intravenous immunoglobulin According to high-quality evidence (5 trials, 269 participants), intravenous immunoglobulin (IVIg) produced more short-term improvement than placebo. Adverse events were more common with IVIg than placebo (high-quality evidence), but serious adverse events were not (moderate-quality evidence, 3 trials, 315 participants). One trial with 19 participants provided moderate-quality evidence of little or no difference in short-term improvement of impairment with plasma exchange in comparison to IVIg. There was little or no difference in short-termimprovement of disability with IVIg in comparison to oral prednisolone (moderate-quality evidence; 1 trial, 29 participants) or intravenous methylprednisolone (high-quality evidence; 1 trial, 45 participants). One unpublished randomised open trial with 35 participants found little or no difference in disability after three months of IVIg compared to oral prednisone; this trial has not yet been included in a CSR. We know from observational studies that serious adverse events related to IVIg do occur. Other immunomodulatory treatments It is uncertain whether the addition of azathioprine (2 mg/kg) to prednisone improved impairment in comparison to prednisone alone, as the quality of the evidence is very low (1 trial, 27 participants). Observational studies show that adverse effects truncate treatment in 10% of people. According to low-quality evidence (1 trial, 60 participants), compared to placebo, methotrexate 15mg/kg did not allowmore participants to reduce corticosteroid or IVIg doses by 20%. Serious adverse events were no more common with methotrexate than with placebo, but observational studies show that methotrexate can cause teratogenicity, abnormal liver function, and pulmonary fibrosis. According to moderate-quality evidence (2 trials, 77 participants), interferon beta-1a (IFN beta-1a) in comparison to placebo, did not allow more people to withdraw from IVIg. According to moderate-quality evidence, serious adverse events were no more common with IFN beta-1a than with placebo. We know of no other completed trials of immunosuppressant or immunomodulatory agents for CIDP. Other treatments We identified no trials of treatments for fatigue or pain in CIDP. Adverse effects Not all trials routinely collected adverse event data; when they did, the quality of evidence was variable. Adverse effects in the short, medium, and long term occur with all interventions. We are not able to make reliable comparisons of adverse events between the interventions included in CSRs. Authors' conclusions We cannot be certain based on available evidence whether daily oral prednisone improves impairment compared to no treatment. However, corticosteroids are commonly used, based on widespread availability, low cost, very low-quality evidence from observational studies, and clinical experience. The weakness of the evidence does not necessarily mean that corticosteroids are ineffective. High-dose monthly oral dexamethasone for six months is probably no more or less effective than daily oral prednisolone. Plasma exchange produces short-termimprovement in impairment as determined by neurological examination, and probably produces short-termimprovement in disability. IVIg produces more short-term improvement in disability than placebo and more adverse events, although serious side effects are probably no more common than with placebo. There is no clear difference in short-term improvement in impairment with IVIg when compared with intravenous methylprednisolone and probably no improvement when compared with either oral prednisolone or plasma exchange. According to observational studies, adverse events related to difficult venous access, use of citrate, and haemodynamic changes occur in 3% to 17% of plasma exchange procedures. It is uncertain whether azathioprine is of benefit as the quality of evidence is very low. Methotrexate may not be of benefit and IFN beta-1a is probably not of benefit. We need further research to identify predictors of response to different treatments and to compare their long-term benefits, safety and cost-effectiveness. There is a need for more randomised trials of immunosuppressive and immunomodulatory agents, routes of administration, and treatments for symptoms of CIDP. C1 [Oaklander, Anne Louise] Mass Gen Hosp, 275 Charles St Warren 310, Boston, MA 02114 USA. [Lunn, Michael P. T.] Natl Hosp Neurol & Neurosurg, Dept Neurol, London, England. [Lunn, Michael P. T.; Hughes, Richard A. C.] Natl Hosp Neurol & Neurosurg, MRC, Ctr Neuromuscular Dis, London, England. [van Schaik, Ivo N.] Univ Amsterdam, Acad Med Ctr, Dept Neurol, Amsterdam, Netherlands. [Frost, Chris] London Sch Hyg & Trop Med, Dept Med Stat, London, England. [Chalk, Colin H.] McGill Univ, Dept Neurol & Neurosurg, Montreal, PQ, Canada. RP Oaklander, AL (reprint author), Mass Gen Hosp, 275 Charles St Warren 310, Boston, MA 02114 USA. EM aloaklander@mgh.harvard.edu FU National Institute for Health Research, Cochrane Review Group Infrastructure Award, UK; GBS Support Group, UK FX Internal sources; National Institute for Health Research, Cochrane Review Group Infrastructure Award, UK.; External sources; GBS Support Group, UK. NR 115 TC 0 Z9 0 U1 0 U2 0 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1469-493X EI 1361-6137 J9 COCHRANE DB SYST REV JI Cochrane Database Syst Rev. PY 2017 IS 1 AR CD010369 DI 10.1002/14651858.CD010369.pub2 PG 39 WC Medicine, General & Internal SC General & Internal Medicine GA EN6EA UT WOS:000396096100007 ER PT J AU Serra, G Uchida, M Battaglia, C Casini, MP De Chiara, L Biederman, J Vicari, S Wozniak, J AF Serra, Giulia Uchida, Mai Battaglia, Claudia Casini, Maria Pia De Chiara, Lavinia Biederman, Joseph Vicari, Stefano Wozniak, Janet TI Pediatric Mania: The Controversy between Euphoria and Irritability SO CURRENT NEUROPHARMACOLOGY LA English DT Article DE Adolescence; bipolar disorder; cardinal symptoms; childhood; irritability; mania ID ONSET BIPOLAR DISORDER; MOOD DYSREGULATION DISORDER; FOLLOW-UP; I DISORDER; CLINICAL PHENOTYPES; DEPRESSIVE DISORDER; SPECTRUM DISORDERS; MAJOR DEPRESSION; RISK-FACTORS; STEP-BD AB Pediatric Bipolar Disorder (BD) is a highly morbid pediatric psychiatric disease, consistently associated with family psychiatric history of mood disorders and associated with high levels of morbidity and disability and with a great risk of suicide. While there is a general consensus on the symptomatology of depression in childhood, the phenomenology of pediatric mania is still highly debated and the course and long-term outcome of pediatric BD still need to be clarified. We reviewed the available studies on the phenomenology of pediatric mania with the aim of summarizing the prevalence, demographics, clinical correlates and course of these two types of pediatric mania. Eighteen studies reported the number of subjects presenting with either irritable or elated mood during mania. Irritability has been reported to be the most frequent clinical feature of pediatric mania reaching a sensitivity of 95-100% in several samples. Only half the studies reviewed reported on number of episodes or cycling patterns and the described course was mostly chronic and ultra- rapid whereas the classical episodic presentation was less common. Few long-term outcome studies have reported a diagnostic stability of mania from childhood to young adult age. Future research should focus on the heterogeneity of irritability aiming at differentiating distinct subtypes of pediatric psychiatric disorders with distinct phenomenology, course, outcome and biomarkers. Longitudinal studies of samples attending to mood presentation, irritable versus elated, and course, chronic versus episodic, may help clarify whether these are meaningful distinctions in the course, treatment and outcome of pediatric onset bipolar disorder. C1 [Serra, Giulia; Battaglia, Claudia; Casini, Maria Pia; Vicari, Stefano] Bambino Gesu Pediat Hosp, Dept Neurosci, Child Psychiat Unit, IRCCS, Rome, Italy. [Serra, Giulia; De Chiara, Lavinia] Sapienza Univ, Sch Med & Psychol, NESMOS Dept Neurosci Mental Hlth & Sensory Organs, St Andrea Hosp, Rome, Italy. [Serra, Giulia; De Chiara, Lavinia] Lucio Bini Mood Disorder Ctr, Rome, Italy. [Uchida, Mai; Biederman, Joseph; Wozniak, Janet] Massachusetts Gen Hosp, Dept Pediat Psychopharmacol, Boston, MA 02114 USA. [Serra, Giulia; Uchida, Mai; Biederman, Joseph; Wozniak, Janet] Harvard Med Sch, Dept Psychiat, Boston, MA USA. RP Serra, G (reprint author), Bambino Gesu Pediat Hosp, Dept Neurosci, Child Psychiat Unit, IRCCS, Rome, Italy. EM giuliaserra@gmail.com NR 53 TC 0 Z9 0 U1 1 U2 1 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y-2, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1570-159X EI 1875-6190 J9 CURR NEUROPHARMACOL JI Curr. Neuropharmacol. PY 2017 VL 15 IS 3 BP 386 EP 393 DI 10.2174/1570159X14666160607100403 PG 8 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA EN3TK UT WOS:000395930600008 ER PT J AU Robinson, EM Cadge, W Zolfrank, AA Cremens, MC Courtwright, AM AF Robinson, Ellen M. Cadge, Wendy Zolfrank, Angelika A. Cremens, M. Cornelia Courtwright, Andrew M. TI AFTER THE DNR Surrogates Who Persist in Requesting Cardiopulmonary Resuscitation SO HASTINGS CENTER REPORT LA English DT Article ID INTENSIVE-CARE UNITS; OF-LIFE CARE; MEDICAL FUTILITY; MORAL DISTRESS; ETHICS CONSULTATION; COMPLICATED GRIEF; AMERICAN; EXPERIENCE; POLICY; BIOETHICS AB In 2006, Massachusetts General Hospital adopted a policy to support doctors who had judged that CPR would not benefit a patient in their care and wanted a DNR order in place, even in the face of objections from the surrogate decision-maker. Although some surrogates ended up accepting the DNR order, others continued to resist. Here's what MGH learned about them. C1 [Robinson, Ellen M.; Zolfrank, Angelika A.; Cremens, M. Cornelia; Courtwright, Andrew M.] Massachusetts Gen Hosp, Optimum Care Comm, Boston, MA 02114 USA. [Cadge, Wendy] Brandeis Univ, Sociol & Womens Gender & Sexual Studies, Waltham, MA 02254 USA. [Zolfrank, Angelika A.] Yale New Haven Med Ctr, Pastoral Educ, 20 York St, New Haven, CT 06504 USA. [Zolfrank, Angelika A.] Yale New Haven Med Ctr, Eth Comm, 20 York St, New Haven, CT 06504 USA. [Cremens, M. Cornelia] Massachusetts Gen Hosp, Inpatient Geriatr Consultat Serv, Boston, MA 02114 USA. RP Robinson, EM (reprint author), Massachusetts Gen Hosp, Optimum Care Comm, Boston, MA 02114 USA. NR 53 TC 3 Z9 3 U1 0 U2 0 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0093-0334 EI 1552-146X J9 HASTINGS CENT REP JI Hastings Cent. Rep. PD JAN-FEB PY 2017 VL 47 IS 1 BP 10 EP 19 DI 10.1002/hast.664 PG 10 WC Ethics; Health Care Sciences & Services; Medical Ethics; Social Sciences, Biomedical SC Social Sciences - Other Topics; Health Care Sciences & Services; Medical Ethics; Biomedical Social Sciences GA EO0FX UT WOS:000396374800007 PM 28074587 ER PT J AU Biswas, S Better, N Pascual, TNB Mercuri, M Vitola, JV Karthikeyan, G Westcott, J Alexanderson, E Allam, AH Al-Mallah, MH Bom, HHS Bouyoucef, SE Flotats, A Jerome, S Kaufman, PA Lele, V Luxenburg, O Mahmarian, JJ Shaw, LJ Underwood, SR Rehani, M Kashyap, R Dondi, M Paez, D Einstein, AJ AF Biswas, Sinjini Better, Nathan Pascual, Thomas N. B. Mercuri, Mathew Vitola, Joao V. Karthikeyan, Ganesan Westcott, James Alexanderson, Erick Allam, Adel H. Al-Mallah, Mouaz H. Bom, Henry Hee-Seung Bouyoucef, Salah E. Flotats, Albert Jerome, Scott Kaufman, Philip A. Lele, Vikram Luxenburg, Osnat Mahmarian, John J. Shaw, Leslee J. Underwood, S. Richard Rehani, Madan Kashyap, Ravi Dondi, Maurizio Paez, Diana Einstein, Andrew J. CA INCAPS Investigators Grp TI Nuclear Cardiology Practices and Radiation Exposure in the Oceania Region: Results From the IAEA Nuclear Cardiology Protocols Study (INCAPS) SO HEART LUNG AND CIRCULATION LA English DT Article DE Myocardial perfusion imaging; Radiation exposure ID AMERICAN-HEART-ASSOCIATION; IONIZING-RADIATION; IMAGING PROCEDURES; RADIOLOGY; RISKS; SPECT; MEDICINE AB Background There is concern about radiation exposure with radionuclide myocardial perfusion imaging (MPI). This sub-study of the International Atomic Energy Agency (IAEA) Nuclear Cardiology Protocols Study reports radiation doses from MPI, and use of dose-optimisation protocols in Australia and New Zealand (ANZ), and compares them with data from the rest of the world. Methods Data were collected from 7911 MPI studies performed in 308 laboratories worldwide in one week in 2013, including 439 MPI studies from 34 ANZ laboratories. For each laboratory, effective radiation dose (ED) and a quality index (QI) score (out of 8) based on pre-specified "best practices'' was determined. Results In ANZ patients, ED ranged from 0.9-17.9 milliSievert (mSv). Median ED was similar in ANZ compared with the rest of the world (10.0 (IQR: 6.5-11.7) vs. 10.0 (IQR 6.4-12.6, P=0.15), as were mean QI scores (5.5 +/- 0.7 vs. 5.4 +/- 1.3, P= 0.84). Use of stress-only imaging (17.6% vs. 31.8% of labs, P= 0.09) and weight-based dosing of technetium-99m (14.7% vs. 30.3%, P= 0.07) was lower in ANZ compared with the rest of the world but this difference was not statistically significant. Median ED was significantly lower in metropolitan versus nonmetropolitan laboratories (10.1 mSv vs. 11.6 mSv, P < 0.01), although mean QI scores were similar (5.4 +/- 0.8 vs. 5.5 +/- 0.7, P= 0.75). Conclusion Across ANZ, there is variability in ED from MPI, and use of radiation safety practices, particularly between metropolitan and non-metropolitan laboratories. Overall, ANZ laboratories have a similar median ED to laboratories in the rest of the world. C1 [Biswas, Sinjini; Better, Nathan; Westcott, James] Royal Melbourne Hosp, Dept Cardiol, Melbourne, Vic, Australia. [Biswas, Sinjini; Better, Nathan; Westcott, James] Royal Melbourne Hosp, Dept Nucl Med, Melbourne, Vic, Australia. [Pascual, Thomas N. B.; Kashyap, Ravi; Dondi, Maurizio; Paez, Diana] IAEA, Div Human Hlth, Sect Nucl Med & Diagnost Imaging, Vienna, Austria. [Mercuri, Mathew; Einstein, Andrew J.] Columbia Univ, Dept Med, Med Ctr, Div Cardiol, New York, NY USA. [Mercuri, Mathew; Einstein, Andrew J.] New York Presbyterian Hosp, New York, NY USA. [Vitola, Joao V.] Quanta Diagnost & Terapia, Curitiba, Parana, Brazil. [Karthikeyan, Ganesan] All India Inst Med Sci, Dept Cardiol, New Delhi, India. [Alexanderson, Erick] Inst Nacl Cardiol Ignacio Chavez, Dept Cardiol Nucl, Mexico City, DF, Mexico. [Allam, Adel H.] Al Azhar Univ, Dept Cardiol, Cairo, Egypt. [Al-Mallah, Mouaz H.] King Saud bin Abdulaziz Univ Hlth Sci, Div Adv Cardiac Imaging, Riyadh, Saudi Arabia. [Bom, Henry Hee-Seung] Chonnam Natl Univ, Sch Med, Dept Nucl Med, Gwangju, South Korea. [Bouyoucef, Salah E.] Ctr Hosp Univ Bab El Oued, Algiers, Algeria. [Flotats, Albert] Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, Dept Nucl Med, Barcelona, Spain. [Jerome, Scott] Intersoc Accreditat Commiss, Ellicott City, MD USA. [Jerome, Scott] Univ Maryland, Div Cardiovasc Med, Baltimore, MD 21201 USA. [Kaufman, Philip A.] Univ Zurich Hosp, Dept Nucl Med & Cardiac Imaging, Zurich, Switzerland. [Lele, Vikram] Jaslok Hosp & Res Ctr, Dept Nucl Med & PET CT, Mumbai, Maharashtra, India. [Luxenburg, Osnat] Minist Hlth, Med Technol & Infrastruct Adm, Jerusalem, Israel. [Luxenburg, Osnat] Gertner Inst Epidemiol & Hlth Policy Res, Israeli Ctr Technol Assessment Hlth Care, Tel Hashomer, Israel. [Mahmarian, John J.] Houston Methodist DeBakey Heart & Vasc Ctr, Dept Cardiol, Houston, TX USA. [Shaw, Leslee J.] Emory Univ, Sch Med, Dept Med, Div Cardiol, Atlanta, GA USA. [Shaw, Leslee J.] Emory Univ, Sch Med, Emory Clin Cardiovasc Res Inst, Atlanta, GA USA. [Underwood, S. Richard] Imperial Coll London, Natl Heart & Lung Inst, London, England. [Underwood, S. Richard] Royal Brompton Hosp, Dept Nucl Med, London, England. [Underwood, S. Richard] Harefield Hosp, Dept Nucl Med, London, England. [Rehani, Madan] IAEA, Radiat Protect Patients Unit, Vienna, Austria. [Rehani, Madan] Harvard Med Sch, Massachusetts Gen Hosp, Dept Radiol, Boston, MA USA. [Einstein, Andrew J.] Columbia Univ, Med Ctr, Dept Radiol, New York, NY USA. RP Biswas, S (reprint author), Royal Melbourne Hosp, Dept Cardiol & Nucl Med, Parkville, Vic 3052, Australia. EM sinjini@gmail.com OI Al-Mallah, Mouaz/0000-0003-2348-0484 NR 26 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 1443-9506 EI 1444-2892 J9 HEART LUNG CIRC JI Heart Lung Circ. PD JAN PY 2017 VL 26 IS 1 BP 25 EP 34 DI 10.1016/j.hlc.2016.05.112 PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EO1QG UT WOS:000396472400005 PM 27425184 ER PT J AU Abreo, AP Dalrymple, LS Chertow, GM Kaysen, GA Herzog, CA Johansen, KL AF Abreo, Adrian P. Dalrymple, Lorien S. Chertow, Glenn M. Kaysen, George A. Herzog, Charles A. Johansen, Kirsten L. TI Predialysis volume overload and patient-reported sleep duration and quality in patients receiving hemodialysis SO HEMODIALYSIS INTERNATIONAL LA English DT Article DE End-stage renal disease; volume overload; sleep ID STAGE RENAL-DISEASE; CHRONIC KIDNEY-DISEASE; MORTALITY RISK; OLDER ADULTS; FLUID SHIFT; DIALYSIS; INSOMNIA; APNEA; ASSOCIATION; COMPLAINTS AB Introduction: Previous studies of patients with end-stage renal disease have examined the role of fluid shifts on apnea-hypopnea episodes, but the association between volume overload and patient-reported sleep quality or duration has not been well-established. Methods: We studied the association between predialysis bioimpedance spectroscopy-derived volume estimates and self-reported sleep quality and duration in 638 patients in the United States Renal Data System ACTIVE/ADIPOSE study receiving hemodialysis from 2009 to 2011. We used questionnaires to assess self-reported sleep duration and quality. We used relative hydration status (fluid overload/extracellular water; FO/ECW) as the primary predictor and examined associations with hours of sleep duration using linear regression. We used multivariable ordinal logistic regression to determine the association between categories of relative hydration status (normal hydration [FO/ECW < 6.8%], mild overhydration [FO/ECW 6.8%-15%], and hyperhydration [FO/ECW > 15%]) and four levels of difficulty with falling asleep, waking, and returning to sleep. Findings: Higher relative hydration status was associated with fewer hours of sleep (-0.31 hours per 10%, 95% confidence interval (CI) -0.49 to -0.13). Compared to the normal hydration group, there was a statistically significant association between higher relative hydration status category and more frequent nighttime waking (OR: mild overhydration 1.92 [95% CI 1.23-2.99], hyperhydration 1.87 [95% CI 1.16-2.99]), a trend toward more difficulty returning to sleep (OR: mild overhydration 1.46 [95% CI 0.94-2.27], hyperhydration 1.52 [95% CI 0.95-2.43]), and no association between relative hydration category and difficulty falling asleep. Discussion: Hydration status was associated with self-reported sleep duration in patients on dialysis. Future studies should prospectively examine the effects of optimizing fluid status on sleep duration and quality. C1 [Abreo, Adrian P.] Louisiana State Univ, Hlth Sci Ctr, Div Nephrol, 1501 Kings Highway, Shreveport, LA 71103 USA. [Dalrymple, Lorien S.; Kaysen, George A.] Univ Calif Davis, Div Nephrol, Davis, CA 95616 USA. [Chertow, Glenn M.] Stanford Univ, Sch Med, Div Nephrol, Stanford, CA 94305 USA. [Kaysen, George A.] Univ Calif Davis, Dept Biochem & Mol Med, Davis, CA 95616 USA. [Herzog, Charles A.] Hennepin Cty Med Ctr, Div Cardiol, Minneapolis, MN 55415 USA. [Herzog, Charles A.] Univ Minnesota, Minneapolis, MN USA. [Johansen, Kirsten L.] Univ Calif San Francisco, Div Nephrol, San Francisco, CA 94143 USA. [Johansen, Kirsten L.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Johansen, Kirsten L.] San Francisco VA Med Ctr, Nephrol Sect, San Francisco, CA USA. RP Abreo, AP (reprint author), Louisiana State Univ, Hlth Sci Ctr, Div Nephrol, 1501 Kings Highway, Shreveport, LA 71103 USA. EM aabreo@lsuhsc.edu FU National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [N01-DK-7-0005, N01-DK-7-5004, K24DK085153, K23 DK093584] FX This work was supported through contracts N01-DK-7-0005 and N01-DK-7-5004 from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), a K24DK085153 grant, and a K23 DK093584 (L.S.D.) grant. NR 30 TC 0 Z9 0 U1 0 U2 0 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1492-7535 EI 1542-4758 J9 HEMODIAL INT JI Hemodial. Int. PD JAN PY 2017 VL 21 IS 1 BP 133 EP 141 DI 10.1111/hdi.12446 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA EK0KX UT WOS:000393616400021 PM 27346666 ER PT J AU Tabri, N Wohl, MJA Eddy, KT Thomas, JJ AF Tabri, Nassim Wohl, Michael J. A. Eddy, Kamryn T. Thomas, Jennifer J. TI Me, myself and money: having a financially focused self-concept and its consequences for disordered gambling SO INTERNATIONAL GAMBLING STUDIES LA English DT Article DE Disordered gambling; gambling motives; money; self-concept; self-worth ID PERSONAL RELATIVE DEPRIVATION; MOTIVES QUESTIONNAIRE; EATING-DISORDERS; BEHAVIOR; ESTEEM; MODEL; CONTINGENCIES; GOALS; WORTH AB The article describes a test of the hypothesis that some people's self-concept is overly focused on financial success and that this focus contributes to disordered gambling. Study 1 reported on the development and validation of the Financially Focused Scale (FFS) with a sample of community gamblers (N = 197). As predicted, participants whose self-concept was financially focused attached greater importance to the money they possess as a domain of self-worth. They also indicated that the money they possess is a more important domain of self-worth relative to other life domains. Importantly, greater financial focus was a positive predictor of disordered gambling severity and did so over and above other known predictors of disordered gambling severity (i. e. personal income, Big-Five personality domains, global self-esteem, personal relative deprivation and materialism). Study 2 (N = 220) replicated and extended the findings of Study 1 by examining the motivational mechanisms that may link being financially focused with disordered gambling severity. As hypothesized, monetary gambling motives mediated the relationship between participants' FFS scores and disordered gambling severity. Having a financially focused self-concept may play a critical role in the development and maintenance of disordered gambling. Addressing this self-concept in treatment may help alleviate gambling disorder. C1 [Tabri, Nassim; Wohl, Michael J. A.] Carleton Univ, Dept Psychol, Ottawa, ON, Canada. [Eddy, Kamryn T.; Thomas, Jennifer J.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Eddy, Kamryn T.; Thomas, Jennifer J.] Harvard Med Sch, Dept Psychiat, Boston, MA USA. RP Wohl, MJA (reprint author), Carleton Univ, Dept Psychol, Ottawa, ON, Canada. EM Michael.Wohl@carleton.ca FU Fonds de Recherche du Quebec sur la Societe et la Culture [173207]; Ontario Problem Gambling Research Centre Investigator Support Grant [3409] FX This research was supported by a postdoctoral fellowship from the Fonds de Recherche du Quebec sur la Societe et la Culture <#173207 > to Tabri and an Ontario Problem Gambling Research Centre Investigator Support Grant [#3409] to Wohl. NR 52 TC 1 Z9 1 U1 1 U2 1 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1445-9795 EI 1479-4276 J9 INT GAMBL STUD JI Int. Gambl. Stud. PY 2017 VL 17 IS 1 BP 30 EP 50 DI 10.1080/14459795.2016.1252414 PG 21 WC Substance Abuse SC Substance Abuse GA EO4SH UT WOS:000396684100003 ER PT J AU Costley, D Nesbitt, H Ternan, N Dooley, J Huang, YY Hamblin, MR McHale, AP Callan, JF AF Costley, David Nesbitt, Heather Ternan, Nigel Dooley, James Huang, Ying-Ying Hamblin, Michael R. McHale, Anthony P. Callan, John F. TI Sonodynamic inactivation of Gram-positive and Gram-negative bacteria using a Rose Bengal-antimicrobial peptide conjugate SO INTERNATIONAL JOURNAL OF ANTIMICROBIAL AGENTS LA English DT Article DE Sonodynamic therapy; Antimicrobial; Sensitiser; Peptide ID PHOTODYNAMIC THERAPY; STAPHYLOCOCCUS-AUREUS; ULTRASOUND; HEMATOPORPHYRIN; RESISTANCE; MECHANISM; INFECTION; AGENTS; CHARGE; TUMORS AB Combating antimicrobial resistance is one of the most serious public health challenges facing society today. The development of new antibiotics or alternative techniques that can help combat antimicrobial resistance is being prioritised by many governments and stakeholders across the globe. Antimicrobial photodynamic therapy is one such technique that has received considerable attention but is limited by the inability of light to penetrate through human tissue, reducing its effectiveness when used to treat deep-seated infections. The related technique sonodynamic therapy (SDT) has the potential to overcome this limitation given the ability of low-intensity ultrasound to penetrate human tissue. In this study, a Rose Bengal-antimicrobial peptide conjugate was prepared for use in antimicrobial SDT (ASDT). When Staphylococcus aureus and Pseudomonas aeruginosa planktonic cultures were treated with the conjugate and subsequently exposed to ultrasound, 5 log and 7 log reductions, respectively, in bacterial numbers were observed. The conjugate also displayed improved uptake by bacterial cells compared with a mammalian cell line (P <= 0.01), whilst pre-treatment of a P. aeruginosa biofilm with ultrasound resulted in a 2.6-fold improvement in sensitiser diffusion (P <= 0.01). A preliminary in vivo experiment involving ASDT treatment of P. aeruginosa-infected wounds in mice demonstrated that ultrasound irradiation of conjugate-treated wounds affects a substantial reduction in bacterial burden. Combined, the results obtained from this study highlight ASDT as a targeted broad-spectrum novel modality with potential for the treatment of deep-seated bacterial infections. (C) 2016 Published by Elsevier B.V. C1 [Costley, David; Nesbitt, Heather; Ternan, Nigel; Dooley, James; McHale, Anthony P.; Callan, John F.] Univ Ulster, Biomed Sci Res Inst, Coleraine BT52 1SA, Londonderry, North Ireland. [Huang, Ying-Ying; Hamblin, Michael R.] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. [Huang, Ying-Ying; Hamblin, Michael R.] Harvard Med Sch, Dept Dermatol, Boston, MA 02115 USA. RP Callan, JF (reprint author), Univ Ulster, Biomed Sci Res Inst, Coleraine BT52 1SA, Londonderry, North Ireland. EM j.callan@ulster.ac.uk FU NIAID NIH HHS [R01 AI050875, R21 AI121700] 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 0924-8579 EI 1872-7913 J9 INT J ANTIMICROB AG JI Int. J. Antimicrob. Agents PD JAN PY 2017 VL 49 IS 1 BP 31 EP 36 DI 10.1016/j.ijantimicag.2016.09.034 PG 6 WC Infectious Diseases; Microbiology; Pharmacology & Pharmacy SC Infectious Diseases; Microbiology; Pharmacology & Pharmacy GA EO1AG UT WOS:000396429300004 PM 27908581 ER PT J AU Triplette, M Attia, E Akgun, K Campo, M Rodriguez-Barradas, M Pipavath, S Shahrir, S Wongtrakool, C Goetz, M Kim, J Hoo, GWS Brown, ST Crothers, K AF Triplette, Matthew Attia, Engi Akgun, Kathleen Campo, Monica Rodriguez-Barradas, Maria Pipavath, Sudhakar Shahrir, Shahida Wongtrakool, Cherry Goetz, Matthew Kim, Joon Hoo, Guy W. Soo Brown, Sheldon T. Crothers, Kristina TI The Differential Impact of Emphysema on Respiratory Symptoms and 6-Minute Walk Distance in HIV Infection SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE COPD; emphysema; HIV; 6-minute walk distance ID OBSTRUCTIVE PULMONARY-DISEASE; ANTIRETROVIRAL THERAPY ERA; IMMUNODEFICIENCY-VIRUS-INFECTION; SPIROMETRY REFERENCE VALUES; VETERANS AGING COHORT; RADIOGRAPHIC EMPHYSEMA; DIFFUSING-CAPACITY; RISK-FACTORS; MORTALITY; ASSOCIATION AB Background: Emphysema is more prevalent in HIV-infected (HIV+) patients independent of smoking behavior. Nonetheless, health effects of emphysema in this population are poorly understood. We determined whether emphysema is associated with a greater burden of pulmonary symptoms and a lower 6-minute walk distance (6MWD) in HIV+ compared with HIV-uninfected (HIV-) subjects. Methods: We performed a cross-sectional analysis of 170 HIV+ and 153 HIV- subjects in the Examinations of HIV-Associated Lung Emphysema (EXHALE) cohort study. Subjects completed a self-assessment of respiratory symptoms, pulmonary function testing, and 6MWD testing as well as a chest computed tomography to determine emphysema severity. We used regression models to determine the association of emphysema with respiratory symptoms and 6MWD in HIV+ subjects and compared this to HIV- subjects. Results: Models stratified by HIV status demonstrated an association between >10% radiographic emphysema and chronic cough and/or phlegm and 6MWD in HIV+ subjects. These associations persisted among the subset without airflow obstruction: those with emphysema had 4.2 (95% confidence interval: 1.3 to 14) times the odds of chronic cough and/or phlegm and walked 60 m (95% confidence interval: 26 to 93) less distance than those without emphysema. There was no association between >10% emphysema and symptoms or 6MWD in HIV- subjects. Conclusions: In our cohort,>10% radiographic emphysema was associated with chronic cough and/or phlegm and lower 6MWD in HIV+ but not HIV- subjects. These findings were robust even among HIV+ subjects with milder forms of emphysema and those without airflow obstruction, highlighting the clinical impact of emphysema in these patients. C1 [Triplette, Matthew; Attia, Engi; Campo, Monica; Shahrir, Shahida; Crothers, Kristina] Univ Washington, Dept Med, Seattle, WA USA. [Akgun, Kathleen] Yale Univ, Sch Med, Dept Internal Med, Vet Affairs Connecticut Healthcare, New Haven, CT 06510 USA. [Rodriguez-Barradas, Maria] Baylor Coll Med, Dept Med, Michael E DeBakey Vet Affairs Med Ctr, Houston, TX 77030 USA. [Pipavath, Sudhakar] Univ Washington, Dept Radiol, Seattle, WA 98195 USA. [Wongtrakool, Cherry] Emory Univ, Sch Med, Dept Med, Atlanta Vet Affairs Med Ctr, Atlanta, GA USA. [Goetz, Matthew; Hoo, Guy W. Soo] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Vet Affairs Greater Los Angeles Healthcare Syst, Los Angeles, CA 90095 USA. [Kim, Joon; Brown, Sheldon T.] James J Peters Vet Affairs Med Ctr, Dept Med, Bronx, NY USA. [Brown, Sheldon T.] Icahn Sch Med Mt Sinai, Dept Med, New York, NY 10029 USA. RP Triplette, M (reprint author), Harborview Med Ctr, 325 Ninth Ave,Campus Box 359762, Seattle, WA 98104 USA. EM mtrip@uw.edu FU National Heart, Lung, and Blood Institute (NHLBI) at the National Institutes of Health (NIH) [R01 HL090342, T32 HL007287-37]; National Institute on Alcohol Abuse and Alcoholism at the NIH [U01 AA013566]; University of Washington Center for AIDS Research, an NIH [P30-AI-027757]; National Institute of Allergy and Infectious Diseases; National Cancer Institute, National Institute of Mental Health; National Institute on Drug Abuse; Eunice Kennedy Shriver National Institute of Child Health and Human Development; NHLBI; National Institute on Aging; Boehringer Ingelheim; Department of Veterans Affairs Biomedical Laboratory Research and Development Program; Astra-Zeneca; National Institutes of Health FX Supported by the National Heart, Lung, and Blood Institute (NHLBI) at the National Institutes of Health (NIH) (R01 HL090342 to K.C., T32 HL007287-37 supporting M.T. under Drs. Robb Glenny and J. Randall Curtis) as well as the National Institute on Alcohol Abuse and Alcoholism at the NIH (U01 AA013566). This research was funded in part by a 2012 developmental grant from the University of Washington Center for AIDS Research, an NIH-funded program under award number P30-AI-027757, which is supported by the following NIH institutes and centers: National Institute of Allergy and Infectious Diseases, National Cancer Institute, National Institute of Mental Health, National Institute on Drug Abuse, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NHLBI, and National Institute on Aging.; S.P. reports receiving support from Boehringer Ingelheim as a consultant and expert advisor. C.W. discloses support from the Department of Veterans Affairs Biomedical Laboratory Research and Development Program, as well as support from Astra-Zeneca as a co-investigator on an industry sponsored clinical study. M.G. reports receiving support from the National Institutes of Health during the conduct of this study. The remaining authors have no funding or conflicts of interest to disclose. NR 48 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 1525-4135 EI 1077-9450 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD JAN 1 PY 2017 VL 74 IS 1 BP E23 EP E29 PG 7 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA EN4RL UT WOS:000395994500004 PM 27716727 ER PT J AU Morton, JF Celum, C Njoroge, J Nakyanzi, A Wakhungu, I Tindimwebwa, E Ongachi, S Sedah, E Okwero, E Ngure, K Odoyo, J Bulya, N Haberer, JE Baeten, JM Heffron, R AF Morton, Jennifer F. Celum, Connie Njoroge, John Nakyanzi, Agnes Wakhungu, Imeldah Tindimwebwa, Edna Ongachi, Snaidah Sedah, Eric Okwero, Emmanuel Ngure, Kenneth Odoyo, Josephine Bulya, Nulu Haberer, Jessica E. Baeten, Jared M. Heffron, Renee CA Partners Demonstration P TI Counseling Framework for HIV-Serodiscordant Couples on the Integrated Use of Antiretroviral Therapy and Pre-exposure Prophylaxis for HIV Prevention SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE counseling; pre-exposure prophylaxis; antiretroviral treatment; couples; HIV-1 prevention; Africa ID FERTILITY INTENTIONS; RISK; TRANSMISSION; PARTNERSHIPS; WOMEN; MEN; INDIVIDUALS; STRATEGIES; INITIATION; INFECTION AB Background: For HIV-serodiscordant couples, integrated delivery of antiretroviral therapy (ART) for HIV-positive partners and timelimited pre-exposure prophylaxis (PrEP) for negative partners virtually eliminates HIV transmission. Standardized messaging, sensitive to the barriers and motivators to HIV treatment and prevention, is needed for widespread scale-up of this approach. Methods: Within the Partners Demonstration Project, a prospective interventional project among 1013 serodiscordant couples in Kenya and Uganda, we offered ART to eligible HIV-positive partners and PrEP to HIV-negative partners before ART initiation and through the HIV-positive partner's first 6 months of ART use. We conducted individual and group discussions with counseling staff to elicit the health communication framework and key messages about ART and PrEP that were delivered to couples. Results: Counseling sessions for serodiscordant couples about PrEP and ART included discussions of HIV serodiscordance, PrEP and ART initiation and integrated use, and PrEP discontinuation. ART messages emphasized daily, lifelong use for treatment and prevention, adherence, viral suppression, resistance, side effects, and safety of ART during pregnancy. PrEP messages emphasized daily dosing, time-limited PrEP use until the HIV-positive partner sustained 6 months of high adherence to ART, adherence, safety during conception, side effects, and other risks for HIV. Conclusions: Counseling messages for HIV-serodiscordant couples are integral to the delivery of time-limited PrEP as a "bridge" to ART-driven viral suppression. Their incorporation into programmatic scale-up will maximize intervention impact on the global epidemic. C1 [Morton, Jennifer F.; Celum, Connie; Baeten, Jared M.; Heffron, Renee] Univ Washington, Dept Global Hlth, 325 Ninth Ave,Box 359927, Seattle, WA 98104 USA. [Celum, Connie; Baeten, Jared M.; Heffron, Renee] Univ Washington, Dept Epidemiol, 325 Ninth Ave,Box 359927, Seattle, WA 98104 USA. [Celum, Connie; Baeten, Jared M.] Univ Washington, Dept Med, Seattle, WA USA. [Njoroge, John; Ongachi, Snaidah] Kenya Govt Med Res Ctr, Clin Res Ctr, Nairobi, Kenya. [Nakyanzi, Agnes; Okwero, Emmanuel; Bulya, Nulu] Makerere Univ, Infect Dis Inst, Kampala, Uganda. [Wakhungu, Imeldah; Sedah, Eric; Odoyo, Josephine] Kenya Govt Med Res Ctr, Microbiol Res, Nairobi, Kenya. [Tindimwebwa, Edna] Kabwohe Clin Res Ctr, Kabwohe, Uganda. [Ngure, Kenneth] Jomo Kenyatta Univ Agr & Technol, Dept Publ & Community Hlth, Nairobi, Kenya. [Haberer, Jessica E.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Haberer, Jessica E.] Harvard Med Sch, Boston, MA USA. RP Heffron, R (reprint author), Univ Washington, Dept Global Hlth, 325 Ninth Ave,Box 359927, Seattle, WA 98104 USA.; Heffron, R (reprint author), Univ Washington, Dept Epidemiol, 325 Ninth Ave,Box 359927, Seattle, WA 98104 USA. EM rheffron@uw.edu FU National Institute of Mental Health of the US National Institutes of Health [R01 MH095507]; Bill & Melinda Gates Foundation [OPP1056051]; American people through the US Agency for International Development (cooperative agreement) [AID-OAA-A-12-00023] FX The Partners Demonstration Project was funded by the National Institute of Mental Health of the US National Institutes of Health (Grant R01 MH095507), the Bill & Melinda Gates Foundation (Grant OPP1056051), and through the generous support of the American people through the US Agency for International Development (cooperative agreement AID-OAA-A-12-00023). Gilead Sciences donated the PrEP medication but had no role in data collection or analysis. The results and interpretation presented here do not necessarily reflect the views of the study funders. NR 34 TC 1 Z9 1 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1525-4135 EI 1077-9450 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD JAN 1 PY 2017 VL 74 SU 1 BP S15 EP S22 PG 8 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA EN5AH UT WOS:000396017500003 PM 27930607 ER PT J AU Balekian, DS Linnemann, RW Hasegawa, K Thadhani, R Camargo, CA AF Balekian, Diana S. Linnemann, Rachel W. Hasegawa, Kohei Thadhani, Ravi Camargo, Carlos A., Jr. TI Cohort Study of Severe Bronchiolitis during Infancy and Risk of Asthma by Age 5 Years SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY-IN PRACTICE LA English DT Article DE Asthma; Atopic dermatitis; Bronchiolitis; Eczema; Prevalence; Respiratory syncytial virus; Risk factors; Wheezing ID RESPIRATORY SYNCYTIAL VIRUS; EARLY-LIFE; CHILDREN; HOSPITALIZATIONS; MEDICAID; ALLERGY AB BACKGROUND: Severe bronchiolitis (ie, bronchiolitis requiring hospital admission) is thought to markedly increase asthma risk, with 30%-50% developing asthma by age 5 years. To date, studies of this association are small, and most are from outside the United States. OBJECTIVE: The objective of this study was to investigate the association between severe bronchiolitis and risk of asthma in a US birth cohort. METHODS: We studied a cohort nested within the Massachusetts General Hospital Obstetric Maternal Study (MOMS), a prospective cohort of pregnant women enrolled during 1998-2006. Children of mothers enrolled in MOMS were included in the analysis if they received care within our health system (n = 3653). Diagnoses and medications were extracted from the children's electronic health records; we also examined pregnancy and perinatal risk factors collected for the underlying pregnancy study. RESULTS: The birth cohort was 52% male, 49% white, and 105 infants (2.9%) had severe bronchiolitis. Overall, 421 children (11.5%) developed asthma by age 5 years. Among the children with severe bronchiolitis, 27.6% developed asthma by age 5 years. In multivariable logistic regression adjusting for 12 risk factors, severe bronchiolitis remained a strong risk factor for developing asthma by age 5 years (odds ratio 2.57; 95% confidence interval 1.61-4.09). Conclusions: In a large Boston birth cohort, the frequency of severe bronchiolitis and childhood asthma was similar to published data. Among children with severe bronchiolitis, the risk of developing asthma was lower than prior studies but still high (27.6%). This difference may be due to different study designs, populations, and outcome definitions studied. (C) 2016 American Academy of Allergy, Asthma & Immunology. C1 [Balekian, Diana S.; Camargo, Carlos A., Jr.] Massachusetts Gen Hosp, Dept Med, Div Rheumatol Allergy & Immunol, Boston, MA 02114 USA. [Balekian, Diana S.; Hasegawa, Kohei; Thadhani, Ravi; Camargo, Carlos A., Jr.] Harvard Med Sch, Boston, MA USA. [Linnemann, Rachel W.] Emory Univ, Sch Med, Dept Pediat, Atlanta, GA USA. [Hasegawa, Kohei; Camargo, Carlos A., Jr.] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. [Thadhani, Ravi] Massachusetts Gen Hosp, Dept Med, Div Nephrol, Boston, MA 02114 USA. RP Camargo, CA (reprint author), Massachusetts Gen Hosp, 125 Nashua St,Suite 920, Boston, MA 02114 USA. EM ccamargo@partners.org FU National Institutes of Health [T32 HL-116275, U01 AI-087881, R01 AI-114552, R21 HL-129909] FX This work was supported by the National Institutes of Health grants T32 HL-116275, U01 AI-087881, R01 AI-114552, and R21 HL-129909. NR 30 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 2213-2198 EI 2213-2201 J9 J ALLER CL IMM-PRACT JI J. Allergy Clin. Immunol.-Pract. PD JAN-FEB PY 2017 VL 5 IS 1 BP 92 EP 96 DI 10.1016/j.jaip.2016.07.004 PG 5 WC Allergy; Immunology SC Allergy; Immunology GA EO1YI UT WOS:000396493400014 PM 27523277 ER PT J AU Levin, AS Otani, IM Lax, T Hochberg, E Banerji, A AF Levin, Amy S. Otani, Iris M. Lax, Timothy Hochberg, Ephraim Banerji, Aleena TI Reactions to Rituximab in an Outpatient Infusion Center: A 5-Year Review SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY-IN PRACTICE LA English DT Review DE Rituximab; Monoclonal antibody; Infusion reaction; Desensitization ID CHRONIC LYMPHOCYTIC-LEUKEMIA; MONOCLONAL-ANTIBODY THERAPY; HYPERSENSITIVITY REACTIONS; LYMPHOMA; DESENSITIZATION; CHEMOTHERAPY; ANAPHYLAXIS; CARBOPLATIN; MANAGEMENT; IDEC-C2B8 AB BACKGROUND: Reactions to rituximab occur frequently, with up to 77% of patients developing a reaction during initial exposure. The safety of rechallenging patients after a reaction is not clear and standard guidelines are lacking. OBJECTIVE: To better understand clinical decision making surrounding rituximab reactions and subsequent rechallenge. METHODS: We performed a 5-year retrospective review of all rituximab reactions at a large academic outpatient infusion center. Patients' demographic characteristics, clinical symptoms, and management of reactions were reviewed. Reaction severity was classified using standard criteria. RESULTS: Between June 2006 and January 2011, 67 patients (mean age, 58 +/- 13 years, 54% men) with at least 1 rituximab reaction were identified. Most reactions occurred during the first exposure to rituximab (63%). Most reactions (n = 59 [88%]) were grade 1 or 2. Fifty-one patients (n = 51 [88%]) were rechallenged with rituximab on the same day as the initial reaction. Most patients with a grade 1 reaction tolerated rechallenge. Conversely, all 4 patients with a grade 3 reaction had a reaction during rechallenge. The outcome of same-day rechallenge after an initial grade 2 reaction was varied; most patients (26 of 31 [84%]) tolerated same-day challenge, but 5 patients had a reaction (all grade 1-2 severity). CONCLUSIONS: Consistent with previous data, our observations suggest that patients who experience grade 1 reactions to rituximab can be safely rechallenged the same day. A grade 3 or 4 reaction should prompt referral to an allergy specialist for risk assessment before additional rituximab administration. Further research is needed to understand the optimal management of patients with grade 2 reactions. (C) 2016 American Academy of Allergy, Asthma & Immunology C1 [Levin, Amy S.; Otani, Iris M.; Banerji, Aleena] Harvard Med Sch, Dept Med, Div Rheumatol Allergy & Immunol, Massachusetts Gen Hosp, Boston, MA USA. [Lax, Timothy] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Dept Med, Div Allergy & Inflammat, Boston, MA USA. [Hochberg, Ephraim] Harvard Med Sch, Dept Med, Ctr Canc, Massachusetts Gen Hosp, Boston, MA USA. RP Levin, AS (reprint author), Massachusetts Gen Hosp, Div Rheumatol Allergy & Immunol, 55 Fruit St, Boston, MA 02114 USA. EM aslevin@partners.org NR 19 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 2213-2198 EI 2213-2201 J9 J ALLER CL IMM-PRACT JI J. Allergy Clin. Immunol.-Pract. PD JAN-FEB PY 2017 VL 5 IS 1 BP 107 EP + DI 10.1016/j.jaip.2016.06.022 PG 8 WC Allergy; Immunology SC Allergy; Immunology GA EO1YI UT WOS:000396493400017 PM 27497683 ER PT J AU Otani, IM Christiansen, SC Busse, P Camargo, CA Zuraw, BL Riedl, MA Banerji, A AF Otani, Iris M. Christiansen, Sandra C. Busse, Paula Camargo, Carlos A., Jr. Zuraw, Bruce L. Riedl, Marc A. Banerji, Aleena TI Emergency Department Management of Hereditary Angioedema Attacks: Patient Perspectives SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY-IN PRACTICE LA English DT Article DE Hereditary angioedema; Hereditary angioedema attacks; Treatment plan; Angioedema management; Emergency department; Angioedema guidelines; On-demand treatment; Patient-reported outcomes; Quality of life; Disease burden ID C1 INHIBITOR DEFICIENCY; UNITED-STATES; DESCRIPTIVE EPIDEMIOLOGY; HOSPITALIZATIONS; VISITS; BURDEN AB BACKGROUND: Emergency department (ED) management of hereditary angioedema (HAE) has been hindered by misdiagnosis and limited treatment options. Food and Drug Administration approval of 4 on-demand HAE therapies starting in 2009 and the publication of ED guidelines for angioedema management in 2014 should facilitate improvement of HAE management in the ED. OBJECTIVE: The objective of this study was to identify patientreported areas for improvement inEDmanagement of HAE attacks. METHODS: Patients with self-reported HAE with C1 inhibitor deficiency who attended the 2015 HAE Association Patient Summit were asked to complete an anonymous 30-question survey. Questions addressed patient characteristics and HAE management in the ED. RESULTS: Patients indicated that understanding of HAE in the ED needed improvement (99%, 104 of 105 patients). Recognition of HAE as a diagnosis (48%, 50 of 105 patients), appreciation of HAE as a serious disease (45%, 47 of 105 patients), and medication management (59%, 62 of 105 patients) were identified as areas needing improvement. Among 39 patients who required ED care within the last year, 6 did not receive any HAE-targeted therapy, and treatment with corticosteroids (n=3), epinephrine (n=2), and antihistamines (n= 7) was reported. Among 68 patients whose treatment plan was to receive home on-demand therapy, 26 required ED care because of an inability to receive on-demand therapy at home as outlined in their treatment plan. Having a treatment plan was associated with a greater likelihood of receiving HAE therapy in the ED (99% vs 74%, P=.002). CONCLUSION: HAE management in the ED can be improved with a focus on recognition of HAE attacks and administration of effective HAE therapies. (C) 2016 American Academy of Allergy, Asthma & Immunology. C1 [Otani, Iris M.; Camargo, Carlos A., Jr.; Banerji, Aleena] Harvard Med Sch, Massachusetts Gen Hosp, Dept Med, Div Rheumatol Allergy & Immunol, Boston, MA USA. [Christiansen, Sandra C.; Zuraw, Bruce L.; Riedl, Marc A.] Univ Calif San Diego, Dept Med, Div Rheumatol Allergy & Immunol, La Jolla, CA 92093 USA. [Busse, Paula] Mt Sinai Sch Med, Dept Med, Div Clin Immunol, New York, NY USA. [Camargo, Carlos A., Jr.] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. RP Otani, IM (reprint author), UCSF Med Ctr, 400 Parnassus Ave,Box 0359, San Francisco, CA 94143 USA. EM iris.otani@ucsf.edu FU CSL Behring; Shire; Alnylan; Arrowhead; BioCryst; Dyax; Ionis; Nektar; Salix; Pharming; Global Blood Therapeutics FX I. M. Otani has received travel support from the Hereditary Angioedema Association. P. Busse has received consultancy fees from CSL Behring and Shire; and has received research support from Shire. B. L. Zuraw has received consultancy fees from Alnylan, Arrowhead, BioCryst, CSL Behring, Dyax, Ionis, Nektar, Shire, and Salix; and has received travel support from US Hereditary Angioedema Association (HAEA). M. A. Riedl is on the US HAEA Medical Advisory Board; has received consultancy fees from Shire, Dyax, CSL Behring, Salix, Arrowhead, BioCryst, Ionis, Global Blood Therapeutics; has received research support from Shire, Dyax, CSL Behring, BioCryst, Pharming, Ionis; and has received lecture fees from Shire, Dyax, Salix, CSL Behring. The rest of the authors declare that they have no relevant conflicts of interest. NR 15 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 2213-2198 EI 2213-2201 J9 J ALLER CL IMM-PRACT JI J. Allergy Clin. Immunol.-Pract. PD JAN-FEB PY 2017 VL 5 IS 1 BP 128 EP + DI 10.1016/j.jaip.2016.06.029 PG 11 WC Allergy; Immunology SC Allergy; Immunology GA EO1YI UT WOS:000396493400020 PM 27665386 ER PT J AU Jhun, I Gaffin, JM Coull, BA Huffaker, MF Petty, CR Sheehan, WJ Baxi, SN Lai, PS Kang, CM Wolfson, JM Gold, DR Koutrakis, P Phipatanakul, W AF Jhun, Iny Gaffin, Jonathan M. Coull, Brent A. Huffaker, Michelle F. Petty, Carter R. Sheehan, William J. Baxi, Sachin N. Lai, Peggy S. Kang, Choong-Min Wolfson, Jack M. Gold, Diane R. Koutrakis, Petros Phipatanakul, Wanda TI School Environmental Intervention to Reduce Particulate Pollutant Exposures for Children with Asthma SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY-IN PRACTICE LA English DT Article DE Asthma; Indoor air quality; Environmental intervention; Air cleaner ID INNER-CITY ASTHMA; AIR-POLLUTION; BLACK CARBON; ELEMENTARY-SCHOOLS; MOUSE ALLERGEN; INDOOR; TRIAL; SCHOOLCHILDREN; ASSOCIATIONS; SYMPTOMS AB BACKGROUND: Home-based interventions to improve indoor air quality have demonstrated benefits for asthma morbidity, yet little is known about the effect of environmental interventions in the school setting. OBJECTIVE: We piloted the feasibility and effectiveness of a classroom-based air cleaner intervention to reduce particulate pollutants in classrooms of children with asthma. METHODS: In this pilot randomized controlled trial, we assessed the effect of air cleaners on indoor air particulate pollutant concentrations in 18 classrooms (9 control, 9 intervention) in 3 urban elementary schools. We enrolled 25 children with asthma (13 control, 12 intervention) aged 6 to 10 years. Classroom air pollutant measurements and spirometry were completed once before and twice after randomization. Asthma symptoms were surveyed every 3 months. RESULTS: Baseline classroom levels of fine particulate matter (particulate matter with diameter of <2.5 mu m [PM2.5]) and black carbon (BC) were 6.3 and 0.41 mu g/m(3), respectively. When comparing the intervention to the control group, classroom PM2.5 levels were reduced by 49% and 42% and BC levels were reduced by 58% and 55% in the first and second follow-up periods, respectively (P<.05 for all comparisons). When comparing the children randomized to intervention and control classrooms, there was a modest improvement in peak flow, but no significant changes in forced expiratory volume in 1 second (FEV1) and asthma symptoms. CONCLUSIONS: In this pilot study, a classroom-based air cleaner intervention led to significant reductions in PM2.5 and BC. Future large-scale studies should comprehensively evaluate the effect of school-based environmental interventions on pediatric asthma morbidity. (C) 2016 American Academy of Allergy, Asthma & Immunology C1 [Jhun, Iny; Gaffin, Jonathan M.; Huffaker, Michelle F.; Sheehan, William J.; Baxi, Sachin N.; Lai, Peggy S.; Gold, Diane R.; Phipatanakul, Wanda] Harvard Med Sch, Boston, MA USA. [Gaffin, Jonathan M.] Boston Childrens Hosp, Div Resp Dis, Boston, MA 02115 USA. [Coull, Brent A.] Harvard TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Huffaker, Michelle F.; Sheehan, William J.; Baxi, Sachin N.; Phipatanakul, Wanda] Boston Childrens Hosp, Div Allergy & Immunol, 300 Longwood Ave, Boston, MA 02115 USA. [Petty, Carter R.] Boston Childrens Hosp, Clin Res Ctr, Boston, MA 02115 USA. [Lai, Peggy S.] Massachusetts Gen Hosp, Div Pulm & Crit Care, Boston, MA 02114 USA. [Lai, Peggy S.; Kang, Choong-Min; Wolfson, Jack M.; Gold, Diane R.; Koutrakis, Petros] Harvard TH Chan Sch Publ Hlth, Dept Environm Hlth, Boston, MA USA. [Gold, Diane R.] Brigham & Womens Hosp, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA. RP Phipatanakul, W (reprint author), Boston Childrens Hosp, Div Allergy & Immunol, 300 Longwood Ave, Boston, MA 02115 USA. EM wanda.phipatanakul@childrens.harvard.edu FU National Institutes of Health (NIH) [U01 AI 110397, R01 AI 073964, K24 AI 106822, U10 HL 098102, K23 AI 106945, K23 AI 104780, P03ES000002]; National Institute of Environmental Health Sciences (NIEHS) [K23ES023700]; Harvard Medical School Scholars in Medicine Office; Harvard Catalyst/The Harvard Clinical and Translational Science Center (NIH Award) [UL1 TR000170]; American Lung Association; American Academy of Allergy, Asthma, and Immunology; Respiratory Diseases Faculty Award; Deborah Munroe Noonan Memorial Award; Harvard University FX This work was supported by National Institutes of Health (NIH) grant nos. U01 AI 110397, R01 AI 073964, K24 AI 106822, U10 HL 098102, K23 AI 106945, K23 AI 104780, and P03ES000002; National Institute of Environmental Health Sciences (NIEHS) grant no. K23ES023700; and Harvard Medical School Scholars in Medicine Office. This work was conducted with the support from Harvard Catalyst/The Harvard Clinical and Translational Science Center (NIH Award UL1 TR000170) and financial contributions from Harvard University and its affiliated academic health care centers. The content is solely the responsibility of the authors and does not necessarily represent the official views of Harvard Catalyst, Harvard University and its affiliated academic health care centers, the National Center for Research Resources, or the NIH. This work was also supported in part by the American Lung Association, the American Academy of Allergy, Asthma, and Immunology, the Respiratory Diseases Faculty Award, and the Deborah Munroe Noonan Memorial Award. We also thank Coway Co., Ltd, for its funding and for donating the air cleaners used in this study. NR 24 TC 0 Z9 0 U1 2 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 2213-2198 EI 2213-2201 J9 J ALLER CL IMM-PRACT JI J. Allergy Clin. Immunol.-Pract. PD JAN-FEB PY 2017 VL 5 IS 1 BP 154 EP + DI 10.1016/j.jaip.2016.07.018 PG 9 WC Allergy; Immunology SC Allergy; Immunology GA EO1YI UT WOS:000396493400023 PM 27641483 ER PT J AU Lax, T Dizon, DS Birrer, M Long, AD Del Carmen, M Goodman, A Krasner, C Penson, RT Growdon, W Camargo, CA Banerji, A AF Lax, Timothy Dizon, Don S. Birrer, Michael Long, Aidan Del Carmen, Marcela Goodman, Annekathryn Krasner, Carolyn Penson, Richard T. Growdon, Whitfield Camargo, Carlos A., Jr. Banerji, Aleena TI Extended carboplatin infusion does not reduce frequency of hypersensitivity reaction at initiation of retreatment in patients with recurrent platinum-sensitive ovarian cancer SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY-IN PRACTICE LA English DT Letter ID PACLITAXEL; MANAGEMENT C1 [Lax, Timothy] Beth Israel Deaconess Med Ctr, Dept Med, Div Allergy & Inflammat, One Brookline Pl,Suite 623, Boston, MA 02445 USA. [Dizon, Don S.; Birrer, Michael; Del Carmen, Marcela; Goodman, Annekathryn; Krasner, Carolyn; Penson, Richard T.; Growdon, Whitfield] Massachusetts Gen Hosp, Med Gynecol Oncol, Gillette Ctr Womens Canc, Boston, MA 02114 USA. [Long, Aidan; Banerji, Aleena] Harvard Med Sch, Massachusetts Gen Hosp, Dept Med, Div Rheumatol Allergy & Immunol, Boston, MA USA. [Camargo, Carlos A., Jr.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA USA. RP Lax, T (reprint author), Beth Israel Deaconess Med Ctr, Dept Med, Div Allergy & Inflammat, One Brookline Pl,Suite 623, Boston, MA 02445 USA. EM tlax@bidmc.harvard.edu NR 9 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 2213-2198 EI 2213-2201 J9 J ALLER CL IMM-PRACT JI J. Allergy Clin. Immunol.-Pract. PD JAN-FEB PY 2017 VL 5 IS 1 BP 177 EP 178 DI 10.1016/j.jaip.2016.07.010 PG 2 WC Allergy; Immunology SC Allergy; Immunology GA EO1YI UT WOS:000396493400028 PM 27641482 ER PT J AU Valenti, R Charidimou, A Xiong, L Boulouis, G Fotiadis, P Ayres, A Riley, G Kuijf, HJ Reijmer, YD Pantoni, L Gurol, ME Davidsdottir, S Greenberg, SM Viswanathan, A AF Valenti, Raffaella Charidimou, Andreas Xiong, Li Boulouis, Gregoire Fotiadis, Panagiotis Ayres, Alison Riley, Grace Kuijf, Hugo J. Reijmer, Yael D. Pantoni, Leonardo Gurol, M. Edip Davidsdottir, Sigurros Greenberg, Steven M. Viswanathan, Anand TI Visuospatial Functioning in Cerebral Amyloid Angiopathy: A Pilot Study SO JOURNAL OF ALZHEIMERS DISEASE LA English DT Article DE Cerebral amyloid angiopathy; neuroimaging markers; neuropsychological assessment; visuospatial functioning ID DISEASE; DYSFUNCTION; IMPAIRMENT; BRAIN AB Cerebral amyloid angiopathy (CAA) is a contributor to cognitive impairment in the elderly. We hypothesized that the posterior cortical predilection of CAA would cause visual-processing impairment. We systematically evaluated visuospatial abilities in 22 non-demented CAA patients. Neurocognitiveevaluation demonstrated visuoperceptual impairment (23% on Benton Facial Recognition Test [BFRT] and 13.6% on Benton Judgment of Line Orientation Test [BJLO]). BFRT was inversely correlated with white matter hyperintensities volume and BJLO with parietal cerebral microbleeds. This pilot study highlights the presence of visual-processing deficits in CAA. The impairment could be related to global disease severity in addition to local brain injury. C1 [Valenti, Raffaella; Charidimou, Andreas; Xiong, Li; Boulouis, Gregoire; Fotiadis, Panagiotis; Ayres, Alison; Riley, Grace; Reijmer, Yael D.; Gurol, M. Edip; Greenberg, Steven M.; Viswanathan, Anand] Harvard Med Sch, Massachusetts Gen Hosp, Ctr Stroke Res, Dept Neurol,Hemorrhag Stroke Res Program, Boston, MA USA. [Valenti, Raffaella; Pantoni, Leonardo] Univ Florence, Neurosci Sect, Dept NEUROFARBA, Florence, Italy. [Kuijf, Hugo J.] Univ Med Ctr Utrecht, Image Sci Inst, Utrecht, Netherlands. [Davidsdottir, Sigurros] Harvard Med Sch, Massachusetts Gen Hosp, Dept Psychiat, Boston, MA USA. RP Viswanathan, A (reprint author), Harvard Med Sch, J Kistler Stroke Res Ctr, 175 Cambridge St,Suite 300, Boston, MA 02114 USA. EM aviswanathan1@partners.org FU NIH [R01AG047975, R01AG026484, P50AG005134, K23AG02872605]; J. William Fulbright Research Scholarschip; Monahan Foundation Biomedical Research Grant FX This work was supported by the NIH (grants R01AG047975, R01AG026484, P50AG005134, K23AG02872605).; G. Boulouis was supported by a J. William Fulbright Research Scholarschip and a Monahan Foundation Biomedical Research Grant. NR 15 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 4 BP 1223 EP 1227 DI 10.3233/JAD-160927 PG 5 WC Neurosciences SC Neurosciences & Neurology GA EN1FY UT WOS:000395757100002 PM 28222510 ER PT J AU Wang, Q Li, WX Dai, SX Guo, YC Han, FF Zheng, JJ Li, GH Huang, JF AF Wang, Qian Li, Wen-Xing Dai, Shao-Xing Guo, Yi-Cheng Han, Fei-Fei Zheng, Jun-Juan Li, Gong-Hua Huang, Jing-Fei TI Meta-Analysis of Parkinson's Disease and Alzheimer's Disease Revealed Commonly Impaired Pathways and Dysregulation of NRF2-Dependent Genes SO JOURNAL OF ALZHEIMERS DISEASE LA English DT Article DE Parkinson's disease; Alzheimer's disease; meta-analysis; MAFF; NRF2 ID ANTIOXIDANT RESPONSE ELEMENT; SMALL MAF PROTEINS; DIFFERENTIALLY EXPRESSED GENES; OXIDATIVE STRESS; NEURODEGENERATIVE DISORDERS; MITOCHONDRIAL DYSFUNCTION; CONSENSUS SEQUENCE; NEURONS; BRAIN; IDENTIFICATION AB Many lines of evidence suggest that Parkinson's disease (PD) and Alzheimer's disease (AD) have common characteristics, such as mitochondrial dysfunction and oxidative stress. As the underlying molecular mechanisms are unclear, we perform a meta-analysis with 9 microarray datasets of PD studies and 7 of AD studies to explore it. Functional enrichment analysis revealed that PD and AD both showed dysfunction in the synaptic vesicle cycle, GABAergic synapses, phagosomes, oxidative phosphorylation, and TCA cycle pathways, and AD had more enriched genes. Comparing the differentially expressed genes between AD and PD, we identified 54 common genes shared by more than six tissues. Among them, 31 downregulated genes contained the antioxidant response element (ARE) consensus sequence bound by NRF2. NRF2 is a transcription factor, which protects cells against oxidative stress through coordinated upregulation of ARE-driven genes. To our surprise, although NRF2 was upregulated, its target genes were all downregulated. Further exploration found that MAFF was upregulated in all tissues and significantly negatively correlated with the 31 NRF2-dependent genes in diseased conditions. Previous studies have demonstrated over-expressed small MAFs can form homodimers and act as transcriptional repressors. Therefore, MAFF might play an important role in dysfunction of NRF2 regulatory network in PD and AD. C1 [Wang, Qian; Li, Wen-Xing; Dai, Shao-Xing; Guo, Yi-Cheng; Zheng, Jun-Juan; Li, Gong-Hua; Huang, Jing-Fei] Chinese Acad Sci, Kunming Inst Zool, State Key Lab Genet Resources & Evolut, Kunming 650223, Yunnan, Peoples R China. [Wang, Qian; Dai, Shao-Xing; Zheng, Jun-Juan; Li, Gong-Hua; Huang, Jing-Fei] Univ Chinese Acad Sci, Kunming Coll Life Sci, Beijing, Peoples R China. [Li, Wen-Xing] Anhui Univ, Inst Hlth Sci, Hefei, Anhui, Peoples R China. [Han, Fei-Fei] Harvard Med Sch, Massachusetts Gen Hosp, Immunometab Computat Ctr, Boston, MA USA. [Huang, Jing-Fei] Soochow Univ, Coll Pharmaceut Sci, KIZ SU Joint Lab Anim Models & Drug Dev, Kunming, Yunnan, Peoples R China. [Huang, Jing-Fei] Collaborat Innovat Ctr Nat Prod & Biol Drugs Yunn, Kunming, Yunnan, Peoples R China. [Huang, Jing-Fei] Chinese Univ Hong Kong, Joint Res Ctr Bioresources & Human Dis, Kunming, Yunnan, Peoples R China. RP Li, GH; Huang, JF (reprint author), Chinese Acad Sci, Kunming Inst Zool, State Key Lab Genet Resources & Evolut, Kunming 650223, Yunnan, Peoples R China. EM ligonghua@mail.kiz.ac.cn; huangjf@mail.kiz.ac.cn OI Li, Wen-Xing/0000-0001-9984-8439; Dai, Shao-Xing/0000-0002-6919-2034 FU National Basic Research Program of China [2013CB835100]; National Natural Science Foundation of China [31401142, 31401137] FX This work was supported by the National Basic Research Program of China (Grant No. 2013CB835100), and the National Natural Science Foundation of China (Grant No. 31401142 and NO. 31401137). NR 65 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 4 BP 1525 EP 1539 DI 10.3233/JAD-161032 PG 15 WC Neurosciences SC Neurosciences & Neurology GA EN1FY UT WOS:000395757100026 PM 28222515 ER PT J AU Li, BQ Wang, H Fu, BY Wang, R Sakadzic, S Boas, DA AF Li, Baoqiang Wang, Hui Fu, Buyin Wang, Ruopeng Sakadzic, Sava Boas, David A. TI Impact of temporal resolution on estimating capillary RBC-flux with optical coherence tomography SO JOURNAL OF BIOMEDICAL OPTICS LA English DT Article DE capillary blood flow; RBC-flux; optical coherence tomography; temporal resolution ID ERYTHROCYTE PERFUSION PATTERN; TRANSIT-TIME HETEROGENEITY; STIMULUS-INDUCED CHANGES; RAT CEREBRAL-CORTEX; BLOOD-FLOW; INDIVIDUAL CAPILLARIES; CONFOCAL MICROSCOPY; BRAIN OXYGENATION; VELOCITY; NETWORK AB Optical coherence tomography (OCT) has been used to measure capillary red blood cell (RBC) flux. However, one important technical issue is that the accuracy of this method is subject to the temporal resolution (Delta t) of the repeated RBC-passage B-scans. A ceiling effect arises due to an insufficient Delta t limiting the maximum RBC-flux that can be measured. In this letter, we first present simulations demonstrating that Delta t = 1.5 ms permits measuring RBC-flux up to 150 RBCs/ s with an underestimation of 9%. The simulations further show that measurements with Delta t = 3 and 4.5 ms provide relatively less accurate estimates for typical physiological fluxes. We provide experimental data confirming the simulation results showing that reduced temporal resolution (i.e., a longer.t) results in an underestimation of mean flux and compresses the distribution of measured fluxes, which potentially confounds physiological interpretation of the results. The results also apply to RBC-passage measurements made with confocal and two-photon microscopy for estimating capillary RBC-flux. (C) 2017 Society of Photo-Optical Instrumentation Engineers (SPIE) C1 [Li, Baoqiang; Wang, Hui; Fu, Buyin; Sakadzic, Sava; Boas, David A.] Harvard Med Sch, Massachusetts Gen Hosp, Opt Div, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Wang, Hui; Wang, Ruopeng] Harvard Med Sch, Massachusetts Gen Hosp, Lab Computat Neuroimaging, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. RP Li, BQ (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Opt Div, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. EM baoqiang.li@mgh.harvard.edu FU National Institutes of Health [R01-EB021018, P01-NS055104, R01-NS091230]; Air Force Office of Sponsored Research [AFOSR FA-9550-15-1-0473] FX This study was supported by the National Institutes of Health grants (R01-EB021018, P01-NS055104, and R01-NS091230). This study was also supported by the Air Force Office of Sponsored Research (AFOSR FA-9550-15-1-0473). NR 27 TC 0 Z9 0 U1 0 U2 0 PU SPIE-SOC PHOTO-OPTICAL INSTRUMENTATION ENGINEERS PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98225 USA SN 1083-3668 EI 1560-2281 J9 J BIOMED OPT JI J. Biomed. Opt. PD JAN PY 2017 VL 22 IS 1 AR 016014 DI 10.1117/1.JBO.22.1.016014 PG 5 WC Biochemical Research Methods; Optics; Radiology, Nuclear Medicine & Medical Imaging SC Biochemistry & Molecular Biology; Optics; Radiology, Nuclear Medicine & Medical Imaging GA EO0EH UT WOS:000396370600024 PM 28125157 ER PT J AU Moult, EM Choi, W Boas, DA Baumann, B Clermont, AC Feener, EP Fujimoto, JG AF Moult, Eric M. Choi, WooJhon Boas, David A. Baumann, Bernhard Clermont, Allen C. Feener, Edward P. Fujimoto, James G. TI Evaluating anesthetic protocols for functional blood flow imaging in the rat eye SO JOURNAL OF BIOMEDICAL OPTICS LA English DT Article DE anesthesia; functional imaging; small animal; blood flow; Doppler OCT; rat ID OPTICAL COHERENCE TOMOGRAPHY; LASER-DOPPLER MEASUREMENTS; HUMAN RETINAL-VESSELS; SPECKLE PHOTOGRAPHY; DOMAIN OCT; NERVE; MRI; MICROANGIOGRAPHY; VISUALIZATION; MICROSPHERES AB The purpose of this study is to evaluate the suitability of five different anesthetic protocols (isoflurane, isoflurane-xylazine, pentobarbital, ketamine-xylazine, and ketamine-xylazine-vecuronium) for functional blood flow imaging in the rat eye. Total retinal blood flow was measured at a series of time points using an ultrahighspeed Doppler OCT system. Additionally, each anesthetic protocol was qualitatively evaluated according to the following criteria: (1) time-stability of blood flow, (2) overall rate of blood flow, (3) ocular immobilization, and (4) simplicity. We observed that different anesthetic protocols produced markedly different blood flows. Different anesthetic protocols also varied with respect to the four evaluated criteria. These findings suggest that the choice of anesthetic protocol should be carefully considered when designing and interpreting functional blood flow studies in the rat eye. (C) The Authors. C1 [Moult, Eric M.; Choi, WooJhon; Baumann, Bernhard; Fujimoto, James G.] MIT, Dept Elect Engn & Comp Sci, Elect Res Lab, 50 Vassar St, Cambridge, MA 02139 USA. [Boas, David A.] Harvard Med Sch, Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Dept Radiol, 13th St, Charlestown, MA 02129 USA. [Baumann, Bernhard] Med Univ Vienna, Ctr Med Phys & Biomed Engn, Waehringer Guertel 18, A-1090 Vienna, Austria. [Clermont, Allen C.; Feener, Edward P.] Joslin Diabet Ctr, Div Res, One Joslin Pl, Boston, MA 02215 USA. RP Fujimoto, JG (reprint author), MIT, Dept Elect Engn & Comp Sci, Elect Res Lab, 50 Vassar St, Cambridge, MA 02139 USA. EM jgfuji@mit.edu OI Baumann, Bernhard/0000-0001-6419-1932 FU National Institute of Health [NIH R01-EY011289-29, R44-EY022864, R01-CA075289-16]; Air Force Office of Scientific Research [FA9550-15-1-0473, FA9550-12-1-0499] FX This work was supported by grants from the National Institute of Health (NIH R01-EY011289-29, R44-EY022864, R01-CA075289-16) and the Air Force Office of Scientific Research (FA9550-15-1-0473 and FA9550-12-1-0499). NR 36 TC 0 Z9 0 U1 0 U2 0 PU SPIE-SOC PHOTO-OPTICAL INSTRUMENTATION ENGINEERS PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98225 USA SN 1083-3668 EI 1560-2281 J9 J BIOMED OPT JI J. Biomed. Opt. PD JAN PY 2017 VL 22 IS 1 AR 016005 DI 10.1117/1.JBO.22.1.016005 PG 6 WC Biochemical Research Methods; Optics; Radiology, Nuclear Medicine & Medical Imaging SC Biochemistry & Molecular Biology; Optics; Radiology, Nuclear Medicine & Medical Imaging GA EO0EH UT WOS:000396370600015 PM 28056146 ER PT J AU Ward, A Arola, N Bohnert, A Lieb, R AF Ward, Amanda Arola, Nicole Bohnert, Amy Lieb, Rebecca TI Social-emotional adjustment and pet ownership among adolescents with autism spectrum disorder SO JOURNAL OF COMMUNICATION DISORDERS LA English DT Article DE Pet ownership; Social impairment; Social-emotional adjustment; Autism ID CHILDREN; LONELINESS; DOGS; ASSOCIATION; DEPRESSION; ANXIETY AB Adolescents with Autism Spectrum Disorder (ASD) often experience poor social-emotional adjustment and interactions with peers, but taking care of a family pet may serve as a buffer. This study utilized 81 parent-adolescent dyads to examine how dimensions of pet ownership (responsibility, comfort, companionship) may be associated with social emotional adjustment (depression, loneliness, friendship quality) among adolescents with ASD, as well as how social impairments may influence these relations. Results revealed that adolescents who took more responsibility for their pet exhibited fewer depressive symptoms. Additionally, parents of more socially impaired adolescents reported better friendship quality than less socially impaired adolescents. Findings suggest taking care of a pet may facilitate better social-emotional adjustment among adolescents with ASD. Published by Elsevier Inc. C1 [Ward, Amanda] Harvard Med Sch, Massachusetts Gen Hosp, 151 Merrimac, Boston, MA 02114 USA. [Arola, Nicole] Univ Minnesota, 2450 Riverside Ave South, Minneapolis, MN 55454 USA. [Bohnert, Amy] Loyola Univ Chicago, 1032 W Sheridan Rd, Chicago, IL 60660 USA. [Lieb, Rebecca] Akron Childrens Hosp, 215 W Bowery St, Akron, OH 44308 USA. RP Ward, A (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, 151 Merrimac, Boston, MA 02114 USA. EM wardkamanda@gmail.com NR 27 TC 0 Z9 0 U1 2 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0021-9924 EI 1873-7994 J9 J COMMUN DISORD JI J. Commun. Disord. PD JAN-FEB PY 2017 VL 65 BP 35 EP 42 DI 10.1016/j.jcomdis.2017.01.002 PG 8 WC Audiology & Speech-Language Pathology; Linguistics; Rehabilitation SC Audiology & Speech-Language Pathology; Linguistics; Rehabilitation GA EN4GC UT WOS:000395965000004 PM 28171740 ER PT J AU Lam, AY Nguyen, JK Parks, JJ Morisky, DE Berry, DL Wolpin, SE AF Lam, Annie Y. Nguyen, Juliet K. Parks, Jason J. Morisky, Donald E. Berry, Donna L. Wolpin, Seth E. TI Addressing low health literacy with "Talking Pill Bottles": A pilot study in a community pharmacy setting SO JOURNAL OF THE AMERICAN PHARMACISTS ASSOCIATION LA English DT Article ID REGIMEN COMPLEXITY INDEX; MEDICATION ADHERENCE; ELECTRONIC REMINDERS; HOSPITAL ADMISSION; PATIENT ADHERENCE; IMPROVE ADHERENCE; CHRONIC DISEASE; BLOOD-PRESSURE; OLDER-ADULTS; PICTOGRAMS AB Objectives: To test the effect of "Talking Pill Bottles" on medication self-efficacy, knowledge, adherence, and blood pressure readings among hypertensive patients with low health literacy and to assess patients' acceptance of this innovation. Design: Longitudinal nonblinded randomized trial with standard treatment and intervention arms. Setting and participants: Two community pharmacies serving an ethnically diverse population in the Pacific Northwest. Participants were consented patients with antihypertension prescriptions who screened positive for low health literacy based on the Test of Functional Health Literacy Short Form. Participants in the intervention arm received antihypertensive medications and recordings of pharmacists' counseling in Talking Pill Bottles at baseline. Control arm participants received antihypertensive medications and usual care instructions. Main outcome measures: Comparison and score changes between baseline and day 90 for medication knowledge test, Self-Efficacy for Appropriate Medication Use Scale (SEAMS), Morisky Medication Adherence Scale (MMAS-8), blood pressure, and responses to semistructured exit interviews and Technology Acceptance Model surveys. Results: Of 871 patients screened for health literacy, 134 eligible participants were enrolled in the trial. The sample was elderly, ethnically diverse, of low income, and experienced regarding hypertension and medication history. In both arms, we found high baseline scores in medication knowledge test, SEAMS, and MMAS-8 and minimal changes in these measures over the 90-day study period. Blood pressure decreased significantly in the intervention arm. Acceptability scores for the Talking Pill Bottle technology were high. Conclusion: Our results suggest that providing audio-assisted medication instructions in Talking Pill Bottles positively affected blood pressure control and was well accepted by patients with low health literacy. Further research involving newly diagnosed patients is needed to mitigate possible ceiling effects that we observed in an experienced population. (C) 2017 Published by Elsevier Inc. on behalf of the American Pharmacists Association. C1 [Lam, Annie Y.] Univ Washington, Sch Pharm, Seattle, WA 98195 USA. [Nguyen, Juliet K.; Parks, Jason J.; Morisky, Donald E.; Wolpin, Seth E.] Univ Washington, Sch Nursing, Dept Biobehav Nursing & Hlth Syst, Seattle, WA 98195 USA. [Morisky, Donald E.] Univ Calif Los Angeles, Fielding Sch Publ Hlth, Los Angeles, CA USA. [Berry, Donna L.] Harvard Sch Med, Dana Farber Canc Inst, Boston, MA USA. RP Lam, AY (reprint author), 8116 SE 77th Pl, Mercer Island, WA 98040 USA. EM aylam@uw.edu FU National Institute for Nursing Research, National Institute for Health: NIH [1R21NR010706-01A1] FX This study was funded by the National Institute for Nursing Research, National Institute for Health: NIH (1R21NR010706-01A1). The funding source has no involvement in the execution of study design, data collection, and interpretation. NR 57 TC 1 Z9 1 U1 4 U2 4 PU AMER PHARMACEUTICAL ASSOC PI WASHINGTON PA 2215 CONSTITUTION AVE NW, WASHINGTON, DC 20037 USA SN 1544-3191 EI 1544-3450 J9 J AM PHARM ASSOC JI J. Am. Pharm. Assoc. PD JAN-FEB PY 2017 VL 57 IS 1 BP 20 EP + DI 10.1016/j.japh.2016.07.003 PG 12 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EO0DO UT WOS:000396368700005 PM 27777076 ER PT J AU Morris, CD Azadnia, P de Val, N Vora, N Honda, A Giang, E Saye-Francisco, K Cheng, YS Lin, XH Mann, CJ Tang, J Sok, D Burton, DR Law, M Ward, AB He, LL Zhu, J AF Morris, Charles D. Azadnia, Parisa de Val, Natalia Vora, Nemil Honda, Andrew Giang, Erick Saye-Francisco, Karen Cheng, Yushao Lin, Xiaohe Mann, Colin J. Tang, Jeffrey Sok, Devin Burton, Dennis R. Law, Mansun Ward, Andrew B. He, Linling Zhu, Jiang TI Differential Antibody Responses to Conserved HIV-1 Neutralizing Epitopes in the Context of Multivalent Scaffolds and Native-Like gp140 Trimers SO MBIO LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; PROXIMAL EXTERNAL REGION; HIGH-MANNOSE PATCH; CRYO-EM STRUCTURE; VACCINE DESIGN; B-CELLS; ENVELOPE GLYCOPROTEINS; HIV-1-NEUTRALIZING ANTIBODIES; ENV TRIMERS; VRC01-CLASS ANTIBODIES AB Broadly neutralizing antibodies (bNAbs) have provided valuable insights into the humoral immune response to HIV-1. While rationally designed epitope scaffolds and well-folded gp140 trimers have been proposed as vaccine antigens, a comparative understanding of their antibody responses has not yet been established. In this study, we probed antibody responses to the N332 supersite and the membrane-proximal external region (MPER) in the context of heterologous protein scaffolds and native-like gp140 trimers. Ferritin nanoparticles and fragment crystallizable (Fc) regions were utilized as multivalent carriers to display scaffold antigens with grafted N332 and MPER epitopes, respectively. Trimeric scaffolds were also identified to stabilize the MPER-containing BG505 gp140.681 trimer in a native-like conformation. Following structural and antigenic evaluation, a subset of scaffold and trimer antigens was selected for immunization in BALB/c mice. Serum binding revealed distinct patterns of antibody responses to these two bNAb targets presented in different structural contexts. For example, the N332 nanoparticles elicited glycan epitope-specific antibody responses that could also recognize the native trimer, while a scaffolded BG505 gp140.681 trimer generated a stronger and more rapid antibody response to the trimer apex than its parent gp140.664 trimer. Furthermore, next-generation sequencing (NGS) of mouse splenic B cells revealed expansion of antibody lineages with long heavy-chain complementarity-determining region 3 (HCDR3) loops upon activation by MPER scaffolds, in contrast to the steady repertoires primed by N332 nanoparticles and a soluble gp140.664 trimer. These findings will facilitate the future development of a coherent vaccination strategy that combines both epitope-focused and trimer-based approaches. IMPORTANCE Both epitope-focused and trimer-based strategies are currently being explored in HIV- 1 vaccine development, which aims to elicit broadly neutralizing antibodies (bNAbs) targeting conserved epitopes on the viral envelope (Env). However, little is known about the differences in antibody response to these bNAb targets presented by foreign scaffolds and native Env. In this study, a systematic effort was undertaken to design multivalent epitope scaffolds and soluble gp140.681 trimers with a complete antigenic surface, and to comparatively analyze the antibody responses elicited by these antigens to the N332 supersite and MPER in a mouse model. This study will inform both epitope-focused and trimer-based vaccine design and will facilitate integration of the two vaccine strategies. C1 [Morris, Charles D.; Azadnia, Parisa; Vora, Nemil; Honda, Andrew; Giang, Erick; Saye-Francisco, Karen; Cheng, Yushao; Lin, Xiaohe; Mann, Colin J.; Tang, Jeffrey; Sok, Devin; Burton, Dennis R.; Law, Mansun; He, Linling; Zhu, Jiang] Scripps Res Inst, Dept Immunol & Microbial Sci, La Jolla, CA 92037 USA. [de Val, Natalia; Ward, Andrew B.; Zhu, Jiang] Scripps Res Inst, Dept Integrat Struct & Computat Biol, La Jolla, CA 92037 USA. [de Val, Natalia; Sok, Devin; Burton, Dennis R.; Ward, Andrew B.] Scripps Res Inst, Neutralizing Antibody Ctr, Int AIDS Vaccine Initiat, La Jolla, CA 92037 USA. [de Val, Natalia; Sok, Devin; Burton, Dennis R.; Ward, Andrew B.] Scripps Res Inst, Collaborat AIDS Vaccine Discovery, La Jolla, CA 92037 USA. [de Val, Natalia; Saye-Francisco, Karen; Sok, Devin; Burton, Dennis R.; Ward, Andrew B.; Zhu, Jiang] Scripps Res Inst, Ctr HIV AIDS Vaccine Immunol & Immunogen Discover, La Jolla, CA 92037 USA. [Burton, Dennis R.] Ragon Inst Massachusetts Gen Hosp Massachusetts I, Cambridge, MA USA. RP He, LL; Zhu, J (reprint author), Scripps Res Inst, Dept Immunol & Microbial Sci, La Jolla, CA 92037 USA.; Zhu, J (reprint author), Scripps Res Inst, Dept Integrat Struct & Computat Biol, La Jolla, CA 92037 USA.; Zhu, J (reprint author), Scripps Res Inst, Ctr HIV AIDS Vaccine Immunol & Immunogen Discover, La Jolla, CA 92037 USA. EM linling@scripps.edu; jiang@scripps.edu FU Scripps Center for HIV/ AIDS Immunology and Immunogen Discovery [CHAVI- ID UM1 AI 100663]; University of California, San Diego, Center for AIDS Research (CFAR), an NIH-funded program [P30 AI036214]; NIAID; NCI; NIMH; NIDA; NICHD; NHLBI; NIA; NIGMS; NIDDK; NIH NIAID [R21 AI118686, R01 AI129698, U19 AI123861]; International AIDS Vaccine Initiative (IAVI); Collaboration for AIDS Vaccine Discovery (CAVD) [OPP1084519, OPP1115782] FX This research was funded by the Scripps Center for HIV/AIDS Immunology and Immunogen Discovery (CHAVI-ID UM1 AI 100663) and in part by a 2015 grant from the University of California, San Diego, Center for AIDS Research (CFAR), an NIH-funded program (P30 AI036214; awarded to Douglas Richman at UCSD, with a sub-ward used to support part of this project), which is supported by the following NIH Institutes and Centers: NIAID, NCI, NIMH, NIDA, NICHD, NHLBI, NIA, NIGMS, and NIDDK. This research was also funded in part by NIH NIAID grants (R21 AI118686 to J. Zhu, R01 AI129698 to J. Zhu, and U19 AI123861 to J. Zhu and M. Law), and also by the International AIDS Vaccine Initiative (IAVI) and its generous donors (who can be found at http:// www. iavi. org) and the Collaboration for AIDS Vaccine Discovery (CAVD) (OPP1084519 and OPP1115782). NR 97 TC 0 Z9 0 U1 3 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 2150-7511 J9 MBIO JI mBio PD JAN-FEB PY 2017 VL 8 IS 1 AR e00036- 17 DI 10.1128/mBio.00036-17 PG 26 WC Microbiology SC Microbiology GA EN2JE UT WOS:000395835000045 ER PT J AU Starrett, GJ Marcelus, C Cantalupo, PG Katz, JP Cheng, JW Akagi, K Thakuria, M Rabinowits, G Wang, LC Symer, DE Pipas, JM Harris, RS DeCaprio, JA AF Starrett, Gabriel J. Marcelus, Christina Cantalupo, Paul G. Katz, Joshua P. Cheng, Jingwei Akagi, Keiko Thakuria, Manisha Rabinowits, Guilherme Wang, Linda C. Symer, David E. Pipas, James M. Harris, Reuben S. DeCaprio, James A. TI Merkel Cell Polyomavirus Exhibits Dominant Control of the Tumor Genome and Transcriptome in Virus-Associated Merkel Cell Carcinoma SO MBIO LA English DT Article ID NONMELANOMA SKIN-CANCER; HEPATITIS-B-VIRUS; MUTATIONAL SIGNATURES; HEPATOCELLULAR-CARCINOMA; DNA-DAMAGE; SOMATIC MUTATIONS; INTEGRATION; MUTAGENESIS; EXPRESSION; APOBEC3B AB Merkel cell polyomavirus is the primary etiological agent of the aggressive skin cancer Merkel cell carcinoma (MCC). Recent studies have revealed that UV radiation is the primary mechanism for somatic mutagenesis in nonviral forms of MCC. Here, we analyze the whole transcriptomes and genomes of primary MCC tumors. Our study reveals that virus-associated tumors have minimally altered genomes compared to non-virus-associated tumors, which are dominated by UV-mediated mutations. Although virus-associated tumors contain relatively small mutation burdens, they exhibit a distinct mutation signature with observable transcriptionally biased kataegic events. In addition, viral integration sites overlap focal genome amplifications in virus-associated tumors, suggesting a potential mechanism for these events. Collectively, our studies indicate that Merkel cell polyomavirus is capable of hijacking cellular processes and driving tumorigenesis to the same severity as tens of thousands of somatic genome alterations. IMPORTANCE A variety of mutagenic processes that shape the evolution of tumors are critical determinants of disease outcome. Here, we sequenced the entire genome of virus-positive and virus-negative primary Merkel cell carcinomas (MCCs), revealing distinct mutation spectra and corresponding expression profiles. Our studies highlight the strong effect that Merkel cell polyomavirus has on the divergent development of viral MCC compared to the somatic alterations that typically drive nonviral tumorigenesis. A more comprehensive understanding of the distinct mutagenic processes operative in viral and nonviral MCCs has implications for the effective treatment of these tumors. C1 [Starrett, Gabriel J.; Harris, Reuben S.] Univ Minnesota, Inst Mol Virol, Masonic Canc Ctr, Dept Biochem Mol Biol & Biophys, Minneapolis, MN 55455 USA. [Marcelus, Christina; Cheng, Jingwei; Rabinowits, Guilherme; DeCaprio, James A.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Cantalupo, Paul G.; Katz, Joshua P.; Pipas, James M.] Univ Pittsburgh, Dept Biol Sci, Pittsburgh, PA 15260 USA. [Cheng, Jingwei; Rabinowits, Guilherme; DeCaprio, James A.] Harvard Med Sch, Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Thakuria, Manisha; Wang, Linda C.] Harvard Med Sch, Brigham & Womens Hosp, Dept Dermatol, Boston, MA USA. [Akagi, Keiko; Symer, David E.] Ohio State Univ, Ctr Comprehens Canc, Human Canc Genet Program, Columbus, OH 43210 USA. [Akagi, Keiko; Symer, David E.] Ohio State Univ, Dept Canc Biol & Genet, Columbus, OH 43210 USA. [Symer, David E.] Ohio State Univ, Dept Biomed Informat, Columbus, OH 43210 USA. [Harris, Reuben S.] Univ Minnesota, Howard Hughes Med Inst, Minneapolis, MN 55455 USA. RP Harris, RS (reprint author), Univ Minnesota, Inst Mol Virol, Masonic Canc Ctr, Dept Biochem Mol Biol & Biophys, Minneapolis, MN 55455 USA.; DeCaprio, JA (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA.; DeCaprio, JA (reprint author), Harvard Med Sch, Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA.; Harris, RS (reprint author), Univ Minnesota, Howard Hughes Med Inst, Minneapolis, MN 55455 USA. EM rsh@umn.edu; james_decaprio@dfci.harvard.edu FU HHS | NIH | National Cancer Institute (NCI) [RO1CA63113, RO1CA173023, PO1CA050661, R21CA170248, R21CA206309]; National Science Foundation (NSF) [00039202] FX This work, including the efforts of James A. DeCaprio, was funded by HHS | NIH | National Cancer Institute (NCI) (RO1CA63113). This work, including the efforts of James A. DeCaprio, was funded by HHS | NIH | National Cancer Institute (NCI) (RO1CA173023). This work, including the efforts of James A. DeCaprio, was funded by HHS | NIH | National Cancer Institute (NCI) (PO1CA050661). This work, including the efforts of James M. Pipas, was funded by HHS | NIH | National Cancer Institute (NCI) (R21CA170248). This work, including the efforts of Gabriel J. Starrett, was funded by National Science Foundation (NSF) (00039202). This work, including the efforts of Reuben S. Harris, was funded by HHS | NIH | National Cancer Institute (NCI) (R21CA206309). NR 61 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 2150-7511 J9 MBIO JI mBio PD JAN-FEB PY 2017 VL 8 IS 1 AR e02079-16 DI 10.1128/mBio.02079-16 PG 14 WC Microbiology SC Microbiology GA EN2JE UT WOS:000395835000067 ER PT J AU Van Tyne, D Gilmore, MS AF Van Tyne, Daria Gilmore, Michael S. TI Raising the Alarmone: Within-Host Evolution of Antibiotic-Tolerant Enterococcus faecium SO MBIO LA English DT Article ID VANCOMYCIN-RESISTANT ENTEROCOCCI; STRESS RESPONSES; INFECTION; VIRULENCE; (P)PPGPP AB Enterococci are ancient commensal bacteria that recently emerged as leading causes of antibiotic-resistant, hospital-acquired infection. Vancomycin-resistant enterococci (VRE) epitomize why drug-resistant enterococcal infections are a problem: VRE readily colonize the antibiotic-perturbed gastrointestinal (GI) tract where they amplify to large numbers, and from there, they infect other body sites, including the bloodstream, urinary tract, and surgical wounds. VRE are resistant to many antimicrobials and host defenses, which facilitates establishment at the site of infection and confounds therapeutic clearance. Having evolved to colonize the GI tract, VRE are comparatively ill adapted to the human bloodstream. A recent study by Honsa and colleagues (E. S. Honsa et al., mBio 8: e02124-16, 2017, https://doi. org/10.1128/ mBio. 02124-16) found that a strain of vancomycin-resistant Enterococcus faecium evolved antibiotic tolerance within the bloodstream of an immunocompromised host by activating the stringent response through mutation of relA. Precisely how VRE colonize and infect and the selective pressures that led to the outgrowth of relA mutants are the subjects of ongoing research. C1 [Van Tyne, Daria; Gilmore, Michael S.] Harvard Med Sch, Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Boston, MA 02115 USA. [Van Tyne, Daria; Gilmore, Michael S.] Harvard Med Sch, Dept Microbiol & Immunobiol, Boston, MA 02115 USA. RP Van Tyne, D; Gilmore, MS (reprint author), Harvard Med Sch, Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Boston, MA 02115 USA.; Van Tyne, D; Gilmore, MS (reprint author), Harvard Med Sch, Dept Microbiol & Immunobiol, Boston, MA 02115 USA. EM vantyne@fas.harvard.edu; michael_gilmore@meei.harvard.edu FU PHS grant [AI083214]; National Institutes of Health [AI072360, AI108710] FX This work is supported by PHS grant AI083214 (Harvard-wide Program on Antibiotic Resistance), as well as grants AI072360 and AI108710 from the National Institutes of Health. NR 19 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 2150-7511 J9 MBIO JI mBio PD JAN-FEB PY 2017 VL 8 IS 1 AR e00066-17 DI 10.1128/mBio.00066-17 PG 4 WC Microbiology SC Microbiology GA EN2JE UT WOS:000395835000076 ER PT J AU Pitt, MB Orlander, JD AF Pitt, Michael B. Orlander, Jay D. TI Bringing mini-chalk talks to the bedside to enhance clinical teaching SO MEDICAL EDUCATION ONLINE LA English DT Article DE Medical education; chalk talks; bedside teaching ID 12 TIPS; SPACING REPETITIONS; MEDICAL-EDUCATION; ROUNDS AB Chalk talks-where the teacher is equipped solely with a writing utensil and a writing surface have been used for centuries, yet little has been written about strategies for their use in medical education. Structured education proximal to patient encounters (during rounds, at the bedside, or in between patients in clinic) maximizes the opportunities for clinical learning. This paper presents a strategy to bring mini-chalk talks (MCTs) to the bedside as a practical way to provide relevant clinical teaching by visually framing teachable moments. Grounded in adult learning theory, MCTs leverage teaching scripts to facilitate discussion, involve learners at multiple levels, and embrace the increased retention associated with visual aids. These authors provide specific recommendations for the design and implementation of MCT sessions including what topics work well, how to prepare, and how to involve and engage the learners. C1 [Pitt, Michael B.] Univ Minnesota, Dept Pediat, Masonic Childrens Hosp, 2450 Riverside Ave,6th Floor East Bldg,M653, Minneapolis, MN 55454 USA. [Orlander, Jay D.] VA Boston Healthcare Syst, Evans Dept Med, Boston, MA USA. [Orlander, Jay D.] Boston Univ, Sch Med, Boston, MA 02118 USA. RP Pitt, MB (reprint author), Univ Minnesota, Dept Pediat, Masonic Childrens Hosp, 2450 Riverside Ave,6th Floor East Bldg,M653, Minneapolis, MN 55454 USA. EM mbpitt@umn.edu NR 37 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 1087-2981 J9 MED EDUC ONLINE JI Med. Educ. Online PY 2017 VL 22 AR 1264120 DI 10.1080/10872981.2017.1264120 PG 7 WC Education & Educational Research SC Education & Educational Research GA EN3TV UT WOS:000395931700001 ER PT J AU Yoshida, A Kitajima, S Li, FK Cheng, CY Takegami, Y Kohno, S Wan, YS Hayashi, N Muranaka, H Nishimoto, Y Nagatani, N Nishiuchi, T Thai, TC Suzuki, S Nakao, S Tanaka, T Hirose, O Barbie, DA Takahashi, C AF Yoshida, Akiyo Kitajima, Shunsuke Li, Fengkai Cheng, Chaoyang Takegami, Yujiro Kohno, Susumu Wan, Yuan Song Hayashi, Naoyuki Muranaka, Hayato Nishimoto, Yuuki Nagatani, Naoko Nishiuchi, Takumi Thai, Tran C. Suzuki, Sawako Nakao, Shinji Tanaka, Tomoaki Hirose, Osamu Barbie, David A. Takahashi, Chiaki TI MicroRNA-140 mediates RB tumor suppressor function to control stem cell-like activity through interleukin-6 SO ONCOTARGET LA English DT Article DE cancer; cancer stem cells; RB; mir-140; interleukin-6 ID BREAST-CANCER; MESENCHYMAL TRANSITION; BIOGENESIS PATHWAYS; OVARIAN-CANCER; EXPRESSION; GROWTH; MIR-140; TARGETS; DICER; TUMORIGENESIS AB We established an in vitro cell culture system to determine novel activities of the retinoblastoma (Rb) protein during tumor progression. Rb depletion in p53-null mouse-derived soft tissue sarcoma cells induced a spherogenic phenotype. Cells retrieved from Rb-depleted spheres exhibited slower proliferation and less efficient BrdU incorporation, however, much higher spherogenic activity and aggressive behavior. We discovered six miRNAs, including mmu-miR-18a, -25, -29b, -140, -337, and -1839, whose expression levels correlated tightly with the Rb status and spherogenic activity. Among these, mmu-miR-140 appeared to be positively controlled by Rb and to antagonize the effect of Rb depletion on spherogenesis and tumorigenesis. Furthermore, among genes potentially targeted by mmu-miR-140, Il-6 was upregulated by Rb depletion and downregulated by mmu-mir-140 overexpression. Altogether, we demonstrate the possibility that mmu-mir-140 mediates the Rb function to downregulate Il-6 by targeting its 3'-untranslated region. Finally, we detected the same relationship among RB, hsa-miR-140 and IL-6 in a human breast cancer cell line MCF-7. Because IL-6 is a critical modulator of malignant features of cancer cells and the RB pathway is impaired in the majority of cancers, hsa-miR-140 might be a promising therapeutic tool that disrupts linkage between tumor suppressor inactivation and pro-inflammatory cytokine response. C1 [Yoshida, Akiyo; Kitajima, Shunsuke; Li, Fengkai; Kohno, Susumu; Wan, Yuan Song; Hayashi, Naoyuki; Muranaka, Hayato; Nishimoto, Yuuki; Nagatani, Naoko; Takahashi, Chiaki] Kanazawa Univ, Canc Res Inst, Div Oncol & Mol Biol, Kanazawa, Ishikawa 9201192, Japan. [Yoshida, Akiyo; Nakao, Shinji] Kanazawa Univ, Grad Sch Med Sci, Dept Cellular Transplantat Biol, Kanazawa, Ishikawa 9208641, Japan. [Kitajima, Shunsuke; Thai, Tran C.; Barbie, David A.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Cheng, Chaoyang; Takegami, Yujiro] DNAFORM Precis Gene Technol, Yokohama, Kanagawa 2300046, Japan. [Hayashi, Naoyuki] Kanazawa Gakuin Univ, Fac Human Hlth Sci, Dept Hlth & Nutr, Kanazawa, Ishikawa 9201302, Japan. [Nishiuchi, Takumi] Kanazawa Univ, Div Funct Genom, Adv Sci Res Ctr, Kanazawa, Ishikawa 9200934, Japan. [Suzuki, Sawako; Tanaka, Tomoaki] Chiba Univ, Grad Sch Med, Deperment Clin Cell Biol & Med, Chiba, Chiba 2608670, Japan. [Hirose, Osamu] Kanazawa Univ, Grad Sch Nat Sci & Technol, Div Elect Engn & Comp Sci, Kanazawa, Ishikawa 9201192, Japan. RP Kitajima, S; Takahashi, C (reprint author), Kanazawa Univ, Canc Res Inst, Div Oncol & Mol Biol, Kanazawa, Ishikawa 9201192, Japan.; Kitajima, S (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. EM shunsuke_kitajima@dfci.harvard.edu FU Program for Next Generation World-Leading Researchers [26290037, 26640070, 5H01487]; Astellas Foundation [25830077, 23701048]; Takeda Science Foundation; Naito Foundation; Daiichi-Sankyo Foundation; Hokkoku Foundation; Hokuriku Bank Research Grant; IMSUT Joint Research Project FX This work was supported by Funding Program for Next Generation World-Leading Researchers to CT, Grant-in-Aid for Scientific Research to CT (26290037, 26640070, 5H01487) and SK (25830077, 23701048), Astellas Foundation for Research on Metabolic Disorders, Takeda Science Foundation, Naito Foundation, Daiichi-Sankyo Foundation for Life Science, Hokkoku Foundation for Cancer Research and IMSUT Joint Research Project to CT, and Hokuriku Bank Research Grant for Young Scientists to SK. NR 52 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 8 BP 13872 EP 13885 DI 10.18632/oncotarget.14681 PG 14 WC Oncology; Cell Biology SC Oncology; Cell Biology GA EN0HX UT WOS:000395692000123 ER PT J AU Mantopoulos, D Vavvas, DG Fine, HF AF Mantopoulos, Dimosthenis Vavvas, Demetrios G. Fine, Howard F. TI Perioperative Risks of Antiplatelet and Anticoagulant Drugs in Vitreoretinal Procedures SO OPHTHALMIC SURGERY LASERS & IMAGING RETINA LA English DT Editorial Material ID VITREOUS HEMORRHAGE; ATRIAL-FIBRILLATION; UNITED-STATES; WARFARIN USE; SURGERY; THERAPY; VITRECTOMY; AGENTS; MAINTENANCE; MANAGEMENT C1 [Mantopoulos, Dimosthenis] Ohio State Univ, Dept Ophthalmol, 915 Olantangy River Rd, Columbus, OH 43212 USA. [Mantopoulos, Dimosthenis] Havener Eye Inst, 915 Olantangy River Rd, Columbus, OH 43212 USA. [Vavvas, Demetrios G.] Massachusetts Eye & Ear Infirm, Dept Ophthalmol, 243 Charles St, Boston, MA 02114 USA. [Fine, Howard F.] Rutgers Univ Med & Dent New Jersey, NJ Retina, Dept Ophthalmol, 10 Plum St,Suite 600, New Brunswick, NJ 08901 USA. RP Mantopoulos, D (reprint author), Ohio State Univ, Dept Ophthalmol, 915 Olantangy River Rd, Columbus, OH 43212 USA.; Mantopoulos, D (reprint author), Havener Eye Inst, 915 Olantangy River Rd, Columbus, OH 43212 USA. EM dimos.manto@gmail.com; vavvas@meei.harvard.edu; hffine@yahoo.com NR 25 TC 0 Z9 0 U1 0 U2 0 PU SLACK INC PI THOROFARE PA 6900 GROVE RD, THOROFARE, NJ 08086 USA SN 2325-8160 EI 2325-8179 J9 OSLI RETINA JI Ophthalmic Surg. Lasers Imag. Retin. PD JAN PY 2017 VL 48 IS 1 BP 4 EP 8 DI 10.3928/23258160-20161219-01 PG 5 WC Ophthalmology; Surgery SC Ophthalmology; Surgery GA EO1OH UT WOS:000396467300001 PM 28060388 ER PT J AU Lakshmi, SP Reddy, AT Banno, A Reddy, RC AF Lakshmi, Sowmya P. Reddy, Aravind T. Banno, Asoka Reddy, Raju C. TI PPAR Agonists for the Prevention and Treatment of Lung Cancer SO PPAR RESEARCH LA English DT Review ID ACTIVATED RECEPTOR-GAMMA; SUPPRESSES TUMOR-GROWTH; NITRATED FATTY-ACIDS; CELL-GROWTH; ALPHA AGONIST; COLON-CANCER; BETA/DELTA; EXPRESSION; MICE; INHIBITION AB Lung cancer is the most common and most fatal of all malignancies worldwide. Furthermore, with more than half of all lung cancer patients presenting with distant metastases at the time of initial diagnosis, the overall prognosis for the disease is poor. There is thus a desperate need for new prevention and treatment strategies. Recently, a family of nuclear hormone receptors, the peroxisome proliferator-activated receptors (PPARs), has attracted significant attention for its role in various malignancies including lung cancer. Three PPARs, PPAR alpha., PPAR beta/delta, and PPARy, display distinct biological activities and varied influences on lung cancer biology. PPAR alpha activation generally inhibits tumorigenesis through its antiangiogenic and anti-inflammatory effects. Activated PPARy is also antitumorigenic and antimetastatic, regulating several functions of cancer cells and controlling the tumor microenvironment. Unlike PPAR alpha and PPAR gamma, whether PPAR beta/delta activation is anti-or protumorigenic or even inconsequential currently remains an open question that requires additional investigation. This review of current literature emphasizes the multifaceted effects of PPAR agonists in lung cancer and discusses how they may be applied as novel therapeutic strategies for the disease. C1 [Lakshmi, Sowmya P.; Reddy, Aravind T.; Banno, Asoka; Reddy, Raju C.] Univ Pittsburgh, Sch Med, Div Pulm Allergy & Crit Care Med, Dept Med, Pittsburgh, PA 15213 USA. [Lakshmi, Sowmya P.; Reddy, Aravind T.; Reddy, Raju C.] Vet Affairs Pittsburgh Healthcare Syst, Pittsburgh, PA 15240 USA. RP Reddy, RC (reprint author), Univ Pittsburgh, Sch Med, Div Pulm Allergy & Crit Care Med, Dept Med, Pittsburgh, PA 15213 USA.; Reddy, RC (reprint author), Vet Affairs Pittsburgh Healthcare Syst, Pittsburgh, PA 15240 USA. EM reddyrc@upmc.edu FU US Department of Veterans Affairs; National Institutes of Health Grants [HL093196, AI125338] FX This work was supported by a Merit Review Award from the US Department of Veterans Affairs and National Institutes of Health Grants HL093196 and AI125338 (RCR). NR 74 TC 0 Z9 0 U1 1 U2 1 PU HINDAWI LTD PI LONDON PA ADAM HOUSE, 3RD FLR, 1 FITZROY SQ, LONDON, WIT 5HE, ENGLAND SN 1687-4757 EI 1687-4765 J9 PPAR RES JI PPAR Res. PY 2017 DI 10.1155/2017/8252796 PG 8 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EN8JW UT WOS:000396247700001 ER PT J AU Grossestreuer, AV Gaieski, DF Abella, BS Wiebe, DJ Moskowitz, A Ikeda, DJ Haukoos, JS Perman, SM AF Grossestreuer, Anne V. Gaieski, David F. Abella, Benjamin S. Wiebe, Douglas J. Moskowitz, Ari Ikeda, Daniel J. Haukoos, Jason S. Perman, Sarah M. TI Factors associated with post-arrest withdrawal of life-sustaining therapy SO RESUSCITATION LA English DT Article DE Cardiopulmonary resuscitation; Heart arrest; Brain; Epidemiology; Prognosis ID HOSPITAL CARDIAC-ARREST; INDUCED HYPOTHERMIA; COMATOSE SURVIVORS; RESUSCITATION; PREDICTORS; PROGNOSIS; DEATH; MODE AB Introduction: Most successfully resuscitated cardiac arrest patients do not survive to hospital discharge. Many have withdrawal of life sustaining therapy (WLST) as a result of the perception of poor neurologic prognosis. The characteristics of these patients and differences in their post-arrest care are largely unknown. Methods: Utilizing the Penn Alliance for Therapeutic Hypothermia Registry, we identified a cohort of 1311 post-arrest patients from 26 hospitals from 2010 to 2014 who remained comatose after return of spontaneous circulation. We stratified patients by whether they had WLST post-arrest and analyzed demographic, arrest, and post-arrest variables. Results: In our cohort, 565 (43%) patients had WLST. In multivariate regression, patients who had WLST were less likely to go to the cardiac catheterization lab (OR 0.40; 95% CI: 0.26-0.62) and had shorter hospital stays (OR 0.93; 95% CI: 0.91-0.95). When multivariate regression was limited to patient demographics and arrest characteristics, patients with WLST were older (OR 1.18; 95% CI: 1.07-1.31 by decade), had a longer arrest duration (OR 1.14; 95% CI: 1.05-1.25 per 10 min), more likely to be female (OR: 1.41; 95% CI: 1.01-1.96), and less likely to have a witnessed arrest (OR 0.65; 95% CI: 0.42-0.98). Conclusion: Patients with WLST differ in terms of demographic, arrest, and post-arrest characteristics and treatments from those who did not have WLST. Failure to account for this variability could affect both clinical practice and the interpretation of research. (C) 2016 Elsevier Ireland Ltd. All rights reserved. C1 [Grossestreuer, Anne V.; Abella, Benjamin S.; Ikeda, Daniel J.] Univ Penn, Ctr Resuscitat Sci, Philadelphia, PA 19104 USA. [Grossestreuer, Anne V.; Abella, Benjamin S.; Ikeda, Daniel J.] Univ Penn, Dept Emergency Med, Philadelphia, PA 19104 USA. [Grossestreuer, Anne V.] Univ Penn, Leonard Davis Inst Hlth Econ, Philadelphia, PA 19104 USA. [Grossestreuer, Anne V.; Wiebe, Douglas J.] Univ Penn, Ctr Clin Epidemiol & Biostat, Philadelphia, PA USA. [Gaieski, David F.] Thomas Jefferson Univ, Dept Emergency Med, Philadelphia, PA 19107 USA. [Moskowitz, Ari] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Haukoos, Jason S.] Denver Hlth Med Ctr, Denver, CO USA. [Haukoos, Jason S.; Perman, Sarah M.] Univ Colorado, Sch Med, Dept Emergency Med, Aurora, CO USA. RP Grossestreuer, AV (reprint author), 3400 Spruce St, Philadelphia, PA 19104 USA. EM agrosses@upenn.edu RI Siry, Bonnie/D-7189-2017 FU American Heart Association; National Institutes of Health, the Patient-Centered Outcomes Research Institute, American Heart Association and CR Bard; Laerdal Medical Corporation; National Institutes of Health [T32HL007374-37] FX Dr. Grossestreuer receives research support from the American Heart Association. Dr Gaieski provides consulting for CR Bard and Stryker Medical and has received honoraria from CR Bard. Dr. Abella has received research funding from the National Institutes of Health, the Patient-Centered Outcomes Research Institute, American Heart Association and CR Bard, in-kind research support from Laerdal Medical Corporation, and honoraria from CR Bard. Dr. Moskowitz receives research support from the National Institutes of Health (#T32HL007374-37). Dr. Haukoos receives research support from the National Institutes of Health. Dr. Perman receives research support from the National Institutes of Health. Dr. Wiebe and Mr. Ikeda declare no conflict of interest. NR 16 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 0300-9572 J9 RESUSCITATION JI Resuscitation PD JAN PY 2017 VL 110 BP 114 EP 119 DI 10.1016/j.resuscitation.2016.10.021 PG 6 WC Critical Care Medicine; Emergency Medicine SC General & Internal Medicine; Emergency Medicine GA EO0HX UT WOS:000396380000025 PM 27840307 ER PT J AU Sasidharan, S Yajnik, V Khalili, H Garber, J Xavier, R Ananthakrishnan, AN AF Sasidharan, Saranya Yajnik, Vijay Khalili, Hamed Garber, John Xavier, Ramnik Ananthakrishnan, Ashwin N. TI Genetic risk factors for serious infections in inflammatory bowel diseases SO SCANDINAVIAN JOURNAL OF GASTROENTEROLOGY LA English DT Article DE Genetics; infections; pneumonia; immunosuppression; Crohn's disease; sepsis ID INTERFERON-GAMMA; OPPORTUNISTIC INFECTIONS; CLOSTRIDIUM-DIFFICILE; ULCERATIVE-COLITIS; IMMUNE-RESPONSES; CROHNS-DISEASE; IFN-GAMMA; ASSOCIATION; POLYMORPHISMS; THERAPY AB Introduction: Immunosuppression, the cornerstone of management of Crohn's disease (CD) and ulcerative colitis (UC) (inflammatory bowel diseases; IBD) is associated with an increased risk of serious infections that is inadequately predicted by clinical risk factors. The role of genetics in determining susceptibility to infections is unknown. Methods: From a prospective-consented patient registry, we identified IBD patients with serious infections requiring hospitalization. Analysis was performed to identify IBD-related and non-IBD related immune response loci on the Immunochip that were associated with serious infections and a genetic risk score (GRS) representing the cumulative burden of the identified single nucleotide polymorphisms was calculated. Multivariable logistic regression used to identify effect of clinical and genetic factors. Results: The study included 1333 IBD patients (795CD, 538 UC) with median disease duration of 13years. A total of 133 patients (10%) had a serious infection requiring hospitalization. Patients with infections were more likely to have CD and had shorter disease duration. The most common infections were skin and soft-tissue, respiratory and urinary tract infections. Eight IBD risk loci and two other polymorphisms were significantly associations with serious infections. Each one point increase in the infection GRS was associated with a 50% increase in risk of infections (OR = 1.53, 95% CI = 1.37-1.70) (p = 1x10(-14)), confirmed on multivariable analysis. Genetic risk factors improved performance of a model predicting infections over clinical covariates alone (p < 0.001). Conclusions: Genetic risk factors may predict susceptibility to infections in patients with IBD. C1 Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA. Harvard Med Sch, Boston, MA USA. RP Ananthakrishnan, AN (reprint author), Massachusetts Gen Hosp, Crohns & Colitis Ctr, 165 Cambridge St,9th Floor, Boston, MA 02114 USA. EM aananthakrishnan@mgh.harvard.edu FU National Institutes of Health [K23 DK097142]; National Institutes of Health (NIH) [P30 DK043351]; Merck; Amgen FX A.N.A. is supported in part by a grant from the National Institutes of Health (K23 DK097142). This work is also supported by the National Institutes of Health (NIH) (P30 DK043351) to the Center for Study of Inflammatory Bowel Diseases. A.N.A. has served on the scientific advisory boards for Abbvie, Takeda, Exact Sciences, and Merck and has received grant support from Merck and Amgen. NR 48 TC 0 Z9 0 U1 1 U2 1 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND SN 0036-5521 EI 1502-7708 J9 SCAND J GASTROENTERO JI Scand. J. Gastroenterol. PY 2017 VL 52 IS 5 BP 570 EP 576 DI 10.1080/00365521.2017.1286381 PG 7 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EN1CA UT WOS:000395746800012 PM 28162010 ER PT J AU Prabhu, M Bateman, BT AF Prabhu, Malavika Bateman, Brian T. TI Postpartum anemia: missed opportunities for prevention and recognition SO TRANSFUSION LA English DT Editorial Material ID PREGNANCY-RELATED MORTALITY; IRON-DEFICIENCY C1 [Prabhu, Malavika] Harvard Med Sch, Massachusetts Gen Hosp, Dept Obstet & Gynecol, Boston, MA USA. [Bateman, Brian T.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Anesthesiol Crit Care & Pain Med, Boston, MA 02115 USA. [Bateman, Brian T.] Harvard Med Sch, Massachusetts Gen Hosp, Div Pharmacoepidemiol & Pharmacoecon, Dept Med, Boston, MA 02115 USA. RP Bateman, BT (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Dept Anesthesiol Crit Care & Pain Med, Boston, MA 02115 USA.; Bateman, BT (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Div Pharmacoepidemiol & Pharmacoecon, Dept Med, Boston, MA 02115 USA. EM bbateman@partners.org FU Eunice Kennedy Shriver National Institute of Child Health & Human Development of the NIH (Bethesda, MD) [K08HD075831] FX BTB is supported by the Eunice Kennedy Shriver National Institute of Child Health & Human Development of the NIH (Bethesda, MD) under Award K08HD075831. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 19 TC 0 Z9 0 U1 1 U2 1 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0041-1132 EI 1537-2995 J9 TRANSFUSION JI Transfusion PD JAN PY 2017 VL 57 IS 1 BP 3 EP 5 DI 10.1111/trf.13927 PG 3 WC Hematology SC Hematology GA EL2CU UT WOS:000394428500002 PM 28097696 ER PT J AU Fung, V Liang, CY Donelan, K Peitzman, CGK Dow, WH Zaslavsky, AM Fireman, B Derose, SF Chernew, ME Newhouse, JP Hsu, J AF Fung, Vicki Liang, Catherine Y. Donelan, Karen Peitzman, Cassandra G. K. Dow, William H. Zaslavsky, Alan M. Fireman, Bruce Derose, Stephen F. Chernew, Michael E. Newhouse, Joseph P. Hsu, John TI Nearly One-Third Of Enrollees In California's Individual Market Missed Opportunities To Receive Financial Assistance SO HEALTH AFFAIRS LA English DT Article AB The Affordable Care Act includes financial assistance that reduces both premiums and cost-sharing amounts for lower-income Americans, to increase the affordability of health insurance coverage and care. To receive both types of assistance, enrollees must purchase a qualified health plan through a public insurance exchange, and those eligible for the cost-sharing reduction must purchase a silver-tier plan. We estimate that 31 percent of individual-market enrollees in California who were likely eligible for financial assistance purchased plans that were not silver tier or that were not sold on the state's exchange and thus missed opportunities to receive premium or cost-sharing assistance or both. Lower-income enrollees who chose plans not eligible for subsidies had two to three times higher odds of reporting difficulty paying premiums and out-of-pocket expenses during the year, compared to those who chose eligible plans. Regardless of how the structure of the individual market evolves in the coming years, efforts are likely needed to steer lower-income enrollees away from financially suboptimal plan choices. C1 [Fung, Vicki; Liang, Catherine Y.; Donelan, Karen] Massachusetts Gen Hosp, Mongan Inst Hlth Policy Ctr, Boston, MA 02114 USA. [Fung, Vicki; Donelan, Karen; Hsu, John] Harvard Med Sch, Dept Med, Boston, MA 02115 USA. [Peitzman, Cassandra G. K.] Harvard Univ, Grad Sch Arts & Sci, Cambridge, MA 02138 USA. [Dow, William H.] Univ Calif Berkeley, Sch Publ Hlth, Div Hlth Policy & Management, Berkeley, CA 94720 USA. [Zaslavsky, Alan M.; Chernew, Michael E.; Hsu, John] Harvard Med Sch, Dept Hlth Care Policy, Boston, MA USA. [Fireman, Bruce] Kaiser Permanente, Div Res, Oakland, CA USA. [Derose, Stephen F.] Permanente Southern Calif, Dept Res & Evaluat, Pasadena, CA USA. [Newhouse, Joseph P.] Harvard Med Sch, Dept Hlth Care Policy, Hlth Policy & Management, Cambridge, MA USA. [Newhouse, Joseph P.] Harvard TH Chan Sch Publ Hlth, Dept Hlth Policy & Management, Cambridge, MA USA. [Newhouse, Joseph P.] Harvard Univ, John F Kennedy Sch Govt, Cambridge, MA 02138 USA. [Newhouse, Joseph P.] NBER, Cambridge, MA 02138 USA. [Hsu, John] Massachusetts Gen Hosp, Mongan Inst Hlth Policy Ctr, Program Clin Econ & Policy Anal, Boston, MA 02114 USA. [Hsu, John] Harvard Med Sch, Dept Med, Boston, MA USA. RP Fung, V (reprint author), Massachusetts Gen Hosp, Mongan Inst Hlth Policy Ctr, Boston, MA 02114 USA.; Fung, V (reprint author), Harvard Med Sch, Dept Med, Boston, MA 02115 USA. EM vfung@mgh.harvard.edu FU Commonwealth Fund FX Funding for this study was provided by the Commonwealth Fund. Joseph Newhouse is a director of and holds equity in Aetna. The authors gratefully acknowledge the contributions of Sara Collins of the Commonwealth Fund and Jordon Peugh of SSRS to this project. NR 17 TC 0 Z9 0 U1 0 U2 0 PU PROJECT HOPE PI BETHESDA PA 7500 OLD GEORGETOWN RD, STE 600, BETHESDA, MD 20814-6133 USA SN 0278-2715 J9 HEALTH AFFAIR JI Health Aff. PD JAN PY 2017 VL 36 IS 1 BP 21 EP 31 DI 10.1377/hlthaff.2016.0472 PG 11 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA EN9RE UT WOS:000396336500004 PM 28069843 ER PT J AU Song, ZR Rose, S Chernew, ME Safran, DG AF Song, Zirui Rose, Sherri Chernew, Michael E. Safran, Dana Gelb TI Lower- Versus Higher-Income Populations In The Alternative Quality Contract: Improved Quality And Similar Spending SO HEALTH AFFAIRS LA English DT Article ID ACCOUNTABLE CARE ORGANIZATIONS; MEDICARE MANAGED CARE; RACIAL DISPARITIES; GLOBAL PAYMENT; OF-CARE; HEALTH; PERFORMANCE; MASSACHUSETTS; EXPENDITURES; OUTCOMES AB As population-based payment models become increasingly common, it is crucial to understand how such payment models affect health disparities. We evaluated health care quality and spending among enrollees in areas with lower versus higher socioeconomic status in Massachusetts before and after providers entered into the Alternative Quality Contract, a two-sided population-based payment model with substantial incentives tied to quality. We compared changes in process measures, outcome measures, and spending between enrollees in areas with lower and higher socioeconomic status from 2006 to 2012 (outcome measures were measured after the intervention only). Quality improved for all enrollees in the Alternative Quality Contract after their provider organizations entered the contract. Process measures improved 1.2 percentage points per year more among enrollees in areas with lower socioeconomic status than among those in areas with higher socioeconomic status. Outcome measure improvement was no different between the subgroups; neither were changes in spending. Larger or comparable improvements in quality among enrollees in areas with lower socioeconomic status suggest a potential narrowing of disparities. Strong pay-for-performance incentives within a population-based payment model could encourage providers to focus on improving quality for more disadvantaged populations. C1 [Song, Zirui] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Song, Zirui] Harvard Med Sch, Boston, MA 02115 USA. [Rose, Sherri] Harvard Med Sch, Dept Hlth Care Policy, Hlth Care Policy Biostat, Boston, MA USA. [Chernew, Michael E.] Harvard Med Sch, Dept Hlth Care Policy, Hlth Care Policy, Boston, MA USA. [Safran, Dana Gelb] Blue Shield Massachusetts, Blue Cross, Performance Measurement & Improvement, Boston, MA USA. [Safran, Dana Gelb] Tufts Univ, Sch Med, Med, Boston, MA 02111 USA. RP Song, ZR (reprint author), Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA.; Song, ZR (reprint author), Harvard Med Sch, Boston, MA 02115 USA. EM zirui_song@post.harvard.edu FU National Institute on Aging MD/PhD National Research Service Award [F30 AG039175]; Commonwealth Fund FX The study was supported by a National Institute on Aging MD/PhD National Research Service Award (to Zirui Song, No. F30 AG039175) and a grant from the Commonwealth Fund (to Michael Chernew). The views expressed in this article are those of the authors and do not necessarily represent the official views of the National Institute on Aging or the National Institutes of Health. The authors are grateful to Angela Li, Lulu Liu, Matthew Day, and Young Sul for assistance with the data. NR 32 TC 0 Z9 0 U1 1 U2 1 PU PROJECT HOPE PI BETHESDA PA 7500 OLD GEORGETOWN RD, STE 600, BETHESDA, MD 20814-6133 USA SN 0278-2715 J9 HEALTH AFFAIR JI Health Aff. PD JAN PY 2017 VL 36 IS 1 BP 74 EP 82 DI 10.1377/hlthaff.2016.0682 PG 9 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA EN9RE UT WOS:000396336500010 PM 28069849 ER PT J AU Baugh, CW Wang, TJ Caterino, JM Baker, ON Brooks, GA Reust, AC Pallin, DJ AF Baugh, Christopher W. Wang, Thomas J. Caterino, Jeffrey M. Baker, Olesya N. Brooks, Gabriel A. Reust, Audrey C. Pallin, Daniel J. TI Emergency Department Management of Patients With Febrile Neutropenia: Guideline Concordant or Overly Aggressive? SO ACADEMIC EMERGENCY MEDICINE LA English DT Article ID CANCER-PATIENTS; HOSPITAL ADMISSION; COMPLICATIONS; ASSOCIATION; PREDICTION; UPDATE; INDEX; CARE AB ObjectivesThe Infectious Diseases Society of America and the American Society of Clinical Oncology recommend risk stratification of patients with febrile neutropenia (FN) and discharge with oral antibiotics for low-risk patients. We studied guideline concordance and clinical outcomes of FN management in our emergency department (ED). MethodsOur urban, tertiary care teaching hospital provides all emergency and inpatient services to a large comprehensive cancer center. We performed a structured chart review of all FN patients seen in our ED from January 2010 to December 2014. Using electronic medical records, we identified all visits by patients with fever and an absolute neutrophil countof <1000 cells/mm(3) and then included only patients without a clear source of infection. Following national guidelines, we classified patients as low or high risk and assessed guideline concordance in disposition and parenteral versus oral antibiotic therapy by risk category as our main outcome measure. ResultsOf 173 qualifying visits, we classified 44 (25%) as low risk and 129 (75%) as high risk. Management was guideline concordant in 121 (70%, 95% confidence interval [CI]= 63% to 77%). Management was guideline discordant in 43 (98%, 95% CI= 88% to 100%) of low-risk patients versus 9 (7%, 95% CI= 3% to 13%) of high-risk patients (relative risk [RR]= 14, 95% CI= 7.5 to 26). Of 52 guideline-discordant cases, 36 (83%, 95% CI= 72% to 93%) involved low-risk cases with treatment that was more aggressive than recommended. ConclusionsGuideline concordance was low among low-risk patients, with management tending to be more aggressive than recommended. Unless data emerge that undermine the guidelines, we believe that many of these hospitalizations and parenteral antibiotic regimens can be avoided, decreasing the risks associated with hospitalization, while improving antibiotic stewardship and patient comfort. C1 [Baugh, Christopher W.; Baker, Olesya N.; Reust, Audrey C.; Pallin, Daniel J.] Brigham & Womens Hosp, Dept Emergency Med, 75 Francis St, Boston, MA 02115 USA. [Wang, Thomas J.] Harvard Med Sch, Boston, MA USA. [Brooks, Gabriel A.] Dana Farber Canc Inst, Gastrointestinal Canc Ctr, Boston, MA 02115 USA. [Caterino, Jeffrey M.] Ohio State Univ, Dept Emergency Med, Wexner Med Ctr, Columbus, OH 43210 USA. RP Baugh, CW (reprint author), Brigham & Womens Hosp, Dept Emergency Med, 75 Francis St, Boston, MA 02115 USA. EM cbaugh@partners.org FU Milton Fund award at Harvard Medical School FX This study was supported by a Milton Fund award at Harvard Medical School. NR 24 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1069-6563 EI 1553-2712 J9 ACAD EMERG MED JI Acad. Emerg. Med. PD JAN PY 2017 VL 24 IS 1 BP 83 EP 91 DI 10.1111/acem.13079 PG 9 WC Emergency Medicine SC Emergency Medicine GA EK4DD UT WOS:000393876400009 PM 27611638 ER PT J AU Guardado-Mendoza, R Chavez, AO Jimenez-Ceja, LM Hansis-Diarte, A DeFronzo, RA Folli, F Tripathy, D AF Guardado-Mendoza, Rodolfo Chavez, Alberto O. Jimenez-Ceja, Lilia M. Hansis-Diarte, Andrea DeFronzo, Ralph A. Folli, Franco Tripathy, Devjit TI Islet amyloid polypeptide response to maximal hyperglycemia and arginine is altered in impaired glucose tolerance and type 2 diabetes mellitus SO ACTA DIABETOLOGICA LA English DT Article DE Insulin secretion; Amylin; Hyperglycemic clamp ID BETA-CELL APOPTOSIS; ENDOPLASMIC-RETICULUM STRESS; PROHORMONE CONVERTASE PC2; INSULIN-SECRETION; AMYLIN RELEASE; ORAL GLUCOSE; HUMANS; PEPTIDE; MODEL; DETERMINANTS AB Pancreatic islet amyloid deposition is a characteristic feature of type 2 diabetes mellitus (T2DM). Islet amyloid polypeptide (IAPP) is co-secreted with insulin, but its secretion profile and relationship to insulin and C-peptide in response to glucose and non-glucose stimuli has not been clearly defined. Forty subjects (13 NGT, 12 IGT and 15 T2DM) participated in an OGTT and two-step hyperglycemic (225 and 400 mg/dl) clamp (80 min/step) followed by an IV arginine bolus. Acute insulin (AIR), C-peptide (ACPR) and IAPP (AIAR) responses during each hyperglycemic step and following arginine (AIR(Arg)) were assessed. AIR and ACPR during both hyperglycemic steps and after arginine progressively decreased from NGT to IGT to T2DM. Fasting IAPP concentrations were higher in T2DM compared to NGT and IGT subjects. The acute IAPP(0-10) was markedly decreased only in T2DM, while the acute IAPP(80-90) response during the second step (80-160 min) of hyperglycemic clamp and in response to arginine was markedly impaired in both IGT and T2DM. The ratio of IAPP/C-peptide during the first (225 mg/dl) and second step (400 mg/dl), and in response to arginine, was decreased in T2DM versus both NGT and IGT (p < 0.01). The acute IAPP(0-10) correlated with ACPR(0-10) (r = 0.665, p < 0.001) and AIR(0-10) (r = 0.543, p < 0.001). Basal IAPP secretion is higher in T2DM and IGT versus NGT but is reduced in response to hyperglycemia and arginine. The IAPP/C-peptide ratio is reduced with prolonged and more severe hyperglycemia in T2DM individuals. NCT00845182. C1 [Guardado-Mendoza, Rodolfo; Chavez, Alberto O.; Jimenez-Ceja, Lilia M.; Hansis-Diarte, Andrea; DeFronzo, Ralph A.; Folli, Franco; Tripathy, Devjit] Univ Texas Hlth Sci Ctr San Antonio, Diabet Div, 7703 Floyd Curl Dr, San Antonio, TX 78229 USA. [Guardado-Mendoza, Rodolfo; Jimenez-Ceja, Lilia M.] Univ Guanajuato, Div Hlth Sci, Dept Med & Nutr, Guanajuato, Mexico. [Guardado-Mendoza, Rodolfo; Jimenez-Ceja, Lilia M.] Hosp Reg Alta Especialidad Bajio, Dept Invest, Guanajuato, Mexico. [DeFronzo, Ralph A.; Tripathy, Devjit] South Texas Vet Hlth Care Syst, Audie L Murphy VA Hosp, San Antonio, TX USA. RP Tripathy, D (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Diabet Div, 7703 Floyd Curl Dr, San Antonio, TX 78229 USA.; Tripathy, D (reprint author), South Texas Vet Hlth Care Syst, Audie L Murphy VA Hosp, San Antonio, TX USA. EM tripathy@uthscsa.edu FU Takeda Pharmaceuticals FX We thank the nurses on the Bartter Research Unit (BRU) for their diligent care of our patients and especially James King, R.N. and John Kincade RN for carrying out the hyperglycemic clamp studies. The study was supported by a research grant from Takeda Pharmaceuticals to Devjit Tripathy. NR 48 TC 0 Z9 0 U1 1 U2 1 PU SPRINGER-VERLAG ITALIA SRL PI MILAN PA VIA DECEMBRIO, 28, MILAN, 20137, ITALY SN 0940-5429 EI 1432-5233 J9 ACTA DIABETOL JI Acta Diabetol. PD JAN PY 2017 VL 54 IS 1 BP 53 EP 61 DI 10.1007/s00592-016-0904-7 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EK3HF UT WOS:000393816500007 PM 27624579 ER PT J AU Joshi, G AF Joshi, G. TI Are there lessons to be learned from the prevailing patterns of psychotropic drug use in patients with autism spectrum disorder? SO ACTA PSYCHIATRICA SCANDINAVICA LA English DT Editorial Material ID REFERRED POPULATION; PSYCHIATRIC COMORBIDITY; YOUTH C1 [Joshi, G.] Massachusetts Gen Hosp, Alan & Lorraine Bressler Clin & Res Program Austi, Boston, MA 02114 USA. [Joshi, G.] Massachusetts Gen Hosp, Clin & Res Program Pediat Psychopharmacol, Boston, MA 02114 USA. [Joshi, G.] Harvard Med Sch, Dept Psychiat, Boston, MA 02115 USA. [Joshi, G.] MIT, Dept Brain & Cognit Sci, McGovern Inst Brain Res, E25-618, Cambridge, MA 02139 USA. RP Joshi, G (reprint author), Massachusetts Gen Hosp, Alan & Lorraine Bressler Clin & Res Program Austi, Boston, MA 02114 USA.; Joshi, G (reprint author), Massachusetts Gen Hosp, Clin & Res Program Pediat Psychopharmacol, Boston, MA 02114 USA.; Joshi, G (reprint author), Harvard Med Sch, Dept Psychiat, Boston, MA 02115 USA.; Joshi, G (reprint author), MIT, Dept Brain & Cognit Sci, McGovern Inst Brain Res, E25-618, Cambridge, MA 02139 USA. EM joshi.gagan@mgh.harvard.edu FU Alan and Lorraine Bressler Clinical and Research Program for Autism Spectrum Disorder; MGH Pediatric Psychopharmacology Council Fund; National Institute of Mental Health [K23MH100450] FX This work was funded in part by the Alan and Lorraine Bressler Clinical and Research Program for Autism Spectrum Disorder, by the MGH Pediatric Psychopharmacology Council Fund, and by the National Institute of Mental Health grant awarded to Gagan Joshi (#K23MH100450). NR 10 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0001-690X EI 1600-0447 J9 ACTA PSYCHIAT SCAND JI Acta Psychiatr. Scand. PD JAN PY 2017 VL 135 IS 1 BP 5 EP 7 DI 10.1111/acps.12683 PG 3 WC Psychiatry SC Psychiatry GA EN9JE UT WOS:000396315700001 PM 27928827 ER PT J AU Stuart, EA Barry, CL Donohue, JM Greenfield, SF Duckworth, K Song, ZR Mechanic, R Kouri, EM Ebnesajjad, C Chernew, ME Huskamp, HA AF Stuart, Elizabeth A. Barry, Colleen L. Donohue, Julie M. Greenfield, Shelly F. Duckworth, Kenneth Song, Zirui Mechanic, Robert Kouri, Elena M. Ebnesajjad, Cyrus Chernew, Michael E. Huskamp, Haiden A. TI Effects of accountable care and payment reform on substance use disorder treatment: evidence from the initial 3 years of the alternative quality contract SO ADDICTION LA English DT Article DE Accountable care organizations; behavioral health; difference-in-differences; drug abuse treatment; global payment; performance measures ID HEALTH-INSURANCE PARITY; CAUSAL INFERENCE; ABUSE TREATMENT; MENTAL-HEALTH; ADDICTION TREATMENT; IMPACT; INTEGRATION; ADJUSTMENT; MODELS; ACT AB Background and Aims Global payment and accountable care reform efforts in the United States may connect more individuals with substance use disorders (SUD) to treatment. We tested whether such changes instituted under an Alternative Quality Contract (AQC) model within the Blue Cross Blue Shield of Massachusetts' (BCBSMA) insurer increased care for individuals with SUD. Design Difference-in-differences design comparing enrollees in AQC organizations with a comparison group of enrollees in organizations not participating in the AQC. Setting Massachusetts, USA. Participants BCBSMA enrollees aged 13-64 years from 2006 to 2011 (3 years prior to and after implementation) representing 1 333 534 enrollees and 42 801 SUD service users. Measurements Outcomes were SUD service use and spending and SUD performance metrics. Primary exposures were enrollment into an AQC provider organization and whether the AQC organization did or did not face risk for behavioral health costs. Findings Enrollees in AQC organizations facing behavioral health risk experienced no change in the probability of using SUD services (1.64 versus 1.66%; P = 0.63), SUD spending ($2807 versus $2700; P = 0.34) or total spending ($12 631 versus $12 849; P = 0.53), or SUD performance metrics (identification: 1.73 versus 1.76%, P = 0.57; initiation: 27.86 versus 27.02%, P = 0.50; engagement: 11.19 versus 10.97%, P = 0.79). Enrollees in AQC organizations not at risk for behavioral health spending experienced a small increase in the probability of using SUD services (1.83 versus 1.66%; P = 0.003) and the identification performance metric (1.92 versus 1.76%; P = 0.007) and a reduction in SUD medication use (11.84 versus 14.03%; P = 0.03) and the initiation performance metric (23.76 versus 27.02%; P = 0.005). Conclusions A global payment and accountable care model introduced in Massachusetts, USA (in which a health insurer provided care providers with fixed prepayments to cover most or all of their patients' care during a specified time-period, incentivizing providers to keep their patients healthy and reduce costs) did not lead to sizable changes in substance use disorder service use during the first 3 years following its implementation. C1 [Stuart, Elizabeth A.; Ebnesajjad, Cyrus] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Mental Hlth, Baltimore, MD 21205 USA. [Barry, Colleen L.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Hlth Policy & Management, Baltimore, MD 21205 USA. [Donohue, Julie M.] Univ Pittsburgh, Sch Publ Hlth, Dept Hlth Policy & Management, Pittsburgh, PA 15260 USA. [Greenfield, Shelly F.] Harvard Med Sch, McLean Hosp, Belmont, MA USA. [Duckworth, Kenneth] Blue Cross & Blue Shield Massachusetts, Boston, MA USA. [Song, Zirui] Harvard Med Sch, Massachusetts Gen Hosp, Dept Med, Boston, MA USA. [Kouri, Elena M.; Chernew, Michael E.; Huskamp, Haiden A.] Harvard Med Sch, Dept Hlth Care Policy, Boston, MA USA. [Mechanic, Robert] Brandeis Univ, Heller Sch Social Policy & Management, Waltham, MA USA. RP Stuart, EA (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, 624 North Broadway,Room 804, Baltimore, MD 21205 USA. EM estuart@jhu.edu FU National Institute on Drug Abuse [R01 DA035214, K24DA019855]; National Institute on Aging [F30-AG039175] FX We thank Dana Gelb Safran PhD at Blue Cross Blue Shield of Massachusetts (BCBSMA) and Jeffrey Simmons MD, formerly of BCBSMA, for their support of the project, and Christina Fu PhD and Hocine Azeni MA of Harvard Medical School for expert programming support. We gratefully acknowledge funding support from the National Institute on Drug Abuse (R01 DA035214; multi-principal investigator: C.L.B. and H.A.H.; K24DA019855, S.F.G.) and the National Institute on Aging (F30-AG039175, Z.S.). NR 32 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0965-2140 EI 1360-0443 J9 ADDICTION JI Addiction PD JAN PY 2017 VL 112 IS 1 BP 124 EP 133 DI 10.1111/add.13555 PG 10 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA EK4NR UT WOS:000393904300025 PM 27517740 ER PT J AU Durazzo, TC Meyerhoff, DJ AF Durazzo, Timothy C. Meyerhoff, Dieter J. TI Psychiatric, Demographic, and Brain Morphological Predictors of Relapse After Treatment for an Alcohol Use Disorder SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article DE Relapse; Alcohol Use Disorders; Magnetic Resonance Imaging; Mood Disorders; Cigarette Smoking ID CHRONIC CIGARETTE-SMOKING; ANTERIOR CINGULATE CORTEX; SUBSTANCE USE DISORDERS; DEPENDENT PATIENTS; SURFACE-AREA; DRINKING; ABSTINENCE; DEPRESSION; RECOVERY; OUTCOMES AB Background: Relapse in alcohol use disorders (AUD) is related to a complex interplay among multiple biological, psychiatric, psychological, and psychosocial factors, which may change dynamically during and after treatment. At treatment entry for AUD, morphological abnormalities in anterior frontal regions and the insula have been observed in those who ultimately relapse following treatment. The goal of this study was to determine whether anterior frontal and insula measures of brain thickness, surface area, and volume predict posttreatment drinking status (i.e., relapser or abstainer) over an extended period after outpatient treatment for AUD, while concurrently considering common psychiatric, psychological, and psychosocial factors previously associated with relapse. Methods: Alcohol-dependent individuals (n = 129) were followed for 18 months after treatment to determine posttreatment drinking status (abstainers [n = 47] or relapsers [n = 82]). Brain morphometrics were derived from FreeSurfer. Receiver operating characteristic (ROC) curve analysis was used to identify the regional brain thickness, surface area, and volume (all scaled to intracranial volume), demographic, psychiatric, other substance use (e.g., cigarette smoking), and alcohol consumption variables, obtained at entry into treatment, that best predicted posttreatment drinking status. Survival analyses determined variables that were related to duration of abstinence after treatment. Results: ROC analyses indicated that mood disorders, education, and volumes of the right caudal anterior cingulate cortex (ACC), right rostral ACC, and total right frontal gray matter were significant predictors of posttreatment drinking status. Among relapsers, survival analyses showed smokers and individuals with a comorbid medical condition relapsed earlier after treatment. Additionally, a greater frequency of smokers relapsed within 6 months of AUD treatment. Conclusions: Results reinforce that relapse in AUD is a function of multiple biological, psychiatric, psychological, and psychosocial factors. Effective treatment of depressive disorders and cigarette smoking concurrent with AUD-focused interventions may promote better treatment outcomes. C1 [Durazzo, Timothy C.] Stanford Univ, Sch Med, Dept Psychiat & Behav Sci, Stanford, CA USA. [Durazzo, Timothy C.] VA Palo Alto Hlth Care Syst, Mental Illness Res & Educ Clin Ctr, Palo Alto, CA USA. [Durazzo, Timothy C.] VA Palo Alto Hlth Care Syst, Sierra Pacific War Related Illness & Injury Study, Palo Alto, CA USA. [Meyerhoff, Dieter J.] Univ Calif San Francisco, Dept Radiol & Biomed Imaging, San Francisco, CA 94143 USA. [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, War Related Illness & Injury Study Ctr, Mental Illness Res & Educ Clin Ctr, 151Y,3801 Miranda Ave, Palo Alto, CA 94304 USA. EM tdurazzo@stanford.edu FU National Institutes of Health [AA10788, DA24136] FX This study was supported by National Institutes of Health (AA10788 to DJM and DA24136 to TCD) and with resources and the use of facilities at the San Francisco VA Medical Center and the VA Palo Alto Health Care System. We thank Dr. Ellen Herbst, Ricky Chen, and colleagues of the Veterans Administration Substance Abuse Day Hospital and Dr. David Pating and colleagues at the Kaiser Permanente Chemical Dependency Recovery Program in San Francisco for their valuable assistance in participant recruitment. We thank Drs. Stefan Gazdzinski and Anderson Mon for MR data acquisition and Thomas Schmidt for assistance with psychiatric assessments and cohort maintenance. We also wish to extend our gratitude to our participants, who made this research possible. NR 64 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-6008 EI 1530-0277 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JAN PY 2017 VL 41 IS 1 BP 107 EP 116 DI 10.1111/acer.13267 PG 10 WC Substance Abuse SC Substance Abuse GA EK4IQ UT WOS:000393890700012 PM 27883214 ER PT J AU Wordingham, SE Swetz, KM AF Wordingham, Sara E. Swetz, Keith M. TI Can Anyone Be Prepared Enough for Life With an LVAD-DT? SO AMERICAN JOURNAL OF BIOETHICS LA English DT Editorial Material ID MECHANICAL CIRCULATORY SUPPORT; PALLIATIVE CARE C1 [Wordingham, Sara E.] Mayo Clin, Coll Med, Phoenix, AZ USA. [Swetz, Keith M.] Univ Alabama, Sch Med, UAB Ctr Palliat & Support Care, Tuscaloosa, AL 35487 USA. [Swetz, Keith M.] Birmingham Vet Affairs Med Ctr, Birmingham, AL USA. RP Wordingham, SE (reprint author), Mayo Clin, Mayo Clin Arizona, Coll Med, Med,Palliat Med, 5777 E Mayo Blvd, Phoenix, AZ 85054 USA. EM wordingham.sara@mayo.edu NR 10 TC 0 Z9 0 U1 0 U2 0 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1526-5161 EI 1536-0075 J9 AM J BIOETHICS JI Am. J. Bioeth. PY 2017 VL 17 IS 2 BP 14 EP 16 PG 3 WC Ethics; Medical Ethics; Social Issues; Social Sciences, Biomedical SC Social Sciences - Other Topics; Medical Ethics; Social Issues; Biomedical Social Sciences GA EL5IN UT WOS:000394654900007 PM 28112619 ER PT J AU Rosenberg, LB Doolittle, D AF Rosenberg, Leah B. Doolittle, David TI Learn and Live?: Understanding the Cultural Focus on Nonbeneficial Cardiopulmonary Resuscitation (CPR) as a Response to Existential Distress About Death and Dying SO AMERICAN JOURNAL OF BIOETHICS LA English DT Editorial Material C1 [Rosenberg, Leah B.; Doolittle, David] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Rosenberg, LB (reprint author), Massachusetts Gen Hosp, Palliat Care, 600 Founders, Boston, MA 02114 USA. EM lbrosenberg@partners.org NR 5 TC 0 Z9 0 U1 0 U2 0 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1526-5161 EI 1536-0075 J9 AM J BIOETHICS JI Am. J. Bioeth. PY 2017 VL 17 IS 2 BP 54 EP 55 PG 2 WC Ethics; Medical Ethics; Social Issues; Social Sciences, Biomedical SC Social Sciences - Other Topics; Medical Ethics; Social Issues; Biomedical Social Sciences GA EL5IN UT WOS:000394654900023 PM 28112614 ER PT J AU Kendrick, JB Zelnick, L Chonchol, MB Siscovick, D Hoofnagle, AN Ix, JH Sarnak, M Shlipak, MG Kestenbaum, B de Boer, IH AF Kendrick, Jessica B. Zelnick, Leila Chonchol, Michel B. Siscovick, David Hoofnagle, Andrew N. Ix, Joachim H. Sarnak, Mark Shlipak, Michael G. Kestenbaum, Bryan de Boer, Ian H. TI Serum Bicarbonate Is Associated with Heart Failure in the Multi-Ethnic Study of Atherosclerosis SO AMERICAN JOURNAL OF NEPHROLOGY LA English DT Article DE Cardiovascular disease; Bicarbonate; Heart failure; Arterial stiffness; Left ventricular mass ID INCIDENT CARDIOVASCULAR-DISEASE; CHRONIC KIDNEY-DISEASE; NUTRITION EXAMINATION SURVEY; STAGE RENAL-DISEASE; METABOLIC-ACIDOSIS; ANION GAP; VASCULAR CALCIFICATION; PLASMA BICARBONATE; BODY-COMPOSITION; NATIONAL-HEALTH AB Background: Low serum bicarbonate concentrations are associated with mortality and kidney disease progression. Data regarding associations between bicarbonate and cardiovascular disease (CVD) are scarce. Methods: We performed a cohort study of 6,229 adult participants from the Multi-Ethnic Study of Atherosclerosis, a community-based cohort free of CVD at baseline. Serum bicarbonate was measured at baseline. Cardiovascular outcomes were defined as: (1) subclinical CVD (left ventricular mass [LVM] and aortic pulse pressure [PP] measured at baseline), (2) incident atherosclerotic cardiovascular events (CVE; composite of myocardial infarction, resuscitated cardiac arrest, stroke, coronary heart disease death, and stroke death), and (3) incident heart failure. Results: During a median (interquartile range) follow-up of 8.5 (7.7-8.6) years, 331 (5.3%) participants had an incident CVE and 174 (2.8%) developed incident heart failure. We stratified analyses by use of diuretics because we observed a significant interaction between diuretic use and bicarbonate with study outcomes. Among diuretic nonusers, with adjustment, bicarbonate 25 mEq/L was associated with an estimated 3.0 g greater LVM (95% CI 0.5-5.0) and 1.0 mm Hg higher aortic PP (95% CI 0.4-2.0) compared to bicarbonate 23-24 mEq/L. Each 1 mEq/L of bicarbonate increase was associated with a 13% higher risk of incident heart failure (hazards ratio 1.13, 95% CI 1.01-2.11). Among diuretic users, higher bicarbonate was not associated with CVD. Bicarbonate was not associated with incident atherosclerotic CVE irrespective of diuretic use. Conclusion: Among nonusers of diuretics in a large community-based study, higher serum bicarbonate concentrations are associated with subclinical CVD and new heart failure. (C) 2016 S. Karger AG, Basel. C1 [Kendrick, Jessica B.; Chonchol, Michel B.] Univ Colorado, Sch Med, Div Renal Dis & Hypertens, Aurora, CO USA. [Kendrick, Jessica B.] Denver Hlth Med Ctr, Denver, CO USA. [Zelnick, Leila; Kestenbaum, Bryan; de Boer, Ian H.] Univ Washington, Kidney Res Inst, Div Nephrol, Seattle, WA 98195 USA. [Hoofnagle, Andrew N.] Univ Washington, Dept Lab Med, Seattle, WA 98195 USA. [Siscovick, David] New York Acad Med, New York, NY USA. [Ix, Joachim H.] Univ Calif San Diego, Dept Med, Div Nephrol & Hypertens, San Diego, CA 92103 USA. [Sarnak, Mark] Tufts Med Ctr, Div Nephrol, Boston, MA USA. [Shlipak, Michael G.] San Francisco VA Med Ctr, Div Gen Internal Med, San Francisco, CA USA. [Shlipak, Michael G.] Univ Calif San Francisco, San Francisco, CA 94143 USA. RP Kendrick, JB (reprint author), Univ Colorado, Denver Hlth Med Ctr, Div Renal Dis & Hypertens, 660 Bannock St,Mail Code 4000, Denver, CO 80204 USA. EM Jessica.Kendrick@ucdenver.edu FU National Institute of Diabetes and Digestive and Kidney Disease [K23 DK087859, 1R01DK081473, R01DK088762, R01DK099199, R01DK098234]; American Heart Association [14EIA18560026]; National Heart, Lung, and Blood Institute [R01HL096875, HHSN268201500003I, N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169]; NCRR [UL1-TR-000040, UL1-TR-001079] FX This work was supported by the National Institute of Diabetes and Digestive and Kidney Disease grants K23 DK087859, 1R01DK081473, R01DK088762, and R01DK099199, R01DK098234, National Heart, Lung, and Blood Institute grant R01HL096875, and an Established Investigator Award from the American Heart Association (14EIA18560026). This research was supported by contracts HHSN268201500003I, N01-HC-95159, N01-HC-95160, N01-HC-95161,N01-HC-95162,N01-HC-95163, N01-HC-95164, N01-HC-95165,N01-HC-95166,N01-HC-95167, N01-HC-95168, and N01-HC-95169 from the National Heart, Lung, and Blood Institute and by grants UL1-TR-000040 and UL1-TR-001079 from NCRR. The authors thank the other investigators, the staff, and the participants of the MESA study for their valuable contributions. A full list of participating MESA investigators and institutions can be found at http://www.mesa-nhlbi.org. NR 43 TC 1 Z9 1 U1 0 U2 0 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 0250-8095 EI 1421-9670 J9 AM J NEPHROL JI Am. J. Nephrol. PY 2017 VL 45 IS 2 BP 118 EP 126 DI 10.1159/000454783 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA EK4YR UT WOS:000393934600004 PM 27941322 ER PT J AU Caballero, D Li, YW Ponsetto, J Zhu, CL Bergwitz, C AF Caballero, Daniel Li, Yuwen Ponsetto, Julian Zhu, Chuanlong Bergwitz, Clemens TI Impaired urinary osteopontin excretion in Npt2a(-/-) mice SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE hypophosphatemia; nephrocalcinosis; NPT2a; osteopontin; rickets ID HEREDITARY HYPOPHOSPHATEMIC RICKETS; SODIUM-PHOSPHATE COTRANSPORTER; X-LINKED HYPOPHOSPHATEMIA; RANDALLS PLAQUES; HYP MOUSE; HYPERCALCIURIA; MUTATIONS; NEPHROCALCINOSIS; KIDNEY; MODEL AB Mutations in the renal sodiumdependent phosphate cotransporters NPT2a and NPT2c have been reported in patients with renal stone disease and nephrocalcinosis. Oral phosphate supplementation is currently thought to reduce risk by reversing the hypercalciuria, but the exact mechanism remains unclear and the relative contribution of modifiers of mineralization such as osteopontin (Opn) to the formation of renal mineral deposits in renal phosphate wasting disorders has not been studied. We observed a marked decrease of renal gene expression and urinary excretion of Opn in Npt2a (-/-) mice, a mouse model of these disorders, at baseline. Following supplementation with phosphate Opn gene expression was restored to wild-type levels in Npt2a (-/-) mice; however, urine excretion of the protein remained low. To further investigate the role of Opn, we used a double-knockout strategy, which provides evidence that loss of Opn worsens the nephrocalcinosis and nephrolithiasis observed in these mice on a high-phosphate diet. These studies suggest that impaired Opn gene expression and urinary excretion in Npt2a (-/-) mice may be an additional risk factor for nephrolithiasis, and normalizing urine Opn levels may improve the therapy of phosphaturic disorders. C1 [Caballero, Daniel; Ponsetto, Julian; Bergwitz, Clemens] Yale Univ, Sch Med, Sect Endocrinol & Metab, New Haven, CT USA. [Li, Yuwen] Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA. [Li, Yuwen] Harvard Med Sch, Boston, MA USA. Massachusetts Gen Hosp, Pediat Nephrol Unit, Boston, MA 02114 USA. [Li, Yuwen] Nanjing Med Univ, Affiliated Hosp 1, Dept Pediat, Nanjing, Jiangsu, Peoples R China. [Zhu, Chuanlong] Nanjing Med Univ, Affiliated Hosp 1, Dept Infect Dis, Nanjing, Jiangsu, Peoples R China. Yale Univ, Sch Med, Dept Pathol, New Haven, CT 06510 USA. RP Bergwitz, C (reprint author), Yale Univ, Sch Med, Anlyan Ctr, Sect Endocrinol & Metab, Off S117,Lab S110,1 Gilbert St, New Haven, CT 06519 USA. EM clemens.bergwitz@yale.edu FU National Institute of Diabetes and Digestive and Kidney Diseases [5K08-DK-078361]; National Kidney Foundation; American Association for Clinical Investigation; National Natural Science Foundation of China [81271713]; Scientific research fund of Anhui Medical University [2011xkj074] FX Support for this study was provided by National Institute of Diabetes and Digestive and Kidney Diseases Grant 5K08-DK-078361 (to C. Bergwitz), Young Investigator Awards by the National Kidney Foundation, and the American Association for Clinical Investigation (to C. Bergwitz), National Natural Science Foundation of China Grant 81271713 (to C. Zhu), and Scientific research fund of Anhui Medical University 2011xkj074 to Yuwen Li. NR 28 TC 0 Z9 0 U1 1 U2 1 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1931-857X EI 1522-1466 J9 AM J PHYSIOL-RENAL JI Am. J. Physiol.-Renal Physiol. PD JAN 1 PY 2017 VL 312 IS 1 BP F77 EP F83 DI 10.1152/ajprenal.00367.2016 PG 7 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA EK4LG UT WOS:000393897600008 PM 27784695 ER PT J AU David, V Francis, C Babitt, JL AF David, Valentin Francis, Connor Babitt, Jodie L. TI Ironing out the cross talk between FGF23 and inflammation SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Review DE fibroblast growth factor 23; mineral metabolism; iron; chronic kidney disease ID GROWTH-FACTOR 23; CHRONIC KIDNEY-DISEASE; CHRONIC-RENAL-FAILURE; DOMINANT HYPOPHOSPHATEMIC RICKETS; LEFT-VENTRICULAR HYPERTROPHY; FAMILIAL TUMORAL CALCINOSIS; VITAMIN-D; ENDOTHELIAL DYSFUNCTION; PARATHYROID-HORMONE; DEHYDROEPIANDROSTERONE-SULFATE AB The bone-secreted hormone fibroblast growth factor 23 (FGF23) has an essential role in phosphate homeostasis by regulating expression of the kidney proximal tubule sodium-phosphate cotrans-porters as well as parathyroid hormone levels. Induction of FGF23 early in chronic kidney disease (CKD) helps to maintain normal phosphorous levels. However, high FGF23 levels become pathological as kidney disease progresses and are associated with an increased risk of CKD progression, cardiovascular events, and death. The factors responsible for increasing FGF23 levels early in CKD are unknown, but recent work has proposed a role for inflammation and disordered iron homeostasis. Notably, FGF23 has recently been shown to elicit an inflammatory response and to display immunomodulatory properties. Here, we will review emerging evidence on the cross talk between inflammation, iron, FGF23, and bone and mineral metabolism and discuss the relevance for CKD patients. C1 [David, Valentin; Francis, Connor] Northwestern Univ, Feinberg Sch Med, Inst Publ Hlth & Med, Dept Med,Div Nephrol & Hypertens, Chicago, IL 60611 USA. [David, Valentin; Francis, Connor] Northwestern Univ, Feinberg Sch Med, Ctr Translat Metab & Hlth, Inst Publ Hlth & Med, Chicago, IL 60611 USA. [Babitt, Jodie L.] Massachusetts Gen Hosp, Harvard Med Sch, Div Nephrol, Program Membrane Biol, Boston, MA 02114 USA. [Babitt, Jodie L.] Massachusetts Gen Hosp, Harvard Med Sch, Ctr Syst Biol, Boston, MA 02114 USA. RP Babitt, JL (reprint author), Massachusetts Gen Hosp, 185 Cambridge St,CPZN 8208, Boston, MA 02114 USA. EM Babitt.jodie@mgh.harvard.edu FU National Institute of Diabetes and Digestive and Kidney Diseases [R01-DK-102815, R01-DK-087727]; Howard Goodman Fellowship Award from Massachusetts General Hospital FX This study was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grants R01-DK-102815 to V. David and R01-DK-087727 to J. L. Babitt and by a Howard Goodman Fellowship Award from the Massachusetts General Hospital to J. L. Babitt. NR 102 TC 0 Z9 0 U1 0 U2 0 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1931-857X EI 1522-1466 J9 AM J PHYSIOL-RENAL JI Am. J. Physiol.-Renal Physiol. PD JAN 1 PY 2017 VL 312 IS 1 BP F1 EP F8 DI 10.1152/ajprenal.00359.2016 PG 8 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA EK4LG UT WOS:000393897600001 PM 27582104 ER PT J AU Kersten, S Arjona, FJ AF Kersten, Simone Arjona, Francisco J. TI Ion transport in the zebrafish kidney from a human disease angle: possibilities, considerations, and future perspectives SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Review DE zebrafish; kidney; ion reabsorption; human disease; translational value ID MITOCHONDRION-RICH CELLS; SLC26 ANION TRANSPORTERS; DISTAL CONVOLUTED TUBULE; CALCIUM-SENSING RECEPTOR; DANIO-RERIO LARVAE; CHLORIDE UPTAKE; FRESH-WATER; MOUSE MODEL; SENSORINEURAL DEAFNESS; MALPIGHIAN TUBULES AB Unique experimental advantages, such as its embryonic/larval transparency, high-throughput nature, and ease of genetic modification, underpin the rapid emergence of the zebrafish (Danio rerio) as a preeminent model in biomedical research. Particularly in the field of nephrology, the zebrafish provides a promising model for studying the physiological implications of human solute transport processes along consecutive nephron segments. However, although the zebrafish might be considered a valuable model for numerous renal ion transport diseases and functional studies of many channels and transporters, not all human renal electrolyte transport mechanisms and human diseases can be modeled in the zebrafish. With this review, we explore the ontogeny of zebrafish renal ion transport, its nephron structure and functi-on, and thereby demonstrate the clinical translational value of this model. By critical assessment of genomic and amino acid conservation of human proteins involved in renal ion handling (channels, transporters, and claudins), kidney and nephron segment conservation, and renal electrolyte transport physiology in the zebrafish, we provide researchers and nephrologists with an indication of the possibilities and considerations of the zebrafish as a model for human renal ion transport. Combined with advanced techniques envisioned for the future, implementation of the zebrafish might expand beyond unraveling pathophysiological mechanisms that underlie distinct genetic or environmentally, i.e., pharmacological and lifestyle, induced renal transport deficits. Specifically, the ease of drug administration and the exploitation of improved genetic approaches might argue for the adoption of the zebrafish as a model for preclinical personalized medicine for distinct renal diseases and renal electrolyte transport proteins. C1 [Kersten, Simone; Arjona, Francisco J.] Radboud Univ Nijmegen, Med Ctr, Radboud Inst Mol Life Sci, Dept Physiol, Nijmegen, Netherlands. [Kersten, Simone] Massachusetts Gen Hosp, Dept Med, Div Nephrol, Charlestown, MA USA. RP Arjona, FJ (reprint author), Radboud Univ Nijmegen, Med Ctr, Radboud Inst Mol Life Sci, Dept Physiol 286, POB 9101, NL-6500 HB Nijmegen, Netherlands. EM Francisco.ArjonaMadueno@radboudumc.nl FU exchange program "Beyond the Frontiers" (Radboud Honors Academy); European Renal Association European Dialysis and Transplant Association [ERA LTF 175-2014] FX S. Kersten is supported by the exchange program "Beyond the Frontiers" (Radboud Honors Academy), which has allowed her to pursue this review. This work was supported by fellowships from the European Renal Association European Dialysis and Transplant Association to F. Arjona (ERA LTF 175-2014 and WGIKD Impulsion Grant). NR 149 TC 0 Z9 0 U1 0 U2 0 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1931-857X EI 1522-1466 J9 AM J PHYSIOL-RENAL JI Am. J. Physiol.-Renal Physiol. PD JAN 1 PY 2017 VL 312 IS 1 BP F172 EP F189 DI 10.1152/ajprenal.00425.2016 PG 18 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA EK4LG UT WOS:000393897600016 PM 27852607 ER PT J AU Cotton, AJ Shipley, LJ Glynn, LH Tracy, J Saxon, AJ AF Cotton, Ann J. Shipley, Leandra J. Glynn, Lisa H. Tracy, Josie Saxon, Andrew J. TI Methadone "callbacks" within a veterans affairs opioid treatment program: Detecting methadone misuse SO AMERICAN JOURNAL ON ADDICTIONS LA English DT Article ID BUPRENORPHINE AB Background and ObjectivesA callback requires patients to bring in take-home methadone doses for inspection. An opioid treatment program (OTP) quality-improvement project examined random versus for-cause callbacks. MethodEighty-two random callbacks and 60 for-cause callbacks were conducted among patients enrolled in an OTP (N=183). ResultsAmong patients with more take home doses, 6% of random callbacks versus 44% of for-cause callbacks were failed. Among patients with fewer take home doses, 36% of for-cause callbacks were failed. Discussion and ConclusionsFor-cause callbacks are more useful than random ones. Scientific SignificanceFor-cause callbacks based on clinical judgment detect methadone misuse. (Am J Addict 2017;26:50-52) C1 [Cotton, Ann J.; Shipley, Leandra J.; Glynn, Lisa H.; Tracy, Josie] US Dept Vet Affairs Puget Sound Hlth Care Syst, Seattle, WA USA. [Cotton, Ann J.; Saxon, Andrew J.] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. [Shipley, Leandra J.; Glynn, Lisa H.; Tracy, Josie; Saxon, Andrew J.] Vet Affairs Puget Sound Hlth Care Syst, Ctr Excellence Subst Abuse Treatment & Educ, Seattle, WA USA. RP Cotton, AJ (reprint author), Univ Washington, VAPSHCS, Dept Psychiat & Behav Sci, MS 116-DDTP,1660 South Columbian, Seattle, WA 98108 USA. EM ann.cotton2@va.gov NR 10 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1055-0496 EI 1521-0391 J9 AM J ADDICTION JI Am. J. Addict. PD JAN PY 2017 VL 26 IS 1 BP 50 EP 52 DI 10.1111/ajad.12479 PG 3 WC Substance Abuse SC Substance Abuse GA EK4FJ UT WOS:000393882200005 PM 28005315 ER PT J AU Zhou, ES AF Zhou, Eric S. TI Improving the Comprehensive Care of Patients With Hypersomnia Disorders: A Commentary on "Behavioral Sleep Medicine Services for Hypersomnia Disorders: A Survey Study" SO BEHAVIORAL SLEEP MEDICINE LA English DT Editorial Material ID NARCOLEPSY C1 [Zhou, Eric S.] Harvard Med Sch, Boston Childrens Hosp, Dana Farber Canc Inst, Boston, MA USA. RP Zhou, ES (reprint author), 450 Brookline Ave, Boston, MA 02215 USA. EM eric_zhou@dfci.harvard.edu NR 5 TC 0 Z9 0 U1 1 U2 1 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1540-2002 EI 1540-2010 J9 BEHAV SLEEP MED JI Behav. Sleep Med. PY 2017 VL 15 IS 2 BP 85 EP 86 DI 10.1080/15402002.2016.1253356 PG 2 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA EK2WY UT WOS:000393788800002 PM 27849365 ER PT J AU Rosenbaum, MW Jones, M Dudley, JC Le, LP Iafrate, AJ Pitman, MB AF Rosenbaum, Matthew W. Jones, Martin Dudley, Jonathan C. Le, Long P. Iafrate, A. John Pitman, Martha B. TI Next-Generation Sequencing Adds Value to the Preoperative Diagnosis of Pancreatic Cysts SO CANCER CYTOPATHOLOGY LA English DT Article DE adenocarcinoma mucinous; carcinoma; DNA sequencing; early detection of cancer; endoscopy; digestive system; molecular sequence data; pancreas; pancreatic cyst; pancreatic ductal; pancreatic neoplasms ID PAPILLARY MUCINOUS NEOPLASMS; EPITHELIAL ATYPIA; RISK-ASSESSMENT; FLUID; MALIGNANCY; MANAGEMENT; CYTOPATHOLOGY; PREVALENCE; GUIDELINES; CYTOLOGY AB BACKGROUND: The diagnosis of a pancreatic cyst as mucinous or high-risk dictates the need for follow-up or surgery. Molecular analysis of aspirated pancreatic cyst fluid (PCF) can provide valuable information not obtained by carcinoembryonic antigen (CEA) analysis or cytology. METHODS: All patients who underwent molecular analysis of PCF between March 2013 and June 2015 were reviewed, including pathology, imaging, and follow-up. Molecular testing was performed using a patented, anchored multiplex polymerase chain reaction next-generation sequencing (NGS) platform, which sequenced numerous hotspots in 39 genes linked with malignancy. Performance of NGS and cytology was calculated using final outcome, as determined by clinicopathologic follow-up. RESULTS: The study cohort included 113 PCFs from 105 patients. In total, 119 variants were detected in 67 PCFs (59%). Variants were more common in intraductal papillary mucinous neoplasms (IPMNs)/cancer than in nonmucinous cysts (P<. 005). The inclusion of v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS)/guanine nucleotide-binding protein (GNAS) variants improved the classification of IPMNs as mucinous from 50% by microscopy to 100%. Seventy-five percent of cancers had high-grade atypia versus 0% of IPMNs and nonmucinous cysts (P<. 002). Variants in tumor protein 53 (TP53), SMAD family member 4 (SMAD4), cycl-independent kinase inhibitor 2A (CDKN2A), and notch1 (NOTCH1) were detected only in malignant cysts. Cytology was similarly specific (100%) for detecting malignant cysts but was more sensitive than the identification of late mutations by NGS (75% vs 46%). CONCLUSIONS: The detection of KRAS/GNAS variants improves the identification of mucinous neoplasms. Variants in TP53, SMAD4, CDKN2A, and NOTCH1 support the diagnosis of a high-risk cyst requiring surgery or additional sampling. Although molecular analysis is not a replacement for cytopathology, it does provide valuable information for accurate preoperative diagnosis, helping to classify mucinous neoplasms and high-risk cysts that require surgical resection. (C) 2016 American Cancer Society. C1 [Rosenbaum, Matthew W.; Le, Long P.; Iafrate, A. John; Pitman, Martha B.] Massachusetts Gen Hosp, Dept Pathol, Warren 219,55 Fruit St, Boston, MA 02114 USA. [Jones, Martin] Concord Repatriat Gen Hosp, Dept Anat Pathol, Sydney, NSW, Australia. [Dudley, Jonathan C.] Stanford Univ, Dept Pathol, Stanford, CA 94305 USA. RP Rosenbaum, MW (reprint author), Massachusetts Gen Hosp, Dept Pathol, Warren 219,55 Fruit St, Boston, MA 02114 USA. EM mrosenbaum2@partners.org FU ArcherDX FX Long P. Le and A. John Iafrate have a patent with the US Patent Office, receive royalties for anchored multiplex-PCR technology, and have equity in and receive royalties from ArcherDX. In addition, A. John Iafrate reports personal fees from ArcherDX during the conduct of the study and personal fees from Roche outside the submitted work. Long P. Le reports personal fees from ArcherDX outside the submitted work. NR 24 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1934-662X EI 1934-6638 J9 CANCER CYTOPATHOL JI Cancer Cytopathol. PD JAN PY 2017 VL 125 IS 1 BP 41 EP 47 DI 10.1002/cncy.21775 PG 7 WC Oncology; Pathology SC Oncology; Pathology GA EK4KN UT WOS:000393895600006 PM 27647802 ER PT J AU Kelley, MJ Jha, G Shoemaker, D Herndon, JE Gu, L Barry, WT Crawford, J Ready, N AF Kelley, Michael J. Jha, Gautam Shoemaker, Debra Herndon, James E., II Gu, Lin Barry, William T. Crawford, Jeffrey Ready, Neal TI Phase II Study of Dasatinib in Previously Treated Patients with Advanced Non-Small Cell Lung Cancer SO CANCER INVESTIGATION LA English DT Article DE Non-small cell lung cancer; Src; gene expression ID STATISTICS; ERLOTINIB; TRIAL AB The Src pathway in activated in about one-third of non-small cell lung cancer (NSCLC) tumors. Dasatinib has Src-inhibitor activity. We examined the activity of dasatinib in 37 patients with advanced, previously treated NSCLC. Among the 29 patients who underwent pre-treatment biopsy for RNA biomarker analysis, 25 were treated with dasatinib 70 mg twice daily. There were no responses. Five patients discontinued treatment due to toxicity. Three patients hadminor biopsy-related pneumothoraces. Given the lack of responses, no biomarkers were analyzed. Dasatinib 70 mg twice daily does not have activity nor is it well tolerated in unselected patients with advanced stage, previously treated NSCLC. C1 [Kelley, Michael J.; Crawford, Jeffrey; Ready, Neal] Duke Univ, Med Ctr, Dept Med, Div Med Oncol, Durham, NC 27710 USA. [Kelley, Michael J.; Shoemaker, Debra; Herndon, James E., II; Gu, Lin; Barry, William T.; Crawford, Jeffrey; Ready, Neal] Duke Univ, Med Ctr, Duke Canc Inst, Durham, NC USA. [Kelley, Michael J.] Durham Vet Affairs Med Ctr, Med Serv, Durham, NC USA. [Jha, Gautam] Univ Minnesota, Dept Med, Div Hematol Oncol & Transplantat, Minneapolis, MN 55455 USA. [Barry, William T.] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. RP Kelley, MJ (reprint author), 508 Fulton St,Hem Onc 111G, Durham, NC 27705 USA. EM kelleym@duke.edu FU Bristol Myers Squibb; Department of Veterans Affairs FX Dr. Kelley received grant support from Bristol Myers Squibb during conducting of the study. This work was funded by a grant from Bristol Myers Squibb. The Department of Veterans Affairs provided indirect research support for the clinical trial at the Durham VA Medical Center. NR 11 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 0735-7907 EI 1532-4192 J9 CANCER INVEST JI Cancer Invest. PY 2017 VL 35 IS 1 BP 32 EP 35 DI 10.1080/07357907.2016.1253710 PG 4 WC Oncology SC Oncology GA EK4OI UT WOS:000393906100003 PM 27911119 ER PT J AU Ramos, JD Casey, MF Crabb, SJ Bamias, A Harshman, LC Wong, YN Bellmunt, J De Giorgi, U Ladoire, S Powles, T Pal, SK Niegisch, G Recine, F Alva, A Agarwal, N Necchi, A Vaishampayan, UN Rosenberg, JE Galsky, MD Yu, EY AF Ramos, Jorge D. Casey, Martin F. Crabb, Simon J. Bamias, Aristotelis Harshman, Lauren C. Wong, Yu-Ning Bellmunt, Joaquim De Giorgi, Ugo Ladoire, Sylvain Powles, Thomas Pal, Sumanta K. Niegisch, Guenter Recine, Federica Alva, Ajjai Agarwal, Neeraj Necchi, Andrea Vaishampayan, Ulka N. Rosenberg, Jonathan E. Galsky, Matthew D. Yu, Evan Y. CA RISC Investigators TI Venous thromboembolism in metastatic urothelial carcinoma or variant histologies: incidence, associative factors, and effect on survival SO CANCER MEDICINE LA English DT Article DE Urothelial; bladder cancer; chemotherapy survival; venous thromboembolism ID BLADDER-CANCER; HEMOSTATIC FACTORS; THROMBOSIS; RISK; CISPLATIN; CHEMOTHERAPY; GEMCITABINE; THERAPY; DISEASE; METHOTREXATE AB Venous thromboembolism (VTE) is common in cancer patients. However, little is known about VTE risk in metastatic urothelial carcinoma or variant histologies (UC/VH). We sought to characterize the incidence, associative factors, including whether various chemotherapy regimens portend different risk, and impact of VTE on survival in metastatic UC/VH patients. Patients diagnosed with metastatic UC/VH from 2000 to 2013 were included in this multicenter retrospective, international study from 29 academic institutions. Cumulative and 6-month VTE incidence rates were determined. The association of first-line chemotherapy (divided into six groups) and other baseline characteristics on VTE were analyzed. Each chemotherapy treatment group and statistically significant baseline clinical characteristics were assessed in a multivariate, competing-risk regression model. VTE patients were matched to non-VTE patients to determine the impact of VTE on overall survival. In all, 1762 patients were eligible for analysis. There were 144 (8.2%) and 90 (5.1%) events cumulative and within the first 6 months, respectively. VTE rates based on chemotherapy group demonstrated no statistical difference when gemcitabine/cisplatin was used as the comparator. Non-urotheilal histology (SHR: 2.67; 95% CI: 1.72-4.16, P<0.001), moderate to severe renal dysfunction (SHR: 2.12; 95% CI: 1.26-3.59, P=0.005), and cardiovascular disease (CVD) or CVD risk factors (SHR: 2.27; 95% CI: 1.49-3.45, P=0.001) were associated with increased VTE rates. Overall survival was worse in patients with VTE (median 6.0 m vs. 10.2 m, P<0.001). Thus, in metastatic UC/VH patients, VTE is common and has a negative impact on survival. We identified multiple associated potential risk factors, although different chemotherapy regimens did not alter risk. C1 [Ramos, Jorge D.; Yu, Evan Y.] Univ Washington, Seattle, WA 98195 USA. [Casey, Martin F.; Galsky, Matthew D.] Icahn Sch Med Mt Sinai, New York, NY 10029 USA. [Crabb, Simon J.] Univ Southampton, Southampton, Hants, England. [Bamias, Aristotelis] Univ Athens, Athens, Greece. [Harshman, Lauren C.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Wong, Yu-Ning] Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. [Bellmunt, Joaquim] Hosp del Mar, Barcelona, Spain. [De Giorgi, Ugo; Recine, Federica] IRCCS, Ist Sci Romagnolo Studio & Cura Tumori IRST, Meldola, Italy. [Ladoire, Sylvain] Georges Francois Leclerc Ctr, Dijon, France. [Ladoire, Sylvain] Univ Bourgogne, Dijon, France. [Powles, Thomas] Barts & London Queen Marys Sch Med & Dent, London, England. [Pal, Sumanta K.] City Hope Natl Med Ctr, Duarte, CA USA. [Niegisch, Guenter] Univ Dusseldorf, Dusseldorf, Germany. [Alva, Ajjai] Univ Michigan, Ann Arbor, MI 48109 USA. [Agarwal, Neeraj] Univ Utah, Salt Lake City, UT USA. [Necchi, Andrea] Fdn IRCCS Ist Nazl Tumori, Milan, Italy. [Vaishampayan, Ulka N.] Karmanos Canc Inst, Detroit, MI USA. [Rosenberg, Jonathan E.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. RP Ramos, JD (reprint author), Fred Hutchinson Canc Res Ctr, 1100 Fairview Ave N,D5-210,POB 19024, Seattle, WA 98109 USA. EM jdramos@fhcrc.org OI Crabb, Simon/0000-0003-3521-9064 FU T32 NIH Training Grant [CA009515] FX This work was funded by T32 NIH Training Grant CA009515. NR 31 TC 0 Z9 0 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2045-7634 J9 CANCER MED-US JI Cancer Med. PD JAN PY 2017 VL 6 IS 1 BP 186 EP 194 DI 10.1002/cam4.986 PG 9 WC Oncology SC Oncology GA EK3ZC UT WOS:000393865900018 PM 28000388 ER PT J AU Li, X Huang, HL Guan, YF Gong, YH He, CY Yi, X Qi, M Chen, ZY AF Li, Xia Huang, Hailiang Guan, Yanfang Gong, Yuhua He, Cheng-Yi Yi, Xin Qi, Ming Chen, Zhi-Ying TI Whole-exome sequencing predicted cancer epitope trees of 23 early cervical cancers in Chinese women SO CANCER MEDICINE LA English DT Article DE Cervical cancer; immunotherapeutic target; neo-epitope; phylogenetic tree ID 21 BREAST CANCERS; INTRATUMOR HETEROGENEITY; CLONAL EVOLUTION; TUMOR-ANTIGENS; LUNG-CANCER; IMMUNOTHERAPY; MUTATIONS; CELLS; PATIENT; ADENOCARCINOMAS AB Emerging evidence suggest that the heterogeneity of cancer limits the efficacy of immunotherapy. To search for optimal therapeutic targets for enhancing the efficacy, we used whole-exome sequencing data of 23 early cervical tumors from Chinese women to investigate the hierarchical structure of the somatic mutations and the neo-epitopes. The putative neo-epitopes were predicted based on the mutant peptides' strong binding with major histocompatibility complex class I molecules. We found that each tumor carried an average of 117 mutations and 61 putative neo-epitopes. Each patient displayed a unique phylogenetic tree in which almost all subclones harbored neo-epitopes, highlighting the importance of individual neo-epitope tree in determination of immunotherapeutic targets. The alterations in FBXW7 and PIK3CA, or other members of the significantly altered ubiquitin-mediated proteolysis and extracellular matrix receptor interaction related pathways, were proposed as the earliest changes triggering the malignant progression. The neo-epitopes involved in these pathways, and located at the top of the hierarchy tree, might become the optimal candidates for therapeutic targets, possessing the potential to mediate T-cell killing of the descendant cells. These findings expanded our understanding in early stage of cervical carcinogenesis and offered an important approach to assist optimizing the immunotherapeutic target selection. C1 [Li, Xia; He, Cheng-Yi; Chen, Zhi-Ying] Chinese Acad Sci, Shenzhen Inst Adv Technol, Lab Gene & Cell Engn, Shenzhen, Peoples R China. [Li, Xia] Chinese Acad Sci, Shenzhen Inst Adv Technol, Res Ctr Biomed Informat Technol, Shenzhen, Peoples R China. [Huang, Hailiang] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA. [Huang, Hailiang] Broad Inst MIT & Harvard, Cambridge, MA 02139 USA. [Guan, Yanfang; Gong, Yuhua; Yi, Xin] Geneplus Beijing, Beijing 102206, Peoples R China. [Qi, Ming] BGI Shenzhen, Shenzhen, Peoples R China. [Qi, Ming] Zhejiang Univ, Affiliated Hosp 1, Ctr Genet & Genom Med,Med Sch, James Watson Inst Genome Sci,Sch Basic Med Sci, Hangzhou, Zhejiang, Peoples R China. [Qi, Ming] Univ Rochester, Med Ctr, Dept Pathol & Lab Med, Rochester, NY 14642 USA. RP Chen, ZY (reprint author), Chinese Acad Sci, Shenzhen Inst Adv Technol, Lab Gene & Cell Engn, Shenzhen, Peoples R China.; Qi, M (reprint author), BGI Shenzhen, Shenzhen, Peoples R China. EM qiming@genomics.cn; zy.chen1@siat.ac.cn FU government funds of Shenzhen, China [SFG 2012.566, SKC 2012.237]; National Natural Science Foundation of China [31501065]; China Postdoctoral Science Foundation [2016M590824] FX This work was supported by the government funds of Shenzhen, China (SFG 2012.566 and SKC 2012.237), the National Natural Science Foundation of China (Grant number: 31501065), and the China Postdoctoral Science Foundation (Grant number: 2016M590824). NR 57 TC 0 Z9 0 U1 3 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2045-7634 J9 CANCER MED-US JI Cancer Med. PD JAN PY 2017 VL 6 IS 1 BP 207 EP 219 DI 10.1002/cam4.953 PG 13 WC Oncology SC Oncology GA EK3ZC UT WOS:000393865900020 PM 27998038 ER PT J AU Topcuoglu, MA Kursun, O Singhal, AB AF Topcuoglu, M. Akif Kursun, Oguzhan Singhal, Aneesh B. TI Coexisting vascular lesions in reversible cerebral vasoconstriction syndrome SO CEPHALALGIA LA English DT Article DE Cerebral vasoconstriction; cerebral vasculitis; thunderclap headache; aneurysm; cervical artery dissection; vascular malformation ID POSTPARTUM ANGIOPATHY; THUNDERCLAP HEADACHE; ARTERY DISSECTIONS; ANEURYSMS; STROKE AB Background: The pathophysiology of reversible cerebral vasoconstriction syndrome (RCVS) is not known. Published cases have documented coexisting cervical artery dissection and unruptured aneurysms, raising the possibility that ultrastructural vessel wall abnormalities underlie the development of vascular lesions as well as RCVS. Methods: In this retrospective study we compared the frequency of neurovascular abnormalities in 158 consecutive RCVS patients, 44 patients with primary angiitis of the central nervous system (PACNS, positive controls), and 177 non-stroke patients with acute neurological symptoms (non-arteriopathy controls). Results: Coexisting neurovascular abnormalities were significantly higher (p<0.001) in RCVS (23%) as compared to the PACNS (5%) or non-arteriopathy groups (8%). Cervical artery dissections were noted only in the RCVS group (8%, p<0.001). The RCVS group had more unruptured aneurysms than PACNS (13% vs. 5%, p = 0.099) or non-arteriopathy controls (13% vs. 7%, p = 0.05). Seven RCVS patients also had other vascular malformations (venous anomaly, cavernous malformations, fibromuscular dysplasia). There was no significant association between coexisting vascular abnormalities and brain lesions or discharge clinical outcome in the RCVS group. Conclusion: The high prevalence and heterogeneous anatomy of coexisting vascular lesions suggest that subtle ultrastructural arterial wall abnormalities may contribute to their development and also predispose to RCVS. C1 [Topcuoglu, M. Akif; Kursun, Oguzhan; Singhal, Aneesh B.] Massachusetts Gen Hosp, Dept Neurol, ACC 729C,55 Fruit St, Boston, MA 02114 USA. [Topcuoglu, M. Akif] Hacettepe Univ Hosp, Dept Neurol, Ankara, Turkey. [Kursun, Oguzhan] Ankara Numune Training & Res Hosp, Neurol Clin, Ankara, Turkey. RP Singhal, AB (reprint author), Massachusetts Gen Hosp, Dept Neurol, ACC 729C,55 Fruit St, Boston, MA 02114 USA. EM asinghal@partners.org NR 23 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0333-1024 EI 1468-2982 J9 CEPHALALGIA JI Cephalalgia PD JAN PY 2017 VL 37 IS 1 BP 29 EP 35 DI 10.1177/0333102416637826 PG 7 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA EK4KK UT WOS:000393895300004 PM 26951336 ER PT J AU Carr, AR Samimi, MS Paholpak, P Jimenez, EE Mendez, MF AF Carr, Andrew R. Samimi, Mersal S. Paholpak, Pongsatorn Jimenez, Elvira E. Mendez, Mario F. TI Emotional quotient in frontotemporal dementia vs. Alzheimer's disease: the role of socioemotional agnosia SO COGNITIVE NEUROPSYCHIATRY LA English DT Article DE Socioemotional functioning; emotional intelligence; dementia; frontotemporal ID BEHAVIORAL VARIANT; NEURODEGENERATIVE DISEASE; DIAGNOSTIC-CRITERIA; SELF-AWARENESS; INTELLIGENCE; SCALE; RECOMMENDATIONS; CONSENSUS; INSIGHT; MIND AB Introduction: Socioemotional dysfunction distinguishes behavioural variant frontotemporal dementia (bvFTD) from other dementias. Patients with bvFTD not only have early social impairment and emotional blunting, but they also have agnosia of their socioemotional dysfunction.Methods: To investigate the relationship between agnosia and dysfunction, we assessed self-knowledge of socioemotional dysfunction with an emotional quotient (EQ) scale administered to 12 patients with bvFTD and a comparison group of 12 age-matched patients with Alzheimer's disease (AD), and compared these self-ratings to caregiver ratings of social dysfunction and emotional blunting.Results: The bvFTD patients self-rated as having higher EQs than the AD patients, particularly higher self-ratings of their Social Skills, an EQ subscale which correlated with increased emotional blunting. On within-groups analysis, the bvFTD patients' high self-ratings of their EQ Appraisal of Emotions correlated with increased socioemotional dysfunction, whereas all of the AD patients' self-ratings correlated appropriately with their degree of dysfunction.Conclusions: Large socioemotional agnosia scores (EQ minus function) distinguishes bvFTD from AD. Additionally, in bvFTD, agnosia specifically for their ability to appreciate others' emotions correlates with the degree of socioemotional dysfunction, suggesting a role for socioemotional agnosia in increasing socioemotional dysfunction. C1 [Carr, Andrew R.; Samimi, Mersal S.; Paholpak, Pongsatorn; Jimenez, Elvira E.; Mendez, Mario F.] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA 90073 USA. [Carr, Andrew R.; Samimi, Mersal S.; Paholpak, Pongsatorn; Jimenez, Elvira E.; Mendez, Mario F.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurol, Los Angeles, CA 90095 USA. [Samimi, Mersal S.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA. [Paholpak, Pongsatorn] Khon Kaen Univ, Dept Psychiat, Khon Kaen, Thailand. [Jimenez, Elvira E.; Mendez, Mario F.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90095 USA. RP Carr, AR (reprint author), VA Greater Los Angeles Healthcare Syst, Los Angeles, CA 90073 USA.; Carr, AR (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurol, Los Angeles, CA 90095 USA. EM andrew.carr@va.gov FU National Institute of Aging [5R01AG050967]; V.A. Geriatrics Research, Education, and Clinical Care fellowship (ARC) FX This work was supported by the National Institute of Aging [grant number 5R01AG050967] and a V.A. Geriatrics Research, Education, and Clinical Care fellowship (ARC). NR 36 TC 0 Z9 0 U1 1 U2 1 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1354-6805 EI 1464-0619 J9 COGN NEUROPSYCHIATRY JI Cogn. Neuropsychiatry PY 2017 VL 22 IS 1 BP 28 EP 38 DI 10.1080/13546805.2016.1259612 PG 11 WC Psychiatry SC Psychiatry GA EK6CL UT WOS:000394012500003 PM 27903133 ER PT J AU Kim, JH Baggish, AL AF Kim, Jonathan H. Baggish, Aaron L. TI Strenuous Exercise and Cardiovascular Disease Outcomes SO CURRENT ATHEROSCLEROSIS REPORTS LA English DT Review DE Exercise; Physical activity; Cardiovascular outcomes; Dose-response; Cardiac pathology ID LONE ATRIAL-FIBRILLATION; CORONARY-HEART-DISEASE; PHYSICAL-ACTIVITY; LEISURE-TIME; VENTRICULAR DYSFUNCTION; PARATHYROID-HORMONE; ENDURANCE EXERCISE; AEROBIC EXERCISE; LIFE EXPECTANCY; CARDIAC FATIGUE AB Purpose of Review This review summarizes several issues at the forefront of recent controversies involving the appropriate exercise dose including epidemiologic data describing mortality trends in those who engage in high levels of physical activity and recent observational data suggesting adverse cardiovascular outcomes among long-term endurance athletes. Recent Findings The benefits of habitual and moderate levels of exercise on cardiovascular disease outcomes in the general population have been well established. However, recent data have questioned whether higher doses of physical and athletic activity are associated with adverse cardiovascular outcomes. Summary Specifically in regard to adverse cardiovascular outcomes, the evidence and limitations of the available data associating veteran endurance athletes with an increased risk of atrial fibrillation, exercise-induced arrhythmogenic cardiac remodeling, and accelerated coronary atherosclerosis will be discussed. This review will also provide a conceptual framework in the context of the clinical management of athletic patients and will highlight key areas of future research that may resolve many of these controversial issues. C1 [Kim, Jonathan H.] Emory Univ, Sch Med, Div Cardiol, Emory Clin Cardiovasc Res Inst, 1462 Clifton Rd NE,Suite 502, Atlanta, GA 30322 USA. [Baggish, Aaron L.] Massachusetts Gen Hosp, Div Cardiol, Cardiovasc Performance Program, Boston, MA 02114 USA. RP Kim, JH (reprint author), Emory Univ, Sch Med, Div Cardiol, Emory Clin Cardiovasc Res Inst, 1462 Clifton Rd NE,Suite 502, Atlanta, GA 30322 USA. EM jonathan.kim@emory.edu FU National Institutes of Health [K23 HL128795, RO1 DA029141, RO1 HL117037, RO1 HL125869] FX Jonathan H. Kim is supported by the National Institutes of Health (K23 HL128795).; Aaron L. Baggish is supported by the National Institutes of Health (RO1 DA029141, RO1 HL117037, RO1 HL125869). The authors declare no conflicts of interest. NR 60 TC 0 Z9 0 U1 3 U2 3 PU CURRENT MEDICINE GROUP PI PHILADELPHIA PA 400 MARKET STREET, STE 700, PHILADELPHIA, PA 19106 USA SN 1523-3804 EI 1534-6242 J9 CURR ATHEROSCLER REP JI Curr. Atheroscleros. Rep. PD JAN PY 2017 VL 19 IS 1 AR 1 DI 10.1007/s11883-017-0636-3 PG 8 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA EK8NE UT WOS:000394179800001 PM 28097467 ER PT J AU Chowdhury, MM Tawakol, A Jaffer, FA AF Chowdhury, Mohammed M. Tawakol, Ahmed Jaffer, Farouc A. TI Molecular Imaging of Atherosclerosis: a Clinical Focus SO CURRENT CARDIOVASCULAR IMAGING REPORTS LA English DT Article DE Atherosclerosis; Molecular imaging; Positron emission tomography; Near-infrared fluorescence; Optical coherence tomography ID POSITRON-EMISSION-TOMOGRAPHY; CAROTID PLAQUE INFLAMMATION; ACUTE CORONARY SYNDROME; ULTRASMALL SUPERPARAMAGNETIC PARTICLES; ACUTE MYOCARDIAL-INFARCTION; IN-VIVO; RISK-FACTORS; IRON-OXIDE; FDG-PET/CT; GA-68-DOTATATE PET/CT AB Purpose of Review Molecular imaging of cardiovascular disease is a powerful clinical and experimental approach that can inform our understanding of atherosclerosis biology. Complementing cross-sectional imaging techniques that provide detailed anatomical information, molecular imaging can further detect important biological changes occurring within atheroma and refine the prediction of vascular complications. Recent Findings Molecular imaging of atherosclerosis can illuminate underlying pathophysiology and serve as a surrogate endpoint in clinical trials of new drugs. Summary This review showcases promising molecular approaches for imaging atherosclerosis, with a focus on positron emission tomography ( PET), magnetic resonance imaging ( MRI), and intravascular near-infrared fluorescence ( NIRF) imaging methods that are in the clinic or close-to-clinical usage. C1 [Chowdhury, Mohammed M.] Univ Cambridge, Dept Surg, Div Vasc & Endovasc Surg, Cambridge, England. [Chowdhury, Mohammed M.] Cambridge Univ Hosp, Cambridge, England. [Tawakol, Ahmed; Jaffer, Farouc A.] Harvard Med Sch, Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02115 USA. [Jaffer, Farouc A.] MGH Cardiovasc Res Ctr, Div Cardiol, 185 Cambridge St,Simches 3206, Boston, MA 02114 USA. RP Jaffer, FA (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02115 USA.; Jaffer, FA (reprint author), MGH Cardiovasc Res Ctr, Div Cardiol, 185 Cambridge St,Simches 3206, Boston, MA 02114 USA. EM fjaffer@mgh.harvard.edu NR 69 TC 0 Z9 0 U1 1 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1941-9066 EI 1941-9074 J9 CURR CARDIOVASC IMAG JI CURR. CARDIOVASC. IMAGING REP. PD JAN PY 2017 VL 10 IS 1 AR 2 DI 10.1007/s12410-017-9397-1 PG 11 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA EL0TS UT WOS:000394335300002 ER PT J AU Nagele, MP Steffel, J Robertson, M Singh, JP Flammer, AJ Bax, JJ Borer, JS Dickstein, K Ford, I Gorcsan, J Gras, D Krum, H Sogaard, P Holzmeister, J Abraham, WT Brugada, J Ruschitzka, F AF Nagele, Matthias P. Steffel, Jan Robertson, Michele Singh, Jagmeet P. Flammer, Andreas J. Bax, Jeroen J. Borer, Jeffrey S. Dickstein, Kenneth Ford, Ian Gorcsan, John, III Gras, Daniel Krum, Henry Sogaard, Peter Holzmeister, Johannes Abraham, William T. Brugada, Josep Ruschitzka, Frank TI Effect of cardiac resynchronization therapy in patients with diabetes randomized in EchoCRT SO EUROPEAN JOURNAL OF HEART FAILURE LA English DT Article DE Heart failure; Cardiac resynchronization therapy; Narrow QRS; Diabetes ID CHRONIC HEART-FAILURE; EUROPEAN-SOCIETY; TASK-FORCE; CARDIOMYOPATHY; ASSOCIATION; MELLITUS; OUTCOMES; DEFIBRILLATOR; GUIDELINES; MORBIDITY AB Aims As patients with heart failure (HF) and concomitant diabetes carry a poor prognosis, this post-hoc subgroup analysis aimed to compare the outcomes of patients with and without diabetes randomized in the Echocardiography Guided Cardiac Resynchronization Therapy (EchoCRT) study. Methods and results EchoCRT randomized patients with a QRS duration <130 ms and echocardiographic evidence of left ventricular dyssynchrony to CRT turned on (CRT= ON) vs. off (CRT= OFF) following device implantation. At study entry, 328 patients (40.5%) had diabetes. The primary outcome (all-cause death or first hospitalization for worsening HF) occurred more frequently in patients with than without diabetes (32.6% vs. 23%, P = 0.003). A significant treatment interaction was observed for the primary outcome indicating a higher risk for CRT= ON vs. CRT-OFF in patients without [26.5% vs. 19.8%, hazard ratio (HR) 1.58, 95% confidence interval (CI) 1.08-2.31] vs. with diabetes (31.4% vs. 34%; HR 0.86, 95% CI 0.58-1.27; P for interaction 0.041). This effect was mainly driven by a lower rate in HF hospitalizations, but was only of borderline significance after multivariate adjustment (P = 0.063). The most pronounced effect was observed in patients with non-ischaemic cardiomyopathy, where a significantly reduced risk of reaching the primary endpoint for CRT= ON vs. CRT-OFF was observed in patients with (HR 0.27, P = 0.003) vs. patients without diabetes (HR 1.79, P = 0.038; P for interaction 0.005). No treatment interaction by diabetes diagnosis was found for mortality endpoints. Conclusion In EchoCRT, HF patients with a narrow QRS complex and coexisting diabetes demonstrated a signal for less harm caused by CRT compared with patients without diabetes, which was driven by differences in hospitalizations owing to HF. C1 [Nagele, Matthias P.; Steffel, Jan; Flammer, Andreas J.; Holzmeister, Johannes; Ruschitzka, Frank] Univ Heart Ctr Zurich, Dept Cardiol, Ramistr 100, CH-8091 Zurich, Switzerland. [Robertson, Michele; Ford, Ian] Univ Glasgow, Robertson Ctr Biostat, Glasgow, Lanark, Scotland. [Singh, Jagmeet P.] Harvard Med Sch, Massachusetts Gen Hosp, Cardiac Arrhythmia Serv, Boston, MA USA. [Bax, Jeroen J.] Leiden Univ, Dept Cardiol, Med Ctr, Leiden, Netherlands. [Borer, Jeffrey S.] State Univ New York Downstate Coll Med, Div Cardiovasc Med, New York, NY USA. [Borer, Jeffrey S.] State Univ New York Downstate Coll Med, Howard Gilman Inst, New York, NY USA. [Borer, Jeffrey S.] State Univ New York Downstate Coll Med, Ron & Jean Schiavone Inst, New York, NY USA. [Dickstein, Kenneth] Univ Bergen, Bergen, Norway. [Dickstein, Kenneth] Stavanger Univ Hosp, Stavanger, Norway. [Gorcsan, John, III] Univ Pittsburgh, Pittsburgh, PA USA. [Gras, Daniel] Nouvelles Clin Nantaises, Nantes, France. [Krum, Henry] Monash Ctr Cardiovasc Res & Educ Therapeut, Melbourne, Vic, Australia. [Sogaard, Peter] Aalborg Univ Hosp, Dept Cardiol, Aalborg, Denmark. [Sogaard, Peter] Aalborg Univ Hosp, Inst Clin, Aalborg, Denmark. [Abraham, William T.] Ohio State Univ, Med Ctr, Div Cardiovasc Med, Columbus, OH 43210 USA. [Brugada, Josep] Univ Barcelona, Hosp Clin, Thorax Inst, Dept Cardiol, E-08007 Barcelona, Spain. RP Ruschitzka, F (reprint author), Univ Heart Ctr Zurich, Dept Cardiol, Ramistr 100, CH-8091 Zurich, Switzerland. EM frank.ruschitzka@usz.ch FU Biotronik [G080067]; GE Healthcare FX This work received no specific funding. The EchoCRT trial was funded by Biotronik (Sponsor Study ID: G080067) and GE Healthcare. NR 30 TC 1 Z9 1 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1388-9842 EI 1879-0844 J9 EUR J HEART FAIL JI Eur. J. Heart Fail. PD JAN PY 2017 VL 19 IS 1 BP 80 EP 87 DI 10.1002/ejhf.655 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EK4SB UT WOS:000393916000008 PM 27862715 ER PT J AU Demetri, GD Blay, JY Casali, PG AF Demetri, George D. Blay, Jean-Yves Casali, Paolo G. TI Advances and controversies in the management of soft tissue sarcomas SO FUTURE ONCOLOGY LA English DT Article DE histology-driven therapy; sarcoma reference centers; soft tissue sarcoma; trabectedin ID PHASE-II TRIAL; ADVANCED ANGIOSARCOMA; IMATINIB MESYLATE; OPEN-LABEL; TRABECTEDIN; CHEMOTHERAPY; LIPOSARCOMA; PACLITAXEL; MECHANISM; LEIOMYOSARCOMA AB Intensive clinical research in the sarcoma field has provided insight into the histopathological diversity of soft tissue sarcomas (STS) and led to the introduction of many new agents that promise to play an important role in the management of patients with STS. While an increasing body of scientific data has advanced our knowledge of this complex family of mesenchymal diseases, several controversies remain to be resolved: Is doxorubicin-based therapy still the definitive standard first-line treatment for all patients with unresectable and/or metastatic STS of all subtypes? Is histology-driven therapy beyond gastrointestinal stromal tumors a reality or are we pursuing an unachievable objective? Are we making practical headway in the establishment of sarcoma reference centers? Is it clearly established which is the best parameter to evaluate the efficacy of a new agent in STS? C1 [Demetri, George D.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Demetri, George D.] Ludwig Ctr Harvard, Boston, MA 02215 USA. [Blay, Jean-Yves] Univ Claude Bernard Lyon 1, Ctr Leon Berard, Lyon, France. [Casali, Paolo G.] Fdn IRCCS Ist Nazl Tumori, Milan, Italy. [Casali, Paolo G.] Univ Milan, Milan, Italy. RP Demetri, GD (reprint author), Dana Farber Canc Inst, Boston, MA 02115 USA.; Demetri, GD (reprint author), Ludwig Ctr Harvard, Boston, MA 02215 USA. EM george_demetri@dfci.harvard.edu FU Adaptimmune; Blueprint Medicines; Caris Life Sciences; Daiichi-Sankyo; Eisai; EMD-Serono; Janssen Oncology; Kolltan Pharmaceuticals; Novartis; PharmaMar; Bayer; Pfizer; Bristol-Myers Squibb; GlaxoSmithKline; Lilly; Merck Sharpe Dohme; Roche; PharmaMar, Madrid, Spain FX GD Demetri has received consultancy fees from Adaptimmune, Blueprint Medicines, Caris Life Sciences, Daiichi-Sankyo, Eisai, EMD-Serono, Janssen Oncology, Kolltan Pharmaceuticals, Novartis and PharmaMar; has received research support from Bayer, Janssen Oncology, Novartis and Pfizer; is a Member of the Board of Directors and Scientific Advisory Board for Blueprint Medicines; is a Consultant for the Scientific Advisory Boards for Caris Life Sciences and Kolltan Pharmaceuticals; has equity in Blueprint Medicines, Caris Life Sciences and Kolltan Pharmaceuticals. J-Y Blay has received grants and research support from Bayer, Bristol-Myers Squibb, GlaxoSmithKline, Lilly, Merck Sharpe & Dohme, Novartis, PharmaMar and Roche. PG Casali has received honoraria for consultancy/advisory role and/or for lectures from: Bayer, Blueprint Medicines, Eisai, Eli Lilly, GlaxoSmithKline, Merck Sharpe & Dohme, Merck Serono, Nektar Therapeutics, Novartis, Pfizer and PharmaMar. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.; Editorial assistance was provided by Content Ed Net (Madrid, Spain) with funding from PharmaMar, Madrid, Spain. NR 31 TC 0 Z9 0 U1 1 U2 1 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1479-6694 EI 1744-8301 J9 FUTURE ONCOL JI Future Oncol. PD JAN PY 2017 VL 13 IS 1 SU S BP 3 EP 11 DI 10.2217/fon-2016-0498 PG 9 WC Oncology SC Oncology GA EL1QG UT WOS:000394394400002 PM 27918199 ER PT J AU Rottman, BM Marcum, ZA Thorpe, CT Gellad, WF AF Rottman, Benjamin Margolin Marcum, Zachary A. Thorpe, Carolyn T. Gellad, Walid F. TI Medication adherence as a learning process: insights from cognitive psychology SO HEALTH PSYCHOLOGY REVIEW LA English DT Review DE Adherence; causal learning; value-expectancy; self-management ID CAUSAL INDUCTION; COMMON-SENSE; PRIMARY-CARE; ILL PATIENTS; MEDICINES; BELIEFS; DISEASE; PATIENT; MODEL; COVARIATION AB Non-adherence to medications is one of the largest contributors to sub-optimal health outcomes. Many theories of adherence include a value-expectancy' component in which a patient decides to take a medication partly based on expectations about whether it is effective, necessary, and tolerable. We propose reconceptualising this common theme as a kind of causal learning' - the patient learns whether a medication is effective, necessary, and tolerable, from experience with the medication. We apply cognitive psychology theories of how people learn cause-effect relations to elaborate this causal-learning challenge. First, expectations and impressions about a medication and beliefs about how a medication works, such as delay of onset, can shape a patient's perceived experience with the medication. Second, beliefs about medications propagate both top-down' and bottom-up', from experiences with specific medications to general beliefs about medications and vice versa. Third, non-adherence can interfere with learning about a medication, because beliefs, adherence, and experience with a medication are connected in a cyclic learning problem. We propose that by conceptualising non-adherence as a causal-learning process, clinicians can more effectively address a patient's misconceptions and biases, helping the patient develop more accurate impressions of the medication. C1 [Rottman, Benjamin Margolin] Univ Pittsburgh, Dept Psychol, Pittsburgh, PA 15260 USA. [Marcum, Zachary A.] Univ Washington, Dept Pharm, Seattle, WA 98195 USA. [Thorpe, Carolyn T.] Univ Pittsburgh, Sch Pharm, Dept Pharm & Therapeut, VA Pittsburgh Healthcare Syst, Pittsburgh, PA 15261 USA. [Gellad, Walid F.] Univ Pittsburgh, Div Gen Med, VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. [Gellad, Walid F.] Univ Pittsburgh, Ctr Pharmaceut Policy & Prescribing, VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. RP Rottman, BM (reprint author), Univ Pittsburgh, Dept Psychol, Pittsburgh, PA 15260 USA. EM rottman@pitt.edu FU NSF [1430439]; VA HSR&D Career Development Award; U.S. Department of Veterans Affairs [IIR 14-297] FX This research was supported by NSF 1430439 (Rottman) and a VA HSR&D Career Development Award (Gellad); U.S. Department of Veterans Affairs [IIR 14-297]. NR 78 TC 0 Z9 0 U1 3 U2 3 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1743-7199 EI 1743-7202 J9 HEALTH PSYCHOL REV JI Health Psychol. Rev. PY 2017 VL 11 IS 1 BP 17 EP 32 DI 10.1080/17437199.2016.1240624 PG 16 WC Psychology, Clinical SC Psychology GA EM2CM UT WOS:000395124000002 PM 27707099 ER PT J AU Wisse, LEM Daugherty, AM Olsen, RK Berron, D Carr, VA Stark, CEL Amaral, RSC Amunts, K Augustinack, JC Bender, AR Bernstein, JD Boccardi, M Bocchetta, M Burggren, A Chakravarty, MM Chupin, M Ekstrom, A de Flores, R Insausti, R Kanel, P Kedo, O Kennedy, KM Kerchner, GA LaRocque, KF Liu, XW Maass, A Malykhin, N Mueller, SG Ofen, N Palombo, DJ Parekh, MB Pluta, JB Pruessner, JC Raz, N Rodrigue, KM Schoemaker, D Shafer, AT Steve, TA Suthana, N Wang, L Winterburn, JL Yassa, MA Yushkevich, PA la Joie, R AF Wisse, Laura E. M. Daugherty, Ana M. Olsen, Rosanna K. Berron, David Carr, Valerie A. Stark, Craig E. L. Amaral, Robert S. C. Amunts, Katrin Augustinack, Jean C. Bender, Andrew R. Bernstein, Jeffrey D. Boccardi, Marina Bocchetta, Martina Burggren, Alison Chakravarty, M. Mallar Chupin, Marie Ekstrom, Arne de Flores, Robin Insausti, Ricardo Kanel, Prabesh Kedo, Olga Kennedy, Kristen M. Kerchner, Geoffrey A. LaRocque, Karen F. Liu, Xiuwen Maass, Anne Malykhin, Nicolai Mueller, Susanne G. Ofen, Noa Palombo, Daniela J. Parekh, Mansi B. Pluta, John B. Pruessner, Jens C. Raz, Naftali Rodrigue, Karen M. Schoemaker, Dorothee Shafer, Andrea T. Steve, Trevor A. Suthana, Nanthia Wang, Lei Winterburn, Julie L. Yassa, Michael A. Yushkevich, Paul A. la Joie, Renaud CA Hippocampal Subfields Grp TI A Harmonized Segmentation Protocol for Hippocampal and Parahippocampal Subregions: Why Do We Need One and What Are the Key Goals? SO HIPPOCAMPUS LA English DT Editorial Material DE hippocampus; segmentation; harmonization; MRI; parahippocampal gyrus ID MEDIAL TEMPORAL-LOBE; HIGH-RESOLUTION MRI; MILD COGNITIVE IMPAIRMENT; IN-VIVO MRI; ALZHEIMERS-DISEASE; PATTERN SEPARATION; SUBFIELD VOLUMES; DENTATE GYRUS; MAGNETIC-RESONANCE; FUNCTIONAL MRI AB The advent of high-resolution magnetic resonance imaging (MRI) has enabled in vivo research in a variety of populations and diseases on the structure and function of hippocampal subfields and subdivisions of the parahippocampal gyrus. Because of the many extant and highly discrepant segmentation protocols, comparing results across studies is difficult. To overcome this barrier, the Hippocampal Subfields Group was formed as an international collaboration with the aim of developing aharmonized protocol for manual segmentation of hippocampal and parahippocampal subregions on high-resolution MRI. In this commentary we discuss the goals for this protocol and the associated key challenges involved in its development. These include differences among existing anatomical reference materials, striking the right balance between reliability of measurements and anatomical validity, and the development of a versatile protocol that can be adopted for the study of populations varying in age and health. The commentary outlines these key challenges, as well as the proposed solution of each, with concrete examples from our working plan. Finally, with two examples, we illustrate how the harmonized protocol, once completed, is expected to impact the field by producing measurements that are quantitatively comparable across labs and by facilitating the synthesis of findings across different studies. (C) 2016 Wiley Periodicals, Inc. C1 [Wisse, Laura E. M.; Pluta, John B.; Yushkevich, Paul A.] Univ Penn, Dept Radiol, Penn Image Comp & Sci Lab, Philadelphia, PA 19104 USA. [Daugherty, Ana M.] Univ Illinois, Beckman Inst Adv Sci & Technol, Champaign, IL 61820 USA. [Olsen, Rosanna K.] Rotman Res Inst, Baycrest Hlth Sci, Toronto, ON, Canada. [Berron, David] Otto Von Guericke Univ, Inst Cognit Neurol & Dementia Res, Magdeburg, Germany. [Carr, Valerie A.; LaRocque, Karen F.] Stanford Univ, Dept Psychol, Palo Alto, CA 94304 USA. [Carr, Valerie A.] San Jose State Univ, Dept Psychol, San Jose, CA 95192 USA. [Stark, Craig E. L.; Yassa, Michael A.] Univ Calif Irvine, Dept Neurobiol & Behav, Irvine, CA 92697 USA. [Amaral, Robert S. C.; Chakravarty, M. Mallar; Winterburn, Julie L.] McGill Univ, Douglas Mental Hlth Univ Inst, Cerebral Imaging Ctr, Montreal, PQ, Canada. [Amaral, Robert S. C.; Chakravarty, M. Mallar; Winterburn, Julie L.] McGill Univ, Dept Psychiat, Montreal, PQ, Canada. [Amaral, Robert S. C.; Chakravarty, M. Mallar; Winterburn, Julie L.] McGill Univ, Dept Biol & Biomed Engn, Montreal, PQ, Canada. [Amaral, Robert S. C.] McGill Univ, Integrated Program Neurosci, Montreal, PQ, Canada. [Amunts, Katrin; Kedo, Olga] Res Ctr Julich, INM 1, Inst Neurosci & Med, Julich, Germany. [Amunts, Katrin] Julich Aachen Res Alliance, JARA BRAIN, Julich, Germany. [Amunts, Katrin] Univ Dusseldorf, C & O Vogt Inst Brain Res, Dusseldorf, Germany. [Augustinack, Jean C.] Harvard Med Sch, Massachusetts Gen Hosp, AA Martinos Ctr Biomed Imaging, Dept Radiol, Boston, MA 02115 USA. [Bender, Andrew R.] Max Planck Inst Human Dev, Ctr Lifespan Psychol, Berlin, Germany. [Bernstein, Jeffrey D.; Kerchner, Geoffrey A.] Stanford Univ, Sch Med, Dept Neurol & Neurol Sci, Palo Alto, CA 94304 USA. [Boccardi, Marina] Univ Geneva, LANVIE Lab Neuroimaging Aging, Geneva, Switzerland. [Bocchetta, Martina] UCL Inst Neurol, Dept Neurodegenerat Dis, Dementia Res Ctr, Queen Sq, London, England. [Burggren, Alison; Suthana, Nanthia] Univ Calif Los Angeles, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90024 USA. [Chupin, Marie] INSERM, CNRS, Inst Cerveau & Moelle Epiniere, UMR S975, Paris, France. [Ekstrom, Arne] Univ Calif Davis, Ctr Neurosci, Davis, CA 95616 USA. [Ekstrom, Arne] Univ Calif Davis, Dept Psychol, Davis, CA 95616 USA. [de Flores, Robin; la Joie, Renaud] Univ Caen, CHU Caen, Ecole Prat Hautes Etud, INSERM U1077,UMR S1077, Caen, France. [Insausti, Ricardo] Univ Castilla La Mancha, Human Neuroanat Lab, Albacete, Spain. [Insausti, Ricardo] Univ Castilla La Mancha, CRIB Sch Med, Albacete, Spain. [Kanel, Prabesh; Liu, Xiuwen] Florida State Univ, Dept Comp Sci, Tallahassee, FL 32306 USA. [Kennedy, Kristen M.; Rodrigue, Karen M.] Univ Texas Dallas, Ctr Vital Longev, Sch Behav & Brain Sci, Dallas, TX 75080 USA. [Maass, Anne] Univ Calif Berkeley, Sch Publ Hlth, Berkeley, CA 94720 USA. [Maass, Anne] Univ Calif Berkeley, Helen Wills Neurosci Inst, Berkeley, CA 94720 USA. [Malykhin, Nicolai] Univ Alberta, Dept Biomed Engn, Edmonton, AB, Canada. [Malykhin, Nicolai] Univ Alberta, Neurosci & Mental Hlth Inst, Edmonton, AB, Canada. [Malykhin, Nicolai] Univ Alberta, Dept Psychiat, Edmonton, AB, Canada. [Mueller, Susanne G.] Univ Calif San Francisco, Dept Radiol, San Francisco, CA 94143 USA. [Mueller, Susanne G.] San Francisco VA Med Ctr, Ctr Imaging Neurodegenerat Dis, San Francisco, CA USA. [Ofen, Noa; Raz, Naftali; Shafer, Andrea T.] Wayne State Univ, Dept Psychol, 71 W Warren Ave, Detroit, MI 48202 USA. [Ofen, Noa; Raz, Naftali; Shafer, Andrea T.] Wayne State Univ, Inst Gerontol, Detroit, MI 48202 USA. [Palombo, Daniela J.] VA Boston Healthcare Syst, Boston, MA USA. [Parekh, Mansi B.] Stanford Univ, Dept Radiol, Palo Alto, CA 94304 USA. [Pruessner, Jens C.; Schoemaker, Dorothee] McGill Univ, McGill Ctr Studies Aging, Fac Med, Montreal, PQ, Canada. [Pruessner, Jens C.; Schoemaker, Dorothee] McGill Univ, Dept Psychol, Montreal, PQ, Canada. [Steve, Trevor A.] Univ Alberta, Dept Med, Div Neurol, Edmonton, AB, Canada. [Suthana, Nanthia] Univ Calif Los Angeles, Dept Neurosurg, Los Angeles, CA 90095 USA. [Wang, Lei] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Yassa, Michael A.] Univ Calif Irvine, Dept Neurol, Irvine, CA 92717 USA. RP Wisse, LEM (reprint author), Richards Bldg 6th Floor,3700 Hamilton Walk, Philadelphia, PA 19104 USA. EM laura.wisse@uphs.upenn.edu RI Bocchetta, Martina/B-6331-2013; OI Bocchetta, Martina/0000-0003-1814-5024; Daugherty, Ana/0000-0002-9980-154X; La Joie, Renaud/0000-0003-2581-8100 FU NIH [R37 011230]; NIH/NINDS [NS076856, NS093052]; Eisai; Canadian League Against Epilepsy (CLAE); NIDA [K01 DA034728]; NIH/NIA [R00 AG-036818]; Alzheimer Association [ADNI 2-12-233036, GI20152980]; US NIA [P50 AG05146]; NIA [R21 AG049220, R00 AG-36848, R01 AG037376]; NIMH [R01 MH102392]; National Sciences and Engineering Research Council Canada; Canadian Institutes of Health Research; Weston Brian Institute; Alzheimer's Association; Michael J. Fox Foundation for Parkinson's Research; Fonds de recherche saute Quebec; NIBIB [R01 EB017255]; Fondation Therese et Rene Planiol pour l'etude du Cerveau FX NIH; Grant number: R37 011230; Grant sponsor: NIH/NINDS; Grant number: NS076856, NS093052; Grant sponsor: Eisai and the Canadian League Against Epilepsy (CLAE); Grant sponsor: NIDA; Grant number: K01 DA034728; Grant sponsor: NIH/NIA; Grant number: R00 AG-036818; Grant sponsor: Alzheimer Association; Grant number: ADNI 2-12-233036; Grant number: GI20152980; Grant sponsor: US NIA; Grant number: P50 AG05146; Grant sponsor: NIA; Grant number: R21 AG049220; Grant sponsor: NIMH; Grant number: R01 MH102392; Grant sponsor: National Sciences and Engineering Research Council Canada, Canadian Institutes of Health Research, Weston Brian Institute, Alzheimer's Association, Michael J. Fox Foundation for Parkinson's Research, and Fonds de recherche saute Quebec; Grant sponsor: NIA; Grant number: R00 AG-36848; Grant sponsor: NIA; Grant number: R01 AG037376; Grant sponsor: NIBIB; Grant number: R01 EB017255; Grant sponsor: Fondation Therese et Rene Planiol pour l'etude du Cerveau. NR 72 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1050-9631 EI 1098-1063 J9 HIPPOCAMPUS JI Hippocampus PD JAN PY 2017 VL 27 IS 1 BP 3 EP 11 DI 10.1002/hipo.22671 PG 9 WC Neurosciences SC Neurosciences & Neurology GA EK4UJ UT WOS:000393922200001 PM 27862600 ER PT J AU Dayton, CJ Malone, JC AF Dayton, Carolyn Joy Malone, Johanna C. TI DEVELOPMENT AND SOCIALIZATION OF PHYSICAL AGGRESSION IN VERY YOUNG BOYS SO INFANT MENTAL HEALTH JOURNAL LA English DT Review DE infant; aggression; parenting; boys; fathers ID TO-FACE INTERACTION; MATERNAL SENSITIVITY BEHAVIOR; INFANT EXTERNALIZING BEHAVIOR; INTIMATE PARTNER VIOLENCE; DYNAMIC-SYSTEMS THEORY; SEX-DIFFERENCES; GENDER-DIFFERENCES; EMOTION EXPRESSION; NEGATIVE EMOTIONS; ATTACHMENT RELATIONSHIPS AB The expression of physical aggression is normative in early child development; it peaks in the second year of life, with steep declines for most children by the third and fourth years as children learn alternatives to aggression. Some children, however, fail to demonstrate declines in aggressive acts, and many of these are boys. The current review uses a dynamic systems (DS) approach to identify early individual and contextual factors that may dynamically influence trajectories of aggression as a characteristic way of engaging within communities and relationships. Within the DS framework, we focus on the parent-infant relationship as central to the development of adaptive emotion-regulation capacities of the infant and young child. Biological sex differences that may influence this early relationship are highlighted, as is the influence of contextual processes such as family violence. Clinical implications suggested by both the empirical and theoretical literatures are then described. C1 [Dayton, Carolyn Joy] Wayne State Univ, Detroit, MI USA. [Malone, Johanna C.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Malone, Johanna C.] Harvard Med Sch, Boston, MA USA. RP Dayton, CJ (reprint author), Wayne State Univ, Sch Social Work, 5447 Woodward Ave, Detroit, MI 48202 USA. EM carolyn.dayton@wayne.edu NR 130 TC 2 Z9 2 U1 4 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0163-9641 EI 1097-0355 J9 INFANT MENT HEALTH J JI Infant Ment. Health J. PD JAN-FEB PY 2017 VL 38 IS 1 SI SI BP 150 EP 165 DI 10.1002/imhj.21622 PG 16 WC Psychology, Developmental SC Psychology GA EK1KS UT WOS:000393684800010 PM 28004406 ER PT J AU Van Der Sloot, KWJ Joshi, AD Bellavance, DR Gilpin, KK Stewart, KO Lochhead, P Garber, JJ Giallourakis, C Yajnik, V Ananthakrishnan, AN Alizadeh, BZ Xavier, RJ Khalili, H AF Van Der Sloot, Kimberley W. J. Joshi, Amit D. Bellavance, Danielle R. Gilpin, Katherine K. Stewart, Kathleen O. Lochhead, Paul Garber, John J. Giallourakis, Cosmas Yajnik, Vijay Ananthakrishnan, Ashwin N. Alizadeh, Behrooz Z. Xavier, Ramnik J. Khalili, Hamed TI Visceral Adiposity, Genetic Susceptibility, and Risk of Complications Among Individuals with Crohn's Disease SO INFLAMMATORY BOWEL DISEASES LA English DT Article DE visceral adipose tissue; obesity; Crohn's disease complications; genetic predisposition ID INFLAMMATORY-BOWEL-DISEASE; BODY-MASS INDEX; ULCERATIVE-COLITIS; GUT MICROBIOME; FOLLOW-UP; FAT AREA; TISSUE; OBESITY; ASSOCIATION; POPULATION AB Introduction: Adipose tissue in mesenteric fat plays a key role in systemic and luminal inflammation. However, little is known about the role of visceral adipose tissue (VAT) and its interaction with genetic predisposition in Crohn's disease (CD) progression. Methods: Our study population included patients with CD enrolled in Prospective Registry in Inflammatory Bowel Disease Study at Massachusetts General Hospital (PRISM). VAT volume was measured from computed tomography using Aquarius 3D. We used logistic regression models to estimate the multivariable-adjusted odds ratio and 95% CI. We tested for effect modification by genetic predisposition using the log likelihood ratio test. Results: Among 482 patients with CD with available data on VAT, 174 developed penetrating disease, 132 developed stricturing disease, 147 developed perianal disease, and 252 required surgery. Compared with individuals in the lowest quartile of VAT volume, the multivariable-adjusted odds ratio of surgery among individuals in the highest quartile was 2.02 (95% CI, 1.09-3.76; P-trend = 0.006). Similarly, the risk of penetrating disease seemed to increase with greater VAT volume (P-trend = 0.022) but not stricturing or perianal disease (all P-trend > 0.23). The associations between VAT volume and CD complications were not modified by genetic predisposition (all P-interaction > 0.12). Conclusions: Visceral adiposity as measured by VAT volume may be associated with a significant increase in the risk of penetrating disease and surgery in CD. Our data suggest that visceral adiposity as measured by VAT may negatively impact long-term progression of CD regardless of genetic predisposition. C1 [Van Der Sloot, Kimberley W. J.; Joshi, Amit D.; Bellavance, Danielle R.; Gilpin, Katherine K.; Lochhead, Paul; Garber, John J.; Giallourakis, Cosmas; Yajnik, Vijay; Ananthakrishnan, Ashwin N.; Xavier, Ramnik J.; Khalili, Hamed] Massachusetts Gen Hosp, Harvard Med Sch, Dept Gastroenterol, Boston, MA 02114 USA. [Van Der Sloot, Kimberley W. J.; Alizadeh, Behrooz Z.] Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, Groningen, Netherlands. [Joshi, Amit D.; Lochhead, Paul; Ananthakrishnan, Ashwin N.; Khalili, Hamed] Massachusetts Gen Hosp, Harvard Med Sch, Clin & Translat Epidemiol Unit, Boston, MA 02114 USA. [Stewart, Kathleen O.] Dartmouth Hitchcock Qual Assurance & Safety, Dept Qual Assurance & Safety, Lebanon, NH USA. [Xavier, Ramnik J.] Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Boston, MA 02114 USA. RP Khalili, H (reprint author), Massachusetts Gen Hosp, Crohns & Colitis Ctr, 165 Cambridge St,9th Floor, Boston, MA 02114 USA. EM hkhalili@mgh.harvard.edu FU American Gastroenterological Association (AGA); National Institute of Diabetes and Digestive and Kidney Diseases [K23 DK099681]; AbbVie; NPS; Janssen Pharmaceuticals; UCB FX H. Khalili is supported by a career development award from the American Gastroenterological Association (AGA) and by National Institute of Diabetes and Digestive and Kidney Diseases (K23 DK099681).; A. N. Ananthakrishnan is a member of the scientific advisory board for Exact Sciences, AbbVie, and Cubist pharmaceuticals. H. Khalili has received consultant fee from AbbVie. V. Yajnik has received consulting fees from NPS, Janssen Pharmaceuticals, and UCB. The remaining authors have no conflict of interest to disclose. NR 42 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 1078-0998 EI 1536-4844 J9 INFLAMM BOWEL DIS JI Inflamm. Bowel Dis. PD JAN PY 2017 VL 23 IS 1 BP 82 EP 88 DI 10.1097/MIB.0000000000000978 PG 7 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EK4LB UT WOS:000393897100016 PM 27893544 ER PT J AU Khalid, F Tauhid, S Chua, AS Healy, BC Stankiewicz, JM Weiner, HL Bakshi, R AF Khalid, Fariha Tauhid, Shahamat Chua, Alicia S. Healy, Brian C. Stankiewicz, James M. Weiner, Howard L. Bakshi, Rohit TI A longitudinal uncontrolled study of cerebral gray matter volume in patients receiving natalizumab for multiple sclerosis SO INTERNATIONAL JOURNAL OF NEUROSCIENCE LA English DT Article DE multiple sclerosis; MRI; natalizumab; gray matter; brain atrophy ID BRAIN ATROPHY; WHITE-MATTER; CONTROLLED TRIAL; PSEUDOATROPHY; THERAPY; MRI; IMPAIRMENT; DISABILITY; PATHOLOGY; OUTCOMES AB Objective: Brain atrophy in multiple sclerosis (MS) selectively affects gray matter (GM), which is highly relevant to disability and cognitive impairment. We assessed cerebral GM volume (GMV) during one year of natalizumab therapy. Design/methods: Patients with relapsing-remitting (n = 18) or progressive (n = 2) MS had MRI similar to 1 year apart during natalizumab treatment. At baseline, patients were on natalizumab for (mean +/- SD) 16.6 +/- 10.9 months with age 38.5 +/- 7.4 and disease duration 9.7 +/- 4.3 years. Results: At baseline, GMV was 664.0 +/- 56.4 ml, Expanded Disability Status Scale (EDSS) score was 2.3 +/- 2.0, timed 25-foot walk (T25FW) was 6.1+/-3.4 s; two patients (10%) had gadolinium (Gd)-enhancing lesions. At follow-up, GMV was 663.9 +/- 60.2 mL; EDSS was 2.6 +/- 2.1 and T25FW was 5.9 +/- 2.9 s. One patient had a mild clinical relapse during the observation period (0.052 annualized relapse rate for the entire cohort). No patients had Gd-enhancing lesions at follow-up. Linear mixed-effect models showed no significant change in annualized GMV [estimated mean change per year 0.338 mL, 95% confidence interval -9.66, 10.34, p = 0.94)], GM fraction (p = 0.92), whole brain parenchymal fraction (p = 0.64), T2 lesion load (p = 0.64), EDSS (p = 0.26) or T25FW (p = 0.79). Conclusions: This pilot study shows no GM atrophy during one year of natalizumab MS therapy. We also did not detect any loss of whole brain volume or progression of cerebral T2 hyperintense lesion volume during the observation period. These MRI results paralleled the lack of clinical worsening. C1 [Khalid, Fariha; Tauhid, Shahamat; Chua, Alicia S.; Healy, Brian C.; Stankiewicz, James M.; Weiner, Howard L.; Bakshi, Rohit] Harvard Med Sch, Brigham & Womens Hosp, Partners MS Ctr, Lab Neuroimaging Res,Dept Neurol, Boston, MA USA. [Bakshi, Rohit] Harvard Med Sch, Brigham & Womens Hosp, Partners MS Ctr, Lab Neuroimaging Res,Dept Radiol, Boston, MA USA. [Healy, Brian C.] Harvard Med Sch, Massachusetts Gen Hosp, Ctr Biostat, Boston, MA USA. RP Bakshi, R (reprint author), Lab Neuroimaging Res, One Brookline Pl, Brookline, MA 02445 USA. EM rbakshi@post.harvard.edu FU Merck-Serono; Genzyme; Novartis; AbbVie; Alkermes; Biogen; Questcor; Teva; Biogen, Inc. [US-TYS-10-10070] FX Dr Healy received research support from Merck-Serono, Genzyme and Novartis. Dr Bakshi received consulting fees from AbbVie, Alkermes, Biogen, Novartis and Questcor and research support from Biogen, Merck-Serono, Novartis, Genzyme and Teva. The other authors have nothing to disclose. This work was presented in preliminary form at the 2015 annual meeting of the American Academy of Neurology, Washington, DC.; This study was supported by Biogen, Inc. [grant number US-TYS-10-10070]. NR 31 TC 0 Z9 0 U1 1 U2 1 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND SN 0020-7454 EI 1563-5279 J9 INT J NEUROSCI JI Int. J. Neurosci. PY 2017 VL 127 IS 5 BP 396 EP 403 DI 10.1080/00207454.2016.1185421 PG 8 WC Neurosciences SC Neurosciences & Neurology GA EK5TE UT WOS:000393988000003 PM 27143245 ER PT J AU Kousoulis, AA Ioakeim-Ioannidou, M Economopoulos, KP AF Kousoulis, Antonis A. Ioakeim-Ioannidou, Myrsini Economopoulos, Konstantinos P. TI Refugee crisis in Greece: not a one-country job SO INTERNATIONAL JOURNAL OF PUBLIC HEALTH LA English DT Editorial Material ID BORDERS C1 [Kousoulis, Antonis A.; Ioakeim-Ioannidou, Myrsini; Economopoulos, Konstantinos P.] Soc Jr Doctors, Athens, Greece. [Kousoulis, Antonis A.] London Sch Hyg & Trop Med, Fac Epidemiol & Populat Hlth, 10 Norwood Ave, London HA0 1LY, England. [Ioakeim-Ioannidou, Myrsini] Univ Athens, Sch Med, Athens, Greece. [Economopoulos, Konstantinos P.] Harvard Med Sch, Massachusetts Gen Hosp, Boston, MA USA. RP Kousoulis, AA (reprint author), London Sch Hyg & Trop Med, Fac Epidemiol & Populat Hlth, 10 Norwood Ave, London HA0 1LY, England. EM antonis.kousoulis@lshtm.ac.uk NR 8 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER BASEL AG PI BASEL PA PICASSOPLATZ 4, BASEL, 4052, SWITZERLAND SN 1661-8556 EI 1661-8564 J9 INT J PUBLIC HEALTH JI Int. J. Public Health PD JAN PY 2017 VL 62 IS 1 BP 1 EP 2 DI 10.1007/s00038-016-0890-0 PG 2 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA EK7WC UT WOS:000394134900001 PM 27757481 ER PT J AU Paul, S Rabito, CA Vedak, P Nigwekar, SU Kroshinsky, D AF Paul, Suchismita Rabito, Carlos A. Vedak, Priyanka Nigwekar, Sagar U. Kroshinsky, Daniela TI The Role of Bone Scintigraphy in the Diagnosis of Calciphylaxis SO JAMA DERMATOLOGY LA English DT Letter C1 [Paul, Suchismita] Harvard Med Sch, Boston, MA USA. [Paul, Suchismita] Univ Miami, Jackson Mem Hosp, Miller Sch Med, Dept Med, Miami, FL 33136 USA. [Paul, Suchismita] Univ Miami, Jackson Mem Hosp, Miller Sch Med, Dept Dermatol & Cutaneous Surg, Miami, FL 33136 USA. [Rabito, Carlos A.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA USA. [Vedak, Priyanka; Kroshinsky, Daniela] Massachusetts Gen Hosp, Dept Dermatol, 55 Fruit St, Boston, MA 02114 USA. [Nigwekar, Sagar U.] Massachusetts Gen Hosp, Dept Nephrol, Boston, MA 02114 USA. RP Kroshinsky, D (reprint author), Massachusetts Gen Hosp, Dept Dermatol, 55 Fruit St, Boston, MA 02114 USA. EM dkroshinsky@mgh.harvard.edu FU National Kidney Foundation's Young Investigator Award; Fund for Medical Discovery Award from the Massachusetts General Hospital's Executive Committee on Research FX Dr Nigwekar reported being supported by the National Kidney Foundation's Young Investigator Award and by the Fund for Medical Discovery Award from the Massachusetts General Hospital's Executive Committee on Research. No other disclosures were reported. 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 2168-6068 EI 2168-6084 J9 JAMA DERMATOL JI JAMA Dermatol. PD JAN PY 2017 VL 153 IS 1 BP 101 EP 103 DI 10.1001/jamadermatol.2015.4591 PG 4 WC Dermatology SC Dermatology GA EK2UM UT WOS:000393782200027 PM 26677101 ER PT J AU Ionescu, DF Cusin, C AF Ionescu, Dawn F. Cusin, Cristina TI Reduction in Suicidal Ideation Following Repeated Doses of Intravenous Ketamine? Reply SO JOURNAL OF CLINICAL PSYCHIATRY LA English DT Letter C1 [Ionescu, Dawn F.; Cusin, Cristina] Massachusetts Gen Hosp, Dept Psychiat, Depress Clin & Res Program, Boston, MA 02114 USA. [Ionescu, Dawn F.; Cusin, Cristina] Harvard Med Sch, Boston, MA 02115 USA. RP Ionescu, DF (reprint author), Massachusetts Gen Hosp, Dept Psychiat, Depress Clin & Res Program, Boston, MA 02114 USA.; Ionescu, DF (reprint author), Harvard Med Sch, Boston, MA 02115 USA. EM dionescu@partners.org NR 2 TC 0 Z9 0 U1 0 U2 0 PU PHYSICIANS POSTGRADUATE PRESS PI MEMPHIS PA P O BOX 752870, MEMPHIS, TN 38175-2870 USA SN 0160-6689 EI 1555-2101 J9 J CLIN PSYCHIAT JI J. Clin. Psychiatry PD JAN PY 2017 VL 78 IS 1 BP E72 EP E72 DI 10.4088/JCP.16lr11210a PG 1 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA EN9OX UT WOS:000396330600009 PM 28129501 ER PT J AU Chang, J Arani, K Chew, S Frosch, MP Gonzalez, RG Maza, N Romero, JM AF Chang, Jennifer Arani, Keerthi Chew, Sheena Frosch, Matthew P. Gonzalez, R. Gilberto Maza, Noor Romero, Javier M. TI Susceptibility Etching on MRI in Patients with Microangiopathy SO JOURNAL OF NEUROIMAGING LA English DT Article DE Suceptibility; MRI; thrombotic microangiopathy; cortical-subcortical junction; gray-white junction; intracerebral hemorrhage ID EXTRACORPOREAL MEMBRANE-OXYGENATION; DISSEMINATED INTRAVASCULAR COAGULATION; THROMBOTIC THROMBOCYTOPENIC PURPURA; REVERSIBLE ENCEPHALOPATHY SYNDROME; CEREBRAL MICROBLEEDS; MICROHEMORRHAGE; BRAIN AB BACKGROUND: We detected a novel imaging sign, which consists of a specific imaging pattern of diffuse susceptibility effect, delineating the cortical-subcortical junction on high-resolution susceptibility-weighted images (SWIs). We describe magnetic resonance imaging findings in 10 patients with "susceptibility etching" and possible association with their abnormal coagulation profile. MATERIALS/METHODS: A retrospective case series study with a search for cases that demonstrated susceptibility effect at the cortical-subcortical junction on SWI sequences was performed. The patients' respective coagulation profiles including prothrombin time, partial thromboplastin time, fibrinogen, D-dimer values, and platelet counts were reviewed. In addition, clinical history and neurological deficits were recorded. RESULTS: We identified 10 patients with the "susceptibility etching" pattern at the cortical-subcortical junction. All patients were acutely ill and had a significantly elevated D-dimer (4,309 mcg/L to > 10,000 mcg/L) with variably reduced platelet count. Two patients had reduced fibrinogen and 5 patients had prolonged international normalized ratio. Of the 10 patients, 4 died during hospitalization, within a few days of imaging. Pathology of 1 patient at autopsy demonstrated findings suggestive of a microvascular thrombotic or embolic event without overt parenchymal microhemorrhage. CONCLUSION: In this preliminary case series, we describe patients with "susceptibility etching" on SWI who were also found to have profound coagulation impairment. While other comorbities may also contribute to this novel sign, we suggest that a possible etiology may be secondary to microvascular in situ formation of fine thrombi and/or emboli lodged into an area of vascular caliber reduction and maybe related to thrombotic microangiopathy. C1 [Chang, Jennifer; Arani, Keerthi; Gonzalez, R. Gilberto; Maza, Noor; Romero, Javier M.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Neuroradiol, Boston, MA USA. [Chew, Sheena] Harvard Med Sch, Massachusetts Gen Hosp, Dept Neurol, Boston, MA USA. [Frosch, Matthew P.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Pathol, Boston, MA USA. RP Romero, JM (reprint author), Massachusetts Gen Hosp, 55 Fruit St,Neuroradiol Gray 2,Room 273A, Boston, MA 02114 USA. EM jmromero@mgh.harvard.edu NR 27 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1051-2284 EI 1552-6569 J9 J NEUROIMAGING JI J. Neuroimaging PD JAN-FEB PY 2017 VL 27 IS 1 BP 43 EP 49 DI 10.1111/jon.12384 PG 7 WC Clinical Neurology; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA EK4MK UT WOS:000393900700007 PM 27539492 ER PT J AU Prakkamakul, S Schaefer, P Gonzalez, G Rapalino, O AF Prakkamakul, Supada Schaefer, Pamela Gonzalez, Gilberto Rapalino, Otto TI MRI Patterns of Isolated Lesions in the Medulla Oblongata SO JOURNAL OF NEUROIMAGING LA English DT Article DE Medulla oblongata; isolated; etiologies; MRI; diagnostic algorithm ID BRAIN-STEM GLIOMAS; CENTRAL-NERVOUS-SYSTEM; ACUTE DISSEMINATED ENCEPHALOMYELITIS; HYPERTROPHIC OLIVARY DEGENERATION; NATURAL-HISTORY; PATIENT; HEMANGIOBLASTOMA; METASTASIS; MANAGEMENT; CAVERNOMAS AB BACKGROUND AND PURPOSE: Isolated lesions of the medulla oblongata are difficult to diagnose due to their rarity and high biopsy risk. Several individual case reports have been published, but a systematic descriptive study is lacking. Our study has three objectives that 1) provide a differential diagnosis, 2) describe magnetic resonance imaging (MRI) findings, and 3) propose a stepwise MRI-based approach to the isolated lesions of the medulla oblongata in nonstroke patients. METHODS: We performed an institutional Review Board-approved retrospective analysis of 34 consecutive cases of isolated medullary lesions from nonstroke causes identified from our imaging database between January 2000 and May 2015. Eleven were excluded due to lack of pretreatment or follow-up MRI. MR studies were reviewed by two blinded neuroradiologists. The diagnosis, demographic data, and MR findings were reported using frequencies and proportions. An MRI-based diagnostic algorithm was proposed. RESULTS: Most lesions were neoplasms (47%), followed by vascular malformations (15%), demyelinating/inflammatory lesions (15%), others (12%), unknown (8%), and infection (3%). Five MRI patterns were identified: 1) cystic lesion, 2) exophytic noncystic lesion, 3) intrinsic lesion with T2 hypointensity, 4) enhancing intrinsic lesion, and 5) nonenhancing intrinsic lesion. All showing patterns 1 and 2 were neoplasms or cysts. All showing pattern 3 were vascular malformations. Patterns 4 and 5 comprised of multiple etiologies. CONCLUSIONS: Neoplasms are the most common cause of isolated medullary lesions in nonstroke patients. Other differential diagnoses include vascular malformations, demyelinating/inflammatory lesions, and infections. A stepwise MRI-based approach can help differentiate between various etiologies. C1 [Prakkamakul, Supada; Schaefer, Pamela; Gonzalez, Gilberto; Rapalino, Otto] Massachusetts Gen Hosp, Dept Radiol, Neuroradiol Div, 55 Fruit St, Boston, MA USA. [Prakkamakul, Supada] Chulalongkorn Univ, Fac Med, Dept Radiol, King Chulalongkorn Mem Hosp,Thai Red Cross Soc, 1873 Rama 4 Rd, Bangkok, Thailand. RP Rapalino, O (reprint author), Massachusetts Gen Hosp, 55 Fruit St, Boston, MA 02114 USA. EM orapalino@mgh.harvard.edu NR 48 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1051-2284 EI 1552-6569 J9 J NEUROIMAGING JI J. Neuroimaging PD JAN-FEB PY 2017 VL 27 IS 1 BP 135 EP 143 DI 10.1111/jon.12361 PG 9 WC Clinical Neurology; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA EK4MK UT WOS:000393900700020 PM 27221582 ER EF