FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Rosenfield, K Matsumura, JS Chaturvedi, S Riles, T Ansel, GM Metzger, DC Wechsler, L Jaff, MR Gray, W AF Rosenfield, Kenneth Matsumura, Jon S. Chaturvedi, Seemant Riles, Tom Ansel, Gary M. Metzger, D. Chris Wechsler, Lawrence Jaff, Michael R. Gray, William CA ACT I Investigators TI Randomized Trial of Stent versus Surgery for Asymptomatic Carotid Stenosis SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID ARTERY STENOSIS; MEDICAL THERAPY; STROKE PREVENTION; ENDARTERECTOMY; DISEASE; RISK; INTERVENTION; ANGIOPLASTY; LESSONS AB BACKGROUND Previous clinical trials have suggested that carotid-artery stenting with a device to capture and remove emboli ("embolic protection") is an effective alternative to carotid endarterectomy in patients at average or high risk for surgical complications. METHODS In this trial, we compared carotid-artery stenting with embolic protection and carotid endarterectomy in patients 79 years of age or younger who had severe carotid stenosis and were asymptomatic (i.e., had not had a stroke, transient ischemic attack, or amaurosis fugax in the 180 days before enrollment) and were not considered to be at high risk for surgical complications. The trial was designed to enroll 1658 patients but was halted early, after 1453 patients underwent randomization, because of slow enrollment. Patients were followed for up to 5 years. The primary composite end point of death, stroke, or myocardial infarction within 30 days after the procedure or ipsilateral stroke within 1 year was tested at a noninferiority margin of 3 percentage points. RESULTS Stenting was noninferior to endarterectomy with regard to the primary composite end point (event rate, 3.8% and 3.4%, respectively; P = 0.01 for noninferiority). The rate of stroke or death within 30 days was 2.9% in the stenting group and 1.7% in the endarterectomy group (P = 0.33). From 30 days to 5 years after the procedure, the rate of freedom from ipsilateral stroke was 97.8% in the stenting group and 97.3% in the endarterectomy group (P = 0.51), and the overall survival rates were 87.1% and 89.4%, respectively (P = 0.21). The cumulative 5-year rate of stroke-free survival was 93.1% in the stenting group and 94.7% in the endarterectomy group (P = 0.44). CONCLUSIONS In this trial involving asymptomatic patients with severe carotid stenosis who were not at high risk for surgical complications, stenting was noninferior to endarterectomy with regard to the rate of the primary composite end point at 1 year. In analyses that included up to 5 years of follow-up, there were no significant differences between the study groups in the rates of non-procedure-related stroke, all stroke, and survival. C1 [Rosenfield, Kenneth; Jaff, Michael R.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Matsumura, Jon S.] Univ Wisconsin, Madison, WI 53706 USA. [Chaturvedi, Seemant] Univ Miami, Miami, FL USA. [Riles, Tom] NYU, Langone Sch Med, New York, NY USA. [Ansel, Gary M.] Ohio Hlth Syst, Columbus, OH USA. [Metzger, D. Chris] Wellmont Cardiovasc Associates Heart Inst, Kingsport, TN USA. [Wechsler, Lawrence] Univ Pittsburgh, Med Ctr, Pittsburgh, PA USA. [Gray, William] Main Line Hlth Syst, Philadelphia, PA USA. [Rosenfield, Kenneth] Massachusetts Gen Hosp, Div Cardiol, 55 Fruit St, Boston, MA 02114 USA. RP Rosenfield, K (reprint author), Massachusetts Gen Hosp, Div Cardiol, 55 Fruit St, Boston, MA 02114 USA. FU Abbott Vascular; ACT I FX Funded by Abbott Vascular; ACT I ClinicalTrials.gov number, NCT00106938. NR 27 TC 49 Z9 50 U1 3 U2 14 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 MAR 17 PY 2016 VL 374 IS 11 BP 1011 EP 1020 DI 10.1056/NEJMoa1515706 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA DG4TR UT WOS:000372066100005 PM 26886419 ER PT J AU Saukkonen, K Sharma, A Mark, EJ AF Saukkonen, Kai Sharma, Amita Mark, Eugene J. TI Case 8-2016: A 71-Year-Old Man with Recurrent Fevers, Hypoxemia, and Lung Infiltrates SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID HYPERSENSITIVITY PNEUMONITIS; UPDATE; CLASSIFICATION; DIAGNOSIS C1 [Saukkonen, Kai] Massachusetts Gen Hosp, Dept Pulm & Crit Care, Boston, MA 02114 USA. [Sharma, Amita] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Mark, Eugene J.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Saukkonen, Kai] Harvard Univ, Sch Med, Dept Pulm & Crit Care, Boston, MA 02115 USA. [Sharma, Amita] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Mark, Eugene J.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Saukkonen, K (reprint author), Massachusetts Gen Hosp, Dept Pulm & Crit Care, Boston, MA 02114 USA.; Saukkonen, K (reprint author), Harvard Univ, Sch Med, Dept Pulm & Crit Care, Boston, MA 02115 USA. NR 8 TC 0 Z9 0 U1 0 U2 3 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD MAR 17 PY 2016 VL 374 IS 11 BP 1077 EP 1085 DI 10.1056/NEJMcpc1505680 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA DG4TR UT WOS:000372066100014 PM 26981938 ER PT J AU Dehghani, N Peyrache, A Telenczuk, B Quyen, MLV Halgren, E Cash, SS Hatsopoulos, NG Destexhe, A AF Dehghani, Nima Peyrache, Adrien Telenczuk, Bartosz Quyen, Michel Le Van Halgren, Eric Cash, Sydney S. Hatsopoulos, Nicholas G. Destexhe, Alain TI Dynamic Balance of Excitation and Inhibition in Human and Monkey Neocortex SO SCIENTIFIC REPORTS LA English DT Article ID INTRACORTICAL ELECTRODE ARRAY; OPTOGENETIC CONTROL; ENSEMBLE RECORDINGS; CORTICAL-NEURONS; NETWORK ACTIVITY; SINGLE-NEURON; IN-VIVO; CELLS; CORTEX; EPILEPSY AB Balance of excitation and inhibition is a fundamental feature of in vivo network activity and is important for its computations. However, its presence in the neocortex of higher mammals is not well established. We investigated the dynamics of excitation and inhibition using dense multielectrode recordings in humans and monkeys. We found that in all states of the wake-sleep cycle, excitatory and inhibitory ensembles are well balanced, and co-fluctuate with slight instantaneous deviations from perfect balance, mostly in slow-wave sleep. Remarkably, these correlated fluctuations are seen for many different temporal scales. The similarity of these computational features with a network model of self-generated balanced states suggests that such balanced activity is essentially generated by recurrent activity in the local network and is not due to external inputs. Finally, we find that this balance breaks down during seizures, where the temporal correlation of excitatory and inhibitory populations is disrupted. These results show that balanced activity is a feature of normal brain activity, and break down of the balance could be an important factor to define pathological states. C1 [Dehghani, Nima] Harvard Univ, Wyss Inst Biol Inspired Engn, Boston, MA 02115 USA. [Dehghani, Nima] New England Complex Syst Inst, Cambridge, MA USA. [Peyrache, Adrien] NYU, Inst Neurosci, Nyc, NY USA. [Peyrache, Adrien] NYU, Ctr Neural Sci, Nyc, NY USA. [Telenczuk, Bartosz; Destexhe, Alain] CNRS, Lab Computat Neurosci, Unite Neurosci Informat & Complexite, Gif Sur Yvette, France. [Quyen, Michel Le Van] Hop La Pitie Salpetriere, CNRS, UMR 7225, Inst Cerveau & Moelle Epiniere,UMRS 1127, Paris, France. [Halgren, Eric] Univ Calif San Diego, Dept Neurosci, Multimodal Imaging Lab, La Jolla, CA 92093 USA. [Halgren, Eric] Univ Calif San Diego, Dept Radiol, La Jolla, CA 92093 USA. [Cash, Sydney S.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Cash, Sydney S.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Hatsopoulos, Nicholas G.] Univ Chicago, Dept Organismal Biol & Anat, Comm Computat Neurosci, 1025 E 57Th St, Chicago, IL 60637 USA. RP Dehghani, N (reprint author), Harvard Univ, Wyss Inst Biol Inspired Engn, Boston, MA 02115 USA.; Dehghani, N (reprint author), New England Complex Syst Inst, Cambridge, MA USA. EM nima.dehghani@wyss.harvard.edu OI Dehghani, Nima/0000-0003-2032-8903 FU Wyss Institute for Biologically-Inspired Engineering at Harvard University; Centre National de la Recherche Scientifique (CNRS, France); Agence Nationale de la Recherche (ANR, France); European Community [FP7-269921, FP7-604102]; National Institutes of Health (NIH) [5R01NS062092, R01EB009282, R01NS045853] FX The research was funded by Wyss Institute for Biologically-Inspired Engineering at Harvard University, Centre National de la Recherche Scientifique (CNRS, France), Agence Nationale de la Recherche (ANR, France), European Community Future and Emerging Technologies program (BrainScales FP7-269921; The Human Brain Project FP7-604102) and National Institutes of Health (NIH grants 5R01NS062092, R01EB009282 and R01NS045853). NR 41 TC 6 Z9 6 U1 5 U2 11 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 MAR 16 PY 2016 VL 6 AR 23176 DI 10.1038/srep23176 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DG4PX UT WOS:000372055300002 PM 26980663 ER PT J AU Fei, T Chen, YW Liu, XS Brown, M AF Fei, Teng Chen, Yiwen Liu, Xiaole Shirley Brown, Myles TI Functional long noncoding RNAs in castration-resistant prostate cancer SO CANCER RESEARCH LA English DT Meeting Abstract CT AACR Special Conference on Noncoding RNAs and Cancer - Mechanisms to Medicines CY DEC 04-07, 2015 CL Boston, MA SP Amer Assoc Canc Res C1 [Fei, Teng; Chen, Yiwen; Liu, Xiaole Shirley; Brown, Myles] Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 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 MAR 15 PY 2016 VL 76 SU 6 MA A22 DI 10.1158/1538-7445.NONRNA15-A22 PG 2 WC Oncology SC Oncology GA DM0VD UT WOS:000376063000044 ER PT J AU Fei, T Chen, YW Brown, M Liu, XS AF Fei, Teng Chen, Yiwen Brown, Myles Liu, X. Shirley TI Dependency of prostate cancer on HNRNPL and its associated RNAs SO CANCER RESEARCH LA English DT Meeting Abstract CT AACR Special Conference on Noncoding RNAs and Cancer - Mechanisms to Medicines CY DEC 04-07, 2015 CL Boston, MA SP Amer Assoc Canc Res C1 [Fei, Teng; Chen, Yiwen; Brown, Myles; Liu, X. Shirley] Dana Farber Canc Inst, Boston, MA 02115 USA. [Fei, Teng; Brown, Myles] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. [Fei, Teng; Brown, Myles] Harvard Univ, Sch Med, Boston, MA USA. [Fei, Teng; Chen, Yiwen; Liu, X. Shirley] Harvard Univ, Sch Publ Hlth, 665 Huntington Ave, Boston, MA 02115 USA. [Chen, Yiwen] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 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 MAR 15 PY 2016 VL 76 SU 6 MA IA11 DI 10.1158/1538-7445.NONRNA15-IA11 PG 2 WC Oncology SC Oncology GA DM0VD UT WOS:000376063000021 ER PT J AU Qu, FF Sun, T Wang, XD Lee, GSM Kantoff, PW AF Qu, Fangfang Sun, Tong Wang, Xiaodong Lee, Gwo-Shu Mary Kantoff, Philip W. TI LncRNA MIR222HG transcribed from the miR-221/222 promoter are associated with the development of castration resistant prostate cancer SO CANCER RESEARCH LA English DT Meeting Abstract CT AACR Special Conference on Noncoding RNAs and Cancer - Mechanisms to Medicines CY DEC 04-07, 2015 CL Boston, MA SP Amer Assoc Canc Res C1 [Qu, Fangfang; Sun, Tong; Wang, Xiaodong; Lee, Gwo-Shu Mary; Kantoff, Philip W.] Dana Farber Canc Inst, Boston, MA 02115 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 MAR 15 PY 2016 VL 76 SU 6 MA A10 DI 10.1158/1538-7445.NONRNA15-A10 PG 2 WC Oncology SC Oncology GA DM0VD UT WOS:000376063000071 ER PT J AU Hasegawa, M Takahashi, H Rajabi, H Alam, M Suzuki, Y Yin, L Tagde, A Maeda, T Hiraki, M Sukhatme, VP Kufe, D AF Hasegawa, Masanori Takahashi, Hidekazu Rajabi, Hasan Alam, Maroof Suzuki, Yozo Yin, Li Tagde, Ashujit Maeda, Takahiro Hiraki, Masayuki Sukhatme, Vikas P. Kufe, Donald TI Functional interactions of the cystine/glutamate antiporter, CD44v and MUC1-C oncoprotein in triple-negative breast cancer cells SO ONCOTARGET LA English DT Article DE xCT; MUC1-C; CD44v; epigenetics; ferroptosis ID GLUTATHIONE SYNTHESIS; TRANSCRIPTION FACTOR; THERAPEUTIC TARGET; REGULATORY LOOP; CARCINOMA CELLS; LUNG-CANCER; ACTIVATION; EXPRESSION; OVEREXPRESSION; OPPORTUNITIES AB The xCT light chain of the cystine/glutamate transporter (system X-C(-)) is of importance for the survival of triple-negative breast cancer (TNBC) cells. The MUC1-C transmembrane oncoprotein is aberrantly overexpressed in TNBC and, like xCT, has been linked to maintaining glutathione (GSH) levels and redox balance. However, there is no known interaction between MUC1-C and xCT. Here we show that silencing MUC1-C is associated with decreases in xCT expression in TNBC cells. The results demonstrate that MUC1-C forms a complex with xCT and the CD44 variant (CD44v), which interacts with xCT and thereby controls GSH levels. MUC1-C binds directly with CD44v and in turn promotes stability of xCT in the cell membrane. The interaction between MUC1-C and xCT is further supported by the demonstration that targeting xCT with silencing or the inhibitor sulfasalazine suppresses MUC1 gene transcription by increasing histone and DNA methylation on the MUC1 promoter. In terms of the functional significance of the MUC1-C/xCT interaction, we show that MUC1-C protects against treatment with erastin, an inhibitor of X C -and inducer of ferroptosis, a form of non-apoptotic cell death. These findings indicate that targeting this novel MUC1-C/ xCT pathway could represent a potential therapeutic approach for promoting TNBC cell death. C1 [Hasegawa, Masanori; Takahashi, Hidekazu; Rajabi, Hasan; Alam, Maroof; Suzuki, Yozo; Yin, Li; Tagde, Ashujit; Maeda, Takahiro; Hiraki, Masayuki; Kufe, Donald] Harvard Univ, Sch Med, Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. [Sukhatme, Vikas P.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Boston, MA 02215 USA. [Takahashi, Hidekazu] Osaka Univ, Dept Gastrointestinal Surg, Grad Sch Med, Suita, Osaka, Japan. [Suzuki, Yozo] Osaka Police Hosp, Dept Surg Gastroenterol, Osaka, Osaka, Japan. RP Kufe, D (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. EM donald_kufe@dfci.harvard.edu FU National Cancer Institute of the National Institutes of Health [CA097098, CA166480]; Lung Cancer Research Foundation FX Research reported in this paper was supported by the National Cancer Institute of the National Institutes of Health under award numbers CA097098 and CA166480, and by the Lung Cancer Research Foundation. NR 43 TC 9 Z9 9 U1 3 U2 3 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD MAR 15 PY 2016 VL 7 IS 11 BP 11756 EP 11769 PG 14 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DL5LW UT WOS:000375679600003 PM 26930718 ER PT J AU de Bruin, LO Yang, W Capuder, K Lee, YN Antolini, M Meyers, R Gellert, M Musunuru, K Manis, J Notarangelo, L AF de Bruin, Lisa Ott Yang, Wei Capuder, Kelly Lee, Yu Nee Antolini, Maddalena Meyers, Robin Gellert, Martin Musunuru, Kiran Manis, John Notarangelo, Luigi TI Rapid generation of novel models of RAG1 deficiency by CRISPR/Cas9-induced mutagenesis in murine zygotes SO ONCOTARGET LA English DT Article DE recombination activation gene 1; RAG1; genome editing; immunodeficiency; CRISPR/Cas9 ID ONE-STEP GENERATION; OMENN-SYNDROME; V(D)J RECOMBINATION; T-CELLS; GRANULOMATOUS-DISEASE; MODIFIED MICE; MUTATIONS; IMMUNODEFICIENCY; LYMPHOCYTES; GENES AB Mutations in the Recombination Activating Gene 1 (RAG1) can cause a wide variety of clinical and immunological phenotypes in humans, ranging from absence of T and B lymphocytes to occurrence of autoimmune manifestations associated with expansion of oligoclonal T cells and production of autoantibodies. Although the mechanisms underlying this phenotypic heterogeneity remain poorly understood, some genotype-phenotype correlations can be made. Currently, mouse models of Rag deficiency are restricted to RAG1(-/-) mice and to knock-in models carrying severe missense mutations. The Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR)/Cas9 system is a novel and powerful gene-editing strategy that permits targeted introduction of DNA double strand breaks with high efficiency through simultaneous delivery of the Cas9 endonuclease and a guide RNA (gRNA). Here, we report on CRISPR-based, single-step generation and characterization of mutant mouse models in which gene editing was attempted around residue 838 of RAG1, a region whose functional role had not been studied previously. C1 [de Bruin, Lisa Ott; Capuder, Kelly; Lee, Yu Nee; Antolini, Maddalena; Notarangelo, Luigi] Harvard Univ, Sch Med, Div Immunol, Boston Childrens Hosp, Boston, MA USA. [de Bruin, Lisa Ott] Wilhelmina Childrens Hosp, Utrecht Univ Med Ctr, Pediat Immunol, Utrecht, Netherlands. [Yang, Wei; Gellert, Martin] NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Meyers, Robin] Boston Childrens Hosp, Program Cellular & Mol Med, Boston, MA USA. [Musunuru, Kiran] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. [Musunuru, Kiran; Notarangelo, Luigi] Harvard Univ, Harvard Stem Cell Inst, Cambridge, MA 02138 USA. [Manis, John] Harvard Univ, Div Transfus Med, Dept Lab Med, Boston Childrens Hosp,Med Sch, Boston, MA USA. RP Notarangelo, L (reprint author), Harvard Univ, Sch Med, Div Immunol, Boston Childrens Hosp, Boston, MA USA.; Notarangelo, L (reprint author), Harvard Univ, Harvard Stem Cell Inst, Cambridge, MA 02138 USA. EM Luigi.Notarangelo@childrens.harvard.edu FU National Institute of Health, National Institute of Allergy and Infectious Diseases [R01AI100887, R21A1088510]; March of Dimes grant [MOD - 6FY10-282]; T32 fellowship grant [5T32AI007512]; intramural program of the National Institute of Diabetes and Digestive and Kidney Diseases, NIH FX This work was supported by grant R01AI100887 from the National Institute of Health, National Institute of Allergy and Infectious Diseases (to LN) and March of Dimes grant MOD - 6FY10-282 (to). LO is supported by T32 fellowship grant 5T32AI007512. The research of WY and MG is supported by the intramural program of the National Institute of Diabetes and Digestive and Kidney Diseases, NIH. JM is supported by grant R21A1088510 from the National Institute of Health, National Institute of Allergy and Infectious Diseases. NR 34 TC 1 Z9 1 U1 0 U2 0 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD MAR 15 PY 2016 VL 7 IS 11 BP 12962 EP 12974 PG 13 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DL5LW UT WOS:000375679600092 ER PT J AU Wang, D Wang, M Jiang, N Zhang, Y Bian, X Wang, XQ Roberts, TM Zhao, JJ Liu, PX Cheng, HL AF Wang, Dong Wang, Min Jiang, Nan Zhang, Yuan Bian, Xing Wang, Xiaoqing Roberts, Thomas M. Zhao, Jean J. Liu, Pixu Cheng, Hailing TI Effective use of PI3K inhibitor BKM120 and PARP inhibitor Olaparib to treat PIK3CA mutant ovarian cancer SO ONCOTARGET LA English DT Article DE ovarian cancer; BKM120; Olaparib; BRCA; combination therapy ID NEGATIVE BREAST-CANCER; DNA-REPAIR; PHASE-I; CELLS; NVP-BKM120; RESISTANCE; MODELS; IDENTIFICATION; COMBINATION; EXPRESSION AB Recent preclinical studies revealed the efficacy of combined use of PI3K inhibitor BKM120 and PARP inhibitor Olaparib in breast and prostate cancers. The current study investigated the effect of such drug combination on ovarian cancer. Here we showed that combined inhibition of PI3K and PARP effectively synergized to inhibit proliferation, survival and invasion in the majority of ovarian cancer cell lines harboring PIK3CA mutations, including SKOV3, HEYA8, and IGROV1. Mechanistically, combined treatment of PARP and PI3K inhibitors resulted in an exacerbated DNA damage response and more substantially reduced AKT/mTOR signaling when compared to single-agent. Notably, ovarian cancer cells responsive to the PI3K/PARP combination displayed decreased BRCA1/2 expression upon drug treatment. Furthermore, the effect of the drug combination was corroborated in an intraperitoneal dissemination xenograft mouse model in which SKOV3 ovarian cancer cells responded with significantly decreased BRCA1 expression, suppressed PI3K/AKT signaling and reduced tumor burden. Collectively, our data suggested that combined inhibition of PI3K and PARP may be an effective therapeutic strategy for ovarian cancers with PIK3CA mutations and that the accompanied BRCA downregulation following PI3K inhibition could serve as a biomarker for the effective response to PARP inhibition. C1 [Wang, Dong; Wang, Min; Jiang, Nan; Zhang, Yuan; Bian, Xing; Wang, Xiaoqing; Liu, Pixu; Cheng, Hailing] Dalian Med Univ, Inst Canc, Inst Canc Stem Cell, Hosp 2, Dalian 116044, Peoples R China. [Wang, Dong] Dept Histol & Embryol, Binzhou Med Coll, Yantai 264000, Peoples R China. [Roberts, Thomas M.; Zhao, Jean J.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Roberts, Thomas M.; Zhao, Jean J.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. RP Liu, PX; Cheng, HL (reprint author), Dalian Med Univ, Inst Canc, Inst Canc Stem Cell, Hosp 2, Dalian 116044, Peoples R China.; Zhao, JJ (reprint author), Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA.; Zhao, JJ (reprint author), Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. EM jean_zhao@dfci.harvard.edu; pixu_liu@dmu.edu.cn; hailingcheng_dmu@163.com FU National Natural Science Foundation of China [81472447, 81372853, 81572586]; Liaoning Provincial Climbing Scholars Supporting Program of China; Program for Changjiang Scholars and Innovative Research Team in University [IRT13049]; Provincial Natural Science Foundation of Liaoning [2014023002] FX This work was supported by the National Natural Science Foundation of China (No. 81472447 to H. Cheng; No. 81372853 and No. 81572586 to P. Liu), Liaoning Provincial Climbing Scholars Supporting Program of China (2012 to P. Liu, 2014 to H. Cheng), Program for Changjiang Scholars and Innovative Research Team in University (No. IRT13049 to P. Liu), and Provincial Natural Science Foundation of Liaoning (No. 2014023002 to P. Liu). NR 41 TC 4 Z9 4 U1 3 U2 5 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD MAR 15 PY 2016 VL 7 IS 11 BP 13153 EP 13166 PG 14 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DL5LW UT WOS:000375679600105 PM 26909613 ER PT J AU Budczies, J Pfarr, N Stenzinger, A Treue, D Endris, V Ismaeel, F Bangemann, N Blohmer, JU Dietel, M Loibl, S Klauschen, F Weichert, W Denkert, C AF Budczies, Jan Pfarr, Nicole Stenzinger, Albrecht Treue, Denise Endris, Volker Ismaeel, Fakher Bangemann, Nikola Blohmer, Jens-Uwe Dietel, Manfred Loibl, Sibylle Klauschen, Frederick Weichert, Wilko Denkert, Carsten TI Ioncopy: a novel method for calling copy number alterations in amplicon sequencing data including significance assessment SO ONCOTARGET LA English DT Article DE targeted sequencing; amplicon sequencing; semiconductor sequencing; copy number alterations; breast cancer ID HER2-POSITIVE BREAST-CANCER; ADJUVANT CHEMOTHERAPY; HER2; SPECIMENS; TRASTUZUMAB; TUMORS; TRIAL; PLUS AB Recently, it has been demonstrated that calling of copy number alterations (CNAs) from amplicon sequencing (AS) data is feasible. Most approaches, however, require non-tumor (germline) DNA for data normalization. Here, we present the method Ioncopy for CNA detection which requires no normal controls and includes a significance assessment for each detected alteration. Ioncopy was evaluated in a cohort of 184 clinically annotated breast carcinomas. A total number of 252 amplifications were detected, of which 183 (72.6%) could be validated by a call of an additional amplicon interrogating the same gene. Moreover, a total number of 33 deletions were found, whereof 27 (81.8%) could be validated. Analyzing the 16 most frequently amplified genes, validation rates of over 89% could be achieved for 11 of these genes. 11 of the top 16 genes showed significant overexpression in the amplified tumors. 89.5% of the HER2-amplified tumors were GRB7 and STARD3 co-amplified, whereas 68.4% of the HER2-amplified tumors had additional MED1 amplifications. Correlations between CNAs measured by amplicons in HER2 exons 19, 20 and 21 were strong (all R > 0.93). AS based detection of HER2 amplifications had a sensitivity of 90.0% and a specificity of 98.8% compared to the gold standard of HER2 immunohistochemistry combined with in situ hybridization. In summary, we developed and validated a novel method for detection and significance assessment of CNAs in amplicon sequencing data. Using Ioncopy, AS offers a straightforward and efficient approach to simultaneously analyze gene amplifications and gene deletions together with simple somatic mutations in a single assay. C1 [Budczies, Jan; Treue, Denise; Dietel, Manfred; Klauschen, Frederick; Denkert, Carsten] Charite, Inst Pathol, Berlin, Germany. [Budczies, Jan; Pfarr, Nicole; Stenzinger, Albrecht; Endris, Volker; Dietel, Manfred; Weichert, Wilko; Denkert, Carsten] Partner Sites Berlin, German Canc Consortium DKTK, Heidelberg, Germany. [Budczies, Jan; Pfarr, Nicole; Stenzinger, Albrecht; Endris, Volker; Dietel, Manfred; Weichert, Wilko; Denkert, Carsten] Partner Sites Berlin, German Canc Consortium DKTK, Munich, Germany. [Pfarr, Nicole; Stenzinger, Albrecht; Endris, Volker; Weichert, Wilko] Univ Heidelberg Hosp, Inst Pathol, Heidelberg, Germany. [Pfarr, Nicole; Weichert, Wilko] Tech Univ Munich, Inst Pathol, D-80290 Munich, Germany. [Stenzinger, Albrecht; Weichert, Wilko] Natl Ctr Tumor Dis NCT, Heidelberg, Germany. [Stenzinger, Albrecht] Harvard Univ, Sch Med, Dept Pathol, CID,Massachusetts Gen Hosp, Boston, MA 02115 USA. [Ismaeel, Fakher] Charite, Dept Gynecol, Berlin, Germany. [Bangemann, Nikola; Blohmer, Jens-Uwe] Charite, Interdisciplinary Breast Ctr, Berlin, Germany. [Loibl, Sibylle] GBG, Neu Isenburg, Germany. RP Budczies, J (reprint author), Charite, Inst Pathol, Berlin, Germany.; Budczies, J (reprint author), Partner Sites Berlin, German Canc Consortium DKTK, Heidelberg, Germany.; Budczies, J (reprint author), Partner Sites Berlin, German Canc Consortium DKTK, Munich, Germany. EM jan.budczies@charite.de FU German Cancer Consortium (DKTK); National Center for Tumor Diseases of the Heidelberg School of Oncology (NCT-HSO), Heidelberg, Germany FX This study was funded by the German Cancer Consortium (DKTK, funding to CD and WW). AS was supported by a fellowship of the National Center for Tumor Diseases of the Heidelberg School of Oncology (NCT-HSO), Heidelberg, Germany. NR 18 TC 3 Z9 3 U1 0 U2 0 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD MAR 15 PY 2016 VL 7 IS 11 BP 13236 EP 13247 PG 12 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DL5LW UT WOS:000375679600112 PM 26910888 ER PT J AU Conery, AR Centore, RC Spillane, KL Follmer, NE Bommi-Reddy, A Hatton, C Bryant, BM Greninger, P Amzallag, A Benes, CH Mertz, JA Sims, RJ AF Conery, Andrew R. Centore, Richard C. Spillane, Kerry L. Follmer, Nicole E. Bommi-Reddy, Archana Hatton, Charlie Bryant, Barbara M. Greninger, Patricia Amzallag, Arnaud Benes, Cyril H. Mertz, Jennifer A. Sims, Robert J., III TI Preclinical Anticancer Efficacy of BET Bromodomain Inhibitors Is Determined by the Apoptotic Response SO CANCER RESEARCH LA English DT Article ID C-MYC; LEUKEMIA; CANCER; RESISTANCE; STRATEGY; ABT-199; TUMORS; DEATH AB Small-molecule inhibitors of the bromodomain and extra-terminal (BET) family of proteins are being tested in clinical trials for a variety of cancers, but patient selection strategies remain limited. This challenge is partly attributed to the heterogeneous responses elicited by BET inhibition (BETi), including cellular differentiation, senescence, and death. In this study, we performed phenotypic and gene-expression analyses of treatment-naive and engineered tolerant cell lines representing human melanoma and leukemia to elucidate the dominant features defining response to BETi. We found that de novo and acquired tolerance to BETi is driven by the robustness of the apoptotic response, and that genetic or pharmacologic manipulation of the apoptotic signaling network can modify the phenotypic response to BETi. We further reveal that the expression signatures of the apoptotic genes BCL2, BCL2L1, and BAD significantly predict response to BETi. Taken together, our findings highlight the apoptotic program as a determinant of response to BETi, and provide a molecular basis for patient stratification and combination therapy development. (C) 2016 AACR. C1 [Conery, Andrew R.; Centore, Richard C.; Spillane, Kerry L.; Follmer, Nicole E.; Bommi-Reddy, Archana; Hatton, Charlie; Bryant, Barbara M.; Mertz, Jennifer A.; Sims, Robert J., III] Constellat Pharmaceut Inc, 215 First St,Suite 200, Cambridge, MA 02142 USA. [Greninger, Patricia; Amzallag, Arnaud; Benes, Cyril H.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Canc, Boston, MA USA. RP Sims, RJ (reprint author), Constellat Pharmaceut Inc, 215 First St,Suite 200, Cambridge, MA 02142 USA. EM robert.Sims@constellationpharma.com NR 18 TC 2 Z9 2 U1 1 U2 3 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 MAR 15 PY 2016 VL 76 IS 6 BP 1313 EP 1319 DI 10.1158/0008-5472.CAN-15-1458 PG 7 WC Oncology SC Oncology GA DL7WR UT WOS:000375851600004 PM 26759243 ER PT J AU Bouillez, A Rajabi, H Pitroda, S Jin, CN Alam, M Kharbanda, A Tagde, A Wong, KK Kufe, D AF Bouillez, Audrey Rajabi, Hasan Pitroda, Sean Jin, Caining Alam, Maroof Kharbanda, Akriti Tagde, Ashujit Wong, Kwok-Kin Kufe, Donald TI Inhibition of MUC1-C Suppresses MYC Expression and Attenuates Malignant Growth in KRAS Mutant Lung Adenocarcinomas SO CANCER RESEARCH LA English DT Article ID BET BROMODOMAIN INHIBITION; C-MYC; CANCER CELLS; THERAPEUTIC STRATEGY; RAS ONCOGENES; TARGET; ONCOPROTEIN; ACTIVATION; TRANSCRIPTION; CATENIN AB Dysregulation of MYC expression is a hallmark of cancer, but the development of agents that target MYC has remained challenging. The oncogenic MUC1-C transmembrane protein is, like MYC, aberrantly expressed in diverse human cancers. The present studies demonstrate that MUC1-C induces MYC expression in KRAS mutant non-small cell lung cancer (NSCLC) cells, an effect that can be suppressed by targeting MUC1-C via shRNA silencing, CRISPR editing, or pharmacologic inhibition with GO-203. MUC1-C activated the WNT/beta-catenin (CTNNB1) pathway and promoted occupancy of MUC1-C/beta-catenin/TCF4 complexes on the MYC promoter. MUC1-C also promoted the recruitment of the p300 histone acetylase (EP300) and, in turn, induced histone H3 acetylation and activation of MYC gene transcription. We also show that targeting MUC1-C decreased the expression of key MYC target genes essential for the growth and survival of NSCLC cells, such as TERT and CDK4. Based on these results, we found that the combination of GO-203 and the BET bromodomain inhibitor JQ1, which targets MYC transcription, synergistically suppressed MYC expression and cell survival in vitro as well as tumor xenograft growth. Furthermore, MUC1 expression significantly correlated with that of MYC and its target genes in human KRAS mutant NSCLC tumors. Taken together, these findings suggest a therapeutic approach for targeting MYC-dependent cancers and provide the framework for the ongoing clinical studies addressing the efficacy of MUC1-C inhibition in solid tumors. (C) 2016 AACR. C1 [Bouillez, Audrey; Rajabi, Hasan; Jin, Caining; Alam, Maroof; Kharbanda, Akriti; Tagde, Ashujit; Wong, Kwok-Kin; Kufe, Donald] Harvard Univ, Dana Farber Canc Inst, Sch Med, 450 Brookline Ave,Dana 830, Boston, MA 02215 USA. [Pitroda, Sean] Univ Chicago, Dept Radiat & Cellular Oncol, Chicago, IL 60637 USA. [Kharbanda, Akriti] Univ Penn, Dept Canc Biol, Witze Lab, Biomedical Res Bldg 2-3,421 Curie Blvd, Philadelphia, PA 19104 USA. RP Kufe, D (reprint author), Harvard Univ, Dana Farber Canc Inst, Sch Med, 450 Brookline Ave,Dana 830, Boston, MA 02215 USA. EM donald_kufe@dfci.harvard.edu RI Tagde, Ashujit/M-9497-2014 OI Tagde, Ashujit/0000-0002-0770-097X FU NCI NIH HHS [R01 CA097098, CA97098, CA166480, R01 CA166480] NR 50 TC 14 Z9 14 U1 3 U2 10 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 MAR 15 PY 2016 VL 76 IS 6 BP 1538 EP 1548 DI 10.1158/0008-5472.CAN-15-1804 PG 11 WC Oncology SC Oncology GA DL7WR UT WOS:000375851600024 PM 26833129 ER PT J AU Jia, Y Juarez, J Li, J Manuia, M Niederst, MJ Tompkins, C Timple, N Vaillancourt, MT Pferdekamper, AC Lockerman, EL Li, C Anderson, J Costa, C Liao, D Murphy, E DiDonato, M Bursulaya, B Lelais, G Barretina, J McNeill, M Epple, R Marsilje, TH Pathan, N Engelman, JA Michellys, PY McNamara, P Harris, J Bender, S Kasibhatla, S AF Jia, Yong Juarez, Jose Li, Jie Manuia, Mari Niederst, Matthew J. Tompkins, Celin Timple, Noelito Vaillancourt, Mei-Ting Pferdekamper, AnneMarie Culazzo Lockerman, Elizabeth L. Li, Chun Anderson, Jennifer Costa, Carlotta Liao, Debbie Murphy, Eric DiDonato, Michael Bursulaya, Badry Lelais, Gerald Barretina, Jordi McNeill, Matthew Epple, Robert Marsilje, Thomas H. Pathan, Nuzhat Engelman, Jeffrey A. Michellys, Pierre-Yves McNamara, Peter Harris, Jennifer Bender, Steven Kasibhatla, Shailaja TI EGF816 Exerts Anticancer Effects in Non-Small Cell Lung Cancer by Irreversibly and Selectively Targeting Primary and Acquired Activating Mutations in the EGF Receptor SO CANCER RESEARCH LA English DT Article ID KINASE INHIBITOR; T790M MUTATION; RESISTANCE; THERAPY; ADENOCARCINOMAS; GEFITINIB; ERLOTINIB; HETEROGENEITY; SENSITIVITY; MECHANISMS AB Non-small cell lung cancer patients carrying oncogenic EGFR mutations initially respond to EGFR-targeted therapy, but later elicit minimal response due to dose-limiting toxicities and acquired resistance. EGF816 is a novel, irreversible mutant-selective EGFR inhibitor that specifically targets EGFR-activating mutations arising de novo and upon resistance acquisition, while sparing wild-type (WT) EGFR. EGF816 potently inhibited the most common EGFR mutations L858R, Ex19del, and T790M in vitro, which translated into strong tumor regressions in vivo in several patient-derived xenograft models. Notably, EGF816 also demonstrated antitumor activity in an exon 20 insertion mutant model. At levels above efficacious doses, EGF816 treatment led to minimal inhibition of WT EGFR and was well tolerated. In single-dose studies, EGF816 provided sustained inhibition of EGFR phosphorylation, consistent with its ability for irreversible binding. Furthermore, combined treatment with EGF816 and INC280, a cMET inhibitor, resulted in durable antitumor efficacy in a xenograft model that initially developed resistance to first-generation EGFR inhibitors via cMET activation. Thus, we report the first preclinical characterization of EGF816 and provide the groundwork for its current evaluation in phase I/II clinical trials in patients harboring EGFR mutations, including T790M. (C) 2016 AACR. C1 [Jia, Yong; Juarez, Jose; Li, Jie; Manuia, Mari; Tompkins, Celin; Timple, Noelito; Vaillancourt, Mei-Ting; Pferdekamper, AnneMarie Culazzo; Li, Chun; Anderson, Jennifer; Liao, Debbie; Murphy, Eric; DiDonato, Michael; Bursulaya, Badry; Lelais, Gerald; McNeill, Matthew; Epple, Robert; Marsilje, Thomas H.; Pathan, Nuzhat; Michellys, Pierre-Yves; McNamara, Peter; Harris, Jennifer; Bender, Steven; Kasibhatla, Shailaja] Novartis Res Fdn, Genom Inst, 10675 John J Hopkins Dr, San Diego, CA 92121 USA. [Niederst, Matthew J.; Lockerman, Elizabeth L.; Costa, Carlotta; Engelman, Jeffrey A.] Harvard Univ, Sch Med, Ctr Canc, Massachusetts Gen Hosp, Charlestown, MA USA. [Barretina, Jordi] Novartis Inst Biomed Res, Cambridge, MA USA. RP Jia, Y; Kasibhatla, S (reprint author), Novartis Res Fdn, Genom Inst, 10675 John J Hopkins Dr, San Diego, CA 92121 USA. EM yjia@gnf.org; skasibhatla@gnf.org RI Mendez, Pedro /J-8955-2016 OI Mendez, Pedro /0000-0001-6713-7907 NR 42 TC 13 Z9 13 U1 1 U2 5 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 MAR 15 PY 2016 VL 76 IS 6 BP 1591 EP 1602 DI 10.1158/0008-5472.CAN-15-2581 PG 12 WC Oncology SC Oncology GA DL7WR UT WOS:000375851600029 PM 26825170 ER PT J AU Nicholl, MB Chen, XH Qin, CL Bai, Q Zhu, ZW Davis, MR Fang, YJ AF Nicholl, Michael B. Chen, Xuhui Qin, Chenglu Bai, Qian Zhu, Ziwen Davis, Matthew R. Fang, Yujiang TI IL-32 has differential effects on proliferation and apoptosis of human melanoma cell lines SO JOURNAL OF SURGICAL ONCOLOGY LA English DT Article DE IL-32; apoptosis; proliferation ID NATURAL-KILLER-CELLS; NF-KAPPA-B; RHEUMATOID-ARTHRITIS; GASTRIC-CANCER; T-CELLS; INTERLEUKIN-32; DEATH; EXPRESSION; GROWTH; METASTASIS AB BackgroundInterleukin-32 (IL-32) is a recently recognized intracellular, proinflammatory cytokine which may play a role in cancer metastasis and patient survival. The role of IL-32 in cancer, especially its direct effect on cancer cells, is not well understood. Material and MethodsClonogenic assay, PCNA staining, Quick Cell Proliferation assay, TUNEL staining, and caspase-3 activity assay were used to investigate the in vitro role for IL-32 in human melanoma growth. We further investigated the possible molecular mechanisms using RT-PCR and immunohistochemical staining. ResultsExogenous administration of IL-32 inhibited proliferation of the HTB-72 human melanoma cell line, but had little effect on other melanoma cell lines. Inhibition of proliferation in HTB-72 correlated with increased expression of p21 and p53. IL-32 administration also increased apoptosis in HTB-72. This finding correlated with increased expression of TRAILR1. ConclusionsThe data presented suggest a direct effect of IL-32 on the growth of human melanoma and give some insight into the mechanisms which may in part govern this effect. J. Surg. Oncol. 2016;113:364-369. (c) 2016 Wiley Periodicals, Inc. C1 [Nicholl, Michael B.; Chen, Xuhui; Qin, Chenglu; Bai, Qian; Zhu, Ziwen; Davis, Matthew R.; Fang, Yujiang] Univ Missouri, Sch Med, Ellis Fischel Canc Ctr, Columbia, MO USA. [Nicholl, Michael B.] South Texas Vet Hlth Care Syst, 7400 Merton Minter Blvd, San Antonio, TX 78229 USA. [Chen, Xuhui; Qin, Chenglu] Luohu Hosp, Shenzhen, Peoples R China. [Fang, Yujiang] Des Moines Univ, Des Moines, IA 50312 USA. RP Nicholl, MB (reprint author), South Texas Vet Hlth Care Syst, Dept Surg, 7400 Merton Minter Blvd, San Antonio, TX 78229 USA.; Fang, YJ (reprint author), Des Moines Univ, Coll Osteopath Med, Dept Microbiol Immunol & Pathol, Des Moines, IA 50312 USA. EM michaelnicholl@gmail.com; yujiang.fang@dmu.edu RI Zhu, Ziwen/I-1895-2014 OI Zhu, Ziwen/0000-0002-6681-9153 FU University of Missouri; Des Moines University FX Grant sponsor: University of Missouri; Grant sponsor: Des Moines University NR 39 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-4790 EI 1096-9098 J9 J SURG ONCOL JI J. Surg. Oncol. PD MAR 15 PY 2016 VL 113 IS 4 BP 364 EP 369 DI 10.1002/jso.24142 PG 6 WC Oncology; Surgery SC Oncology; Surgery GA DK1YK UT WOS:000374711400004 PM 27100023 ER PT J AU Montgomery, B Eisenberger, MA Rettig, MB Chu, F Pili, R Stephenson, JJ Vogelzang, NJ Koletsky, AJ Nordquist, LT Edenfield, WJ Mamlouk, K Ferrante, KJ Taplin, ME AF Montgomery, Bruce Eisenberger, Mario A. Rettig, Matthew B. Chu, Franklin Pili, Roberto Stephenson, Joseph J. Vogelzang, Nicholas J. Koletsky, Alan J. Nordquist, Luke T. Edenfield, William J. Mamlouk, Khalid Ferrante, Karen J. Taplin, Mary-Ellen TI Androgen Receptor Modulation Optimized for Response (ARMOR) Phase I and II Studies: Galeterone for the Treatment of Castration-Resistant Prostate Cancer SO CLINICAL CANCER RESEARCH LA English DT Article ID ANTITUMOR EFFICACY; INCREASED SURVIVAL; CLINICAL-TRIALS; XENOGRAFT MODEL; PROGRESSION; ABIRATERONE; ENZALUTAMIDE; CHEMOTHERAPY; GROWTH; TESTOSTERONE AB Purpose: Galeterone is a selective, multitargeted agent that inhibits CYP17, antagonizes the androgen receptor (AR), and reduces AR expression in prostate cancer cells by causing an increase in AR protein degradation. These open-label phase I and II studies [Androgen Receptor Modulation Optimized for Response-1 (ARMOR1) and ARMOR2 part 1] evaluated the efficacy and safety of galeterone in patients with treatment-naive nonmetastatic or metastatic castration-resistant prostate cancer (CRPC) and established a dose for further study. Experimental Design: In ARMOR1, 49 patients received increasing doses (650-2,600 mg) of galeterone in capsule formulation; 28 patients in ARMOR2 part 1 received increasing doses (1,700-3,400 mg) of galeterone in tablet formulation for 12 weeks. Patients were evaluated biweekly for safety and efficacy, and pharmacokinetic parameters were assessed. Results: InARMOR1, across all doses, 49.0% (24/49) achieved a >= 30% decline in prostate-specific antigen (PSA; PSA30) and 22.4% (11/49) demonstrated a >= 50% PSA decline (PSA50). In ARMOR2 part 1, across all doses, PSA30 was 64.0% (16/25) and PSA50 was 48.0% (12/25). In the 2,550-mg dose cohort, PSA30 was 72.7% (8/11) and PSA50 was 54.5% (6/11). Galeterone was well tolerated; the most common adverse events were fatigue, increased liver enzymes, gastrointestinal events, and pruritus. Most were mild or moderate in severity and required no action and there were no apparent mineralocorticoid excess (AME) events. Conclusions: The efficacy and safety from ARMOR1 and ARMOR2 part 1 and the pharmacokinetic results support the galeterone tablet dose of 2,550 mg/d for further study. Galeterone was well tolerated and demonstrated pharmacodynamic changes consistent with its selective, multifunctional AR signaling inhibition. (C) 2015 AACR. C1 [Montgomery, Bruce] Univ Washington, Seattle, WA 98195 USA. [Eisenberger, Mario A.] Johns Hopkins Univ, James Buchanan Brady Urol Inst, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. [Rettig, Matthew B.] UCLA Jonsson Comprehens Canc Ctr, Los Angeles, CA USA. [Chu, Franklin] San Bernadino Urol Associates, San Bernardino, CA USA. [Pili, Roberto] Indiana Univ Sch Med, Indianapolis, IN 46202 USA. [Stephenson, Joseph J.] Inst Translat Oncol Res, Greenville, SC USA. [Vogelzang, Nicholas J.] Comprehens Canc Ctr Nevada, Las Vegas, NV USA. [Vogelzang, Nicholas J.] US Oncol Res, Las Vegas, NV USA. [Koletsky, Alan J.] Lynn Canc Inst, Boca Raton, FL USA. [Nordquist, Luke T.] Urol Canc Ctr, Omaha, NE USA. [Nordquist, Luke T.] GU Res Network, Omaha, NE USA. [Edenfield, William J.] Greenville Hosp Syst, Greenville, SC USA. [Edenfield, William J.] Univ Med Ctr, Greenville, SC USA. [Mamlouk, Khalid; Ferrante, Karen J.] Tokai Pharmaceut, Cambridge, MA USA. [Taplin, Mary-Ellen] Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. RP Taplin, ME (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. EM Mary_Taplin@dfci.harvard.edu FU Tokai Pharmaceuticals, Cambridge, MA FX Data analysis support was provided by Sarah Hunter of Cd3. Technical editorial and medical writing support was provided by Beth Kamp, PharmD. Funding for this support was provided by Tokai Pharmaceuticals, Cambridge, MA. NR 33 TC 12 Z9 13 U1 1 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD MAR 15 PY 2016 VL 22 IS 6 BP 1356 EP 1363 DI 10.1158/1078-0432.CCR-15-1432 PG 8 WC Oncology SC Oncology GA DI2WD UT WOS:000373358900010 PM 26527750 ER PT J AU Merchant, MS Wright, M Baird, K Wexler, LH Rodriguez-Galindo, C Bernstein, D Delbrook, C Lodish, M Bishop, R Wolchok, JD Streicher, H Mackall, CL AF Merchant, Melinda S. Wright, Matthew Baird, Kristin Wexler, Leonard H. Rodriguez-Galindo, Carlos Bernstein, Donna Delbrook, Cindy Lodish, Maya Bishop, Rachel Wolchok, Jedd D. Streicher, Howard Mackall, Crystal L. TI Phase I Clinical Trial of Ipilimumab in Pediatric Patients with Advanced Solid Tumors SO CLINICAL CANCER RESEARCH LA English DT Article ID METASTATIC MELANOMA; CTLA-4 BLOCKADE; CANCER-IMMUNOTHERAPY; ADVERSE EVENTS; ANTIBODY; EFFICACY; INTERLEUKIN-2; NEUROBLASTOMA; ADOLESCENTS; CHILDREN AB Purpose: Ipilimumab is a first-in-class immune checkpoint inhibitor approved for treatment of metastatic melanoma but not studied in children until this phase I protocol. Experimental Design: This study examined safety, pharmacokinetics, and immunogenicity, and immune correlates of ipilimumab administered to subjects <= 21 years old with recurrent or progressive solid tumors. Dose escalation cohorts received 1, 3, 5, or 10 mg/m(2) intravenously every 3 weeks in a 3 + 3 design. Response was assessed after 6 weeks and 12 weeks, and then every 3 months. Treatment was continued until disease progression or unacceptable toxicity. Results: Thirty-three patients received 72 doses of ipilimumab. Patients enrolled had melanoma (n = 12), sarcoma (n = 17), or other refractory solid tumors (n = 4). Immune-related adverse events included pancreatitis, pneumonitis, colitis, endocrinopathies, and transaminitis with dose-limiting toxicities observed at 5 and 10 mg/kg dose levels. Pharmacokinetics revealed a half-life of 8 to 15 days. At day 21, subjects had increased levels of cycling T cells, but no change in regulatory T-cell populations. Six subjects had confirmed stable disease for 4 to 10 cycles (melanoma, osteosarcoma, clear cell sarcoma, and synovial sarcoma). Conclusions: Ipilimumab was safely administered to pediatric patients using management algorithms for immune-related toxicities. The spectrum of immune-related adverse events is similar to those described in adults; however, many of the pediatric toxicities were evident after a single dose. Although no objective tumor regressions were observed with ipilimumab as a single agent, subjects with immune-related toxicities had an increased overall survival compared with those who showed no evidence of breaking tolerance. (C) 2015 AACR. C1 [Merchant, Melinda S.; Wright, Matthew; Baird, Kristin; Bernstein, Donna; Delbrook, Cindy; Mackall, Crystal L.] NCI, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. [Wexler, Leonard H.] Mem Sloan Kettering Canc Ctr, Dept Pediat, 1275 York Ave, New York, NY 10021 USA. [Wexler, Leonard H.; Wolchok, Jedd D.] Weill Cornell Med Coll, New York, NY USA. [Rodriguez-Galindo, Carlos] Dana Farber Canc Inst, Pediat Oncol, Boston, MA 02115 USA. [Lodish, Maya] NICHHD, NIH, Bethesda, MD 20892 USA. [Bishop, Rachel] NEI, NIH, Bethesda, MD 20892 USA. [Wolchok, Jedd D.] Mem Sloan Kettering Canc Ctr, Dept Med, 1275 York Ave, New York, NY 10021 USA. [Streicher, Howard] NCI, Invest Drug Branch, NIH, Bethesda, MD 20892 USA. RP Mackall, CL (reprint author), NCI, 10 Ctr Dr,Bldg 10 CRC,Room 1W-3750, Bethesda, MD 20892 USA. EM mackallc@mail.nih.gov FU NIH, NCI FX This research was supported in part by the Intramural Research Program of the NIH, NCI. NR 32 TC 8 Z9 9 U1 2 U2 6 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 MAR 15 PY 2016 VL 22 IS 6 BP 1364 EP 1370 DI 10.1158/1078-0432.CCR-15-0491 PG 7 WC Oncology SC Oncology GA DI2WD UT WOS:000373358900011 PM 26534966 ER PT J AU Raje, N Vescio, R Montgomery, CW Badros, A Munshi, N Orlowski, R Hadala, JT Warsi, G Argonza-Aviles, E Ericson, SG Anderson, KC AF Raje, Noopur Vescio, Robert Montgomery, Charles W. Badros, Ashraf Munshi, Nikhil Orlowski, Richard Hadala, Joseph T. Warsi, Ghulam Argonza-Aviles, Eliza Ericson, Solveig G. Anderson, Kenneth C. TI Bone Marker-Directed Dosing of Zoledronic Acid for the Prevention of Skeletal Complications in Patients with Multiple Myeloma: Results of the Z-MARK Study SO CLINICAL CANCER RESEARCH LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; PATHOLOGICAL FRACTURES; CLODRONIC ACID; WORKING GROUP; DOUBLE-BLIND; DISEASE; OSTEONECROSIS; METASTASES; JAW; BISPHOSPHONATES AB Purpose: Zoledronic acid (ZOL) given every 3 to 4 weeks can reduce skeletal-related events (SRE) in patients with bone lesions from multiple myeloma. This study evaluated efficacy and safety of less-frequent ZOL dosing based on bone turnover markers in patients with 1 to 2 years of prior bisphosphonate therapy. Experimental Design: Patients received ZOL (4 mg) every 4 or 12 weeks based on urinary N-telopeptide of type 1 collagen (uNTX) levels (every 4 weeks ifuNTX >= 50 nmol/mmol creatinine, every 12 weeks if uNTX < 50). Results: Of 121 patients enrolled (mean age, 63.8 years; median follow-up, 21 months), 4 patients started ZOL every 4 weeks and 117 received ZOL every 12 weeks based on uNTX at study entry. All 4 patients who initiated ZOL every 4 weeks switched to every 12 weeks due to decreased uNTX. Thirty-eight of 117 patients who initiated ZOL every 12 weeks switched to ZOL every 4 weeks due to disease progression (n = 20), increased uNTX (n = 14), and SREs (n = 4). Overall SRE incidence was low; 7 (5.8%) and 5 (4.9%) patients experienced an SRE during years 1 and 2, respectively. Mean (SD) SRE rate at year 2 was 0.01 (0.03) per person-year. The 2-year incidence rate for osteonecrosis of jaw was 3.3%. Four deaths were reported, none related to ZOL. Conclusions: Less frequent ZOL dosing (every 12 weeks over 2 years) maintains a low SRE rate and can be safely administered for up to 4 years. 2015 AACR. C1 [Raje, Noopur] Massachusetts Gen Hosp, Ctr Canc, 55 Fruit St,POB216, Boston, MA 02114 USA. [Raje, Noopur] Harvard Univ, Sch Med, Boston, MA USA. [Vescio, Robert] Cedars Sinai Samuel Oschin Comprehens Canc Ctr, Los Angeles, CA USA. [Montgomery, Charles W.] Hematol & Oncol Associates, Tupelo, MS USA. [Badros, Ashraf] Univ Maryland, Marlene & Stewart Greenebaum Canc Ctr, Blood & Marrow Transplant Program, Baltimore, MD 21201 USA. [Munshi, Nikhil] Boston Vet Adm Healthcare Syst, Boston, MA USA. [Orlowski, Richard] Carolina Oncol Specialists, Hickory, NC USA. [Hadala, Joseph T.; Warsi, Ghulam; Argonza-Aviles, Eliza; Ericson, Solveig G.] Novartis Pharmaceut, E Hanover, NJ USA. [Anderson, Kenneth C.] Dana Farber Partners Canc Care Inst, Boston, MA USA. RP Raje, N (reprint author), Massachusetts Gen Hosp, Ctr Canc, 55 Fruit St,POB216, Boston, MA 02114 USA. EM NRAJE@mgh.harvard.edu FU Novartis Pharmaceuticals Corporation FX Financial support for this study and medical editorial assistance were provided by Novartis Pharmaceuticals Corporation. NR 26 TC 1 Z9 1 U1 2 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD MAR 15 PY 2016 VL 22 IS 6 BP 1378 EP 1384 DI 10.1158/1078-0432.CCR-15-1864 PG 7 WC Oncology SC Oncology GA DI2WD UT WOS:000373358900013 PM 26644410 ER PT J AU McCleary, NJ Sato, K Nishihara, R Inamura, K Morikawa, T Zhang, XH Wu, K Yamauchi, M Kim, SA Sukawa, Y Mima, K Qian, ZR Fuchs, CS Ogino, S Meyerhardt, JA AF McCleary, Nadine J. Sato, Kaori Nishihara, Reiko Inamura, Kentaro Morikawa, Teppei Zhang, Xuehong Wu, Kana Yamauchi, Mai Kim, Sun A. Sukawa, Yasutaka Mima, Kosuke Qian, Zhi Rong Fuchs, Charles S. Ogino, Shuji Meyerhardt, Jeffrey A. TI Prognostic Utility of Molecular Factors by Age at Diagnosis of Colorectal Cancer SO CLINICAL CANCER RESEARCH LA English DT Article ID ISLAND METHYLATOR PHENOTYPE; III COLON-CANCER; POPULATION-BASED SAMPLE; BODY-MASS INDEX; PHYSICAL-ACTIVITY; ADJUVANT CHEMOTHERAPY; BRAF MUTATION; MICROSATELLITE INSTABILITY; ELDERLY-PATIENTS; PIK3CA MUTATION AB Purpose: We hypothesized that adverse prognostic associations of specific tumor molecular factors vary by patient age at colorectal cancer diagnosis. Experimental Design: We examined the prognostic associations and interactions by age at colorectal cancer diagnosis (<60 vs. 60-74 vs. >= 75 years old) of key molecular factors-CpG island methylator phenotype (CIMP), microsatellite instability (MSI), KRAS, BRAF, and PIK3CA mutations, and nuclear CTNNB1 expression status-on colorectal cancer-specific survival (CSS) and overall survival (OS), using 1,280 incident colorectal cancer cases (median age, 69 years; range, 38-91 years) within the Nurses' Health Study and Health Professionals Follow-up Study cohorts. Results: MSI-high was associated with better survival, whereas BRAF mutation was associated with worse survival, but these associations did not appreciably differ by age group. Status of CIMP, KRAS mutation, or PIK3CA mutation was not associated with prognosis regardless of age. Nuclear CTNNB1 expression was associated with a trend toward worse prognosis among older adults [age >= 75 years; multivariate HR, 1.67; 95% confidence interval (CI), 0.89-3.13 (for CSS); multivariate HR, 1.44; 95% CI, 0.93-2.24 (for OS)] but not among younger patients, and there was a statistically significant interaction by age (P-interaction = 0.03 for CSS; P-interaction = 0.007 for OS). Conclusions: Tumor nuclear CTNNB1 expression may be associated with higher mortality among older patients with colorectal cancer but not among younger patients. Our findings need to be confirmed in independent datasets. Detailed exploration of tumor molecular signatures in older patients with colorectal cancer in large populations is warranted. (C) 2015 AACR. C1 [McCleary, Nadine J.; Sato, Kaori; Nishihara, Reiko; Inamura, Kentaro; Yamauchi, Mai; Kim, Sun A.; Sukawa, Yasutaka; Mima, Kosuke; Qian, Zhi Rong; Fuchs, Charles S.; Ogino, Shuji; Meyerhardt, Jeffrey A.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Nishihara, Reiko; Ogino, Shuji] Harvard Univ, TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Nishihara, Reiko] Harvard Univ, TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Nishihara, Reiko; Wu, Kana; Fuchs, Charles S.] Harvard Univ, TH Chan Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Morikawa, Teppei] Tokyo Univ Hosp, Dept Pathol, Tokyo 113, Japan. [Zhang, Xuehong] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA. [Zhang, Xuehong; Ogino, Shuji] Harvard Univ, Sch Med, Boston, MA USA. [Ogino, Shuji] Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA. RP McCleary, NJ (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. EM nj_mccleary@dfci.harvard.edu FU National Comprehensive Cancer Network Young Investigator Award; Dana-Farber Cancer Institute Gloria Spivak Faculty Advancement Fund; Dana-Farber Cancer Institute/Harvard Cancer Center SPORE (NCI) [P50 CA127003]; NCI [R01 CA151993, R35 CA197735, K07 CA190673, UM1 CA186107, P01 CA87969, R01 CA49449, P01 CA55075, UM1 CA167552]; Paula and Russell Agrusa Fund for Colorectal Cancer Research; Friends of the Dana-Farber Cancer Institute FX This project was supported in part by the National Comprehensive Cancer Network Young Investigator Award and Dana-Farber Cancer Institute Gloria Spivak Faculty Advancement Fund (to N.J. McCleary), the Dana-Farber Cancer Institute/Harvard Cancer Center SPORE (NCI grant P50 CA127003 to C.S. Fuchs), NCI grants R01 CA151993 (to S. Ogino), R35 CA197735 (to S. Ogino), K07 CA190673 (to R. Nishihara), UM1 CA186107 (to M.J. Stampfer), P01 CA87969 (to S.E. Hankinson), R01 CA49449 (to S.E. Hankinson), P01 CA55075 (to W.C. Willett), and UM1 CA167552 (to W.C. Willett), and supports from the Paula and Russell Agrusa Fund for Colorectal Cancer Research (to C.S. Fuchs) and the Friends of the Dana-Farber Cancer Institute (to S. Ogino). NR 46 TC 0 Z9 0 U1 0 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 MAR 15 PY 2016 VL 22 IS 6 BP 1489 EP 1498 DI 10.1158/1078-0432.CCR-15-0946 PG 10 WC Oncology SC Oncology GA DI2WD UT WOS:000373358900024 PM 26490308 ER PT J AU Zeng, MY Cisalpino, D Varadarajan, S Hellman, J Warren, HS Cascalho, M Inohara, N Nunez, G AF Zeng, Melody Y. Cisalpino, Daniel Varadarajan, Saranyaraajan Hellman, Judith Warren, H. Shaw Cascalho, Marilia Inohara, Naohiro Nunez, Gabriel TI Gut Microbiota-Induced Immunoglobulin G Controls Systemic Infection by Symbiotic Bacteria and Pathogens SO IMMUNITY LA English DT Article ID PEPTIDOGLYCAN-ASSOCIATED LIPOPROTEIN; TOLL-LIKE RECEPTORS; MEMBRANE PROTEIN-A; COMMENSAL BACTERIA; MUREIN-LIPOPROTEIN; ESCHERICHIA-COLI; NATURAL IGG; SEPSIS; RESPONSES; CELLS AB The gut microbiota is compartmentalized in the intestinal lumen and induces local immune responses, but it remains unknown whether the gut microbiota can induce systemic response and contribute to systemic immunity. We report that selective gut symbiotic gram-negative bacteria were able to disseminate systemically to induce immunoglobulin G (IgG) response, which primarily targeted gram-negative bacterial antigens and conferred protection against systemic infections by E. coli and Salmonella by directly coating bacteria to promote killing by phagocytes. T cells and Toll-like receptor 4 on B cells were important in the generation of microbiota-specific IgG. We identified murein lipoprotein (MLP), a highly conserved gram-negative outer membrane protein, as a major antigen that induced systemic IgG homeostatically in both mice and humans. Administration of anti-MLP IgG conferred crucial protection against systemic Salmonella infection. Thus, our findings reveal an important function for the gut microbiota in combating systemic infection through the induction of protective IgG. C1 [Zeng, Melody Y.; Cisalpino, Daniel; Varadarajan, Saranyaraajan; Inohara, Naohiro; Nunez, Gabriel] Univ Michigan, Sch Med, Dept Pathol, Ann Arbor, MI 48109 USA. [Zeng, Melody Y.; Cisalpino, Daniel; Varadarajan, Saranyaraajan; Inohara, Naohiro; Nunez, Gabriel] Univ Michigan, Sch Med, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA. [Cisalpino, Daniel] Univ Fed Minas Gerais, Inst Biol Sci, Dept Microbiol, BR-31270901 Belo Horizonte, MG, Brazil. [Hellman, Judith] Univ Calif San Francisco, Dept Anesthesia & Perioperat Care, Div Crit Care Med, San Francisco, CA 94110 USA. [Warren, H. Shaw] Massachusetts Gen Hosp, Infect Dis Unit, Boston, MA 02114 USA. [Cascalho, Marilia] Univ Michigan, Sch Med, Dept Surg, Transplantat Biol, Ann Arbor, MI 48109 USA. [Cascalho, Marilia] Univ Michigan, Sch Med, Dept Microbiol & Immunol, Ann Arbor, MI 48109 USA. RP Nunez, G (reprint author), Univ Michigan, Sch Med, Dept Pathol, Ann Arbor, MI 48109 USA.; Nunez, G (reprint author), Univ Michigan, Sch Med, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA. EM gabriel.nunez@umich.edu FU NIH [T32DK094775, T32HL007517, R01 GM59694, 5R21AI117561, DK091191, DK095782]; University of Michigan Center for Gastrointestinal Research [NIH 5P30DK034933] FX We thank N. Kamada for suggestions and critical reading of the manuscript, W.V. Giannobile (University of Michigan School of Dentistry) for providing human serum samples, and L. Burmeister for mouse care and husbandry. We appreciate assistance from Joel Whitfield from the University of Michigan ELISA Core, the Flow Cytometry Core, the Gnotobiotic Animal Facility, and the Host Microbiome Initiative at the University of Michigan Medical School. D.C. was an exchange student from the PDSE program of the CAPES agency from Brazil. M.Y.Z. was supported by NIH training grants T32DK094775 and T32HL007517 and received additional research support from the University of Michigan Center for Gastrointestinal Research (NIH 5P30DK034933). This work was supported by NIH grants R01 GM59694 (H.S.W.), 5R21AI117561 (M.C.), and DK091191 and DK095782 (G.N.). NR 45 TC 18 Z9 19 U1 3 U2 7 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 MAR 15 PY 2016 VL 44 IS 3 BP 647 EP 658 DI 10.1016/j.immuni.2016.02.006 PG 12 WC Immunology SC Immunology GA DH4VR UT WOS:000372784200021 PM 26944199 ER PT J AU Tyrrell, J Richmond, RC Palmer, TM Feenstra, B Rangarajan, J Metrustry, S Cavadino, A Paternoster, L Armstrong, LL De Silva, NMG Wood, AR Horikoshi, M Geller, F Myhre, R Bradfield, JP Kreiner-Moller, E Huikari, V Painter, JN Hottenga, JJ Allard, C Berry, DJ Bouchard, L Das, S Evans, DM Hakonarson, H Hayes, MG Heikkinen, J Hofman, A Knight, B Lind, PA McCarthy, MI McMahon, G Medland, SE Melbye, M Morris, AP Nodzenski, M Reichetzeder, C Ring, SM Sebert, S Sengpiel, V Sorensen, TIA Willemsen, G de Geus, EJC Martin, NG Spector, TD Power, C Jarvelin, MR Bisgaard, H Grant, SFA Nohr, EA Jaddoe, VW Jacobsson, B Murray, JC Hocher, B Hattersley, AT Scholtens, DM Smith, GD Hivert, MF Felix, JF Hypponen, E Lowe, WL Frayling, TM Lawlor, DA Freathy, RM AF Tyrrell, Jessica Richmond, Rebecca C. Palmer, Tom M. Feenstra, Bjarke Rangarajan, Janani Metrustry, Sarah Cavadino, Alana Paternoster, Lavinia Armstrong, Loren L. De Silva, N. Maneka G. Wood, Andrew R. Horikoshi, Momoko Geller, Frank Myhre, Ronny Bradfield, Jonathan P. Kreiner-Moller, Eskil Huikari, Ville Painter, Jodie N. Hottenga, Jouke-Jan Allard, Catherine Berry, Diane J. Bouchard, Luigi Das, Shikta Evans, David M. Hakonarson, Hakon Hayes, M. Geoffrey Heikkinen, Jani Hofman, Albert Knight, Bridget Lind, Penelope A. McCarthy, Mark I. McMahon, George Medland, Sarah E. Melbye, Mads Morris, Andrew P. Nodzenski, Michael Reichetzeder, Christoph Ring, Susan M. Sebert, Sylvain Sengpiel, Verena Sorensen, Thorkild I. A. Willemsen, Gonneke de Geus, Eco J. C. Martin, Nicholas G. Spector, Tim D. Power, Christine Jarvelin, Marjo-Riitta Bisgaard, Hans Grant, Struan F. A. Nohr, Ellen A. Jaddoe, Vincent W. Jacobsson, Bo Murray, Jeffrey C. Hocher, Berthold Hattersley, Andrew T. Scholtens, Denise M. Smith, George Davey Hivert, Marie-France Felix, Janine F. Hypponen, Elina Lowe, William L., Jr. Frayling, Timothy M. Lawlor, Debbie A. Freathy, Rachel M. CA EGG Consortium TI Genetic Evidence for Causal Relationships Between Maternal Obesity-Related Traits and Birth Weight SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID GENOME-WIDE ASSOCIATION; GESTATIONAL DIABETES-MELLITUS; PREGNANCY OUTCOME HAPO; VITAMIN-D STATUS; BODY-MASS INDEX; MENDELIAN RANDOMIZATION; INSULIN-RESISTANCE; COHORT PROFILE; BLOOD-PRESSURE; FETAL-GROWTH AB IMPORTANCE Neonates born to overweight or obese women are larger and at higher risk of birth complications. Many maternal obesity-related traits are observationally associated with birth weight, but the causal nature of these associations is uncertain. OBJECTIVE To test for genetic evidence of causal associations of maternal body mass index (BMI) and related traits with birth weight. DESIGN, SETTING, AND PARTICIPANTS Mendelian randomization to test whether maternal BMI and obesity-related traits are potentially causally related to offspring birth weight. Data from 30 487 women in 18 studies were analyzed. Participants were of European ancestry from population-or community-based studies in Europe, North America, or Australia and were part of the Early Growth Genetics Consortium. Live, term, singleton offspring born between 1929 and 2013 were included. EXPOSURES Genetic scores for BMI, fasting glucose level, type 2 diabetes, systolic blood pressure (SBP), triglyceride level, high-density lipoprotein cholesterol (HDL-C) level, vitamin D status, and adiponectin level. MAIN OUTCOME AND MEASURE Offspring birth weight from 18 studies. RESULTS Among the 30 487 newborns the mean birth weight in the various cohorts ranged from 3325 g to 3679 g. The maternal genetic score for BMI was associated with a 2-g (95% CI, 0 to 3 g) higher offspring birth weight per maternal BMI-raising allele (P =.008). The maternal genetic scores for fasting glucose and SBP were also associated with birth weight with effect sizes of 8 g (95% CI, 6 to 10 g) per glucose-raising allele (P = 7 x 10(-14)) and -4 g (95% CI, -6 to -2g) per SBP-raising allele (P = 1x10(-5)), respectively. A 1-SD (approximate to 4 points) genetically higher maternal BMI was associated with a 55-g higher offspring birth weight (95% CI, 17 to 93 g). A 1-SD (approximate to 7.2mg/dL) genetically higher maternal fasting glucose concentration was associated with 114-g higher offspring birth weight (95% CI, 80 to 147 g). However, a 1-SD (approximate to 10mmHg) genetically higher maternal SBP was associated with a 208-g lower offspring birth weight (95% CI, -394 to -21 g). For BMI and fasting glucose, genetic associations were consistent with the observational associations, but for systolic blood pressure, the genetic and observational associations were in opposite directions. CONCLUSIONS AND RELEVANCE In this mendelian randomization study, genetically elevated maternal BMI and blood glucose levels were potentially causally associated with higher offspring birth weight, whereas genetically elevated maternal SBP was potentially causally related to lower birth weight. If replicated, these findings may have implications for counseling and managing pregnancies to avoid adverse weight-related birth outcomes. C1 [Freathy, Rachel M.] Royal Devon & Exeter Hosp, Inst Biomed & Clin Sci, Univ Exeter, Barrack Rd, Exeter EX2 5DW, Devon, England. [Lawlor, Debbie A.] Univ Bristol, MRC Integrat Epidemiol Unit, Oakfield Rd, Bristol BS8 2BN, Avon, England. [Tyrrell, Jessica; Wood, Andrew R.; Knight, Bridget; Hattersley, Andrew T.; Frayling, Timothy M.; Freathy, Rachel M.] Univ Exeter, Royal Devon & Exeter Hosp, Sch Med, Inst Biomed & Clin Sci, Exeter, Devon, England. [Tyrrell, Jessica] Univ Exeter, Knowledge Spa, European Ctr Environm & Human Hlth, Truro, England. [Richmond, Rebecca C.; Evans, David M.; McMahon, George; Ring, Susan M.; Smith, George Davey; Lawlor, Debbie A.] Univ Bristol, Sch Social & Community Med, Bristol, Avon, England. [Richmond, Rebecca C.; Jaddoe, Vincent W.; Smith, George Davey; Felix, Janine F.] Univ Med Ctr Rotterdam, Erasmus MC, Generat Study Grp R, Rotterdam, Netherlands. [Richmond, Rebecca C.; Paternoster, Lavinia; De Silva, N. Maneka G.; Evans, David M.; Ring, Susan M.; Sorensen, Thorkild I. A.; Lawlor, Debbie A.; Freathy, Rachel M.] Univ Bristol, Integrat Epidemiol Unit, Med Res Council, Bristol BS8 1TH, Avon, England. [Palmer, Tom M.] Univ Warwick, Warwick Med Sch, Div Hlth Sci, Coventry CV4 7AL, W Midlands, England. [Palmer, Tom M.] Univ Lancaster, Dept Math & Stat, Lancaster, England. [Feenstra, Bjarke; Geller, Frank; Melbye, Mads] Statens Serum Inst, Dept Epidemiol Res, DK-2300 Copenhagen, Denmark. [Rangarajan, Janani; Nodzenski, Michael; Scholtens, Denise M.] Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, Chicago, IL 60611 USA. [Metrustry, Sarah; Spector, Tim D.] St Thomas Hosp, Kings Coll London, Dept Twin Res, London, England. [Cavadino, Alana; Berry, Diane J.] Wolfson Inst Prevent Med, Ctr Environm & Prevent Med, Barts, England. [Cavadino, Alana; Berry, Diane J.] Queen Mary Univ London, London Sch Med & Dent, London, England. [Cavadino, Alana; Power, Christine; Hypponen, Elina] UCL, UCL Inst Child Hlth, Populat Policy & Practice, London WC1E 6BT, England. [Armstrong, Loren L.; Hayes, M. Geoffrey; Lowe, William L., Jr.] Northwestern Univ, Feinberg Sch Med, Div Endocrinol Metab & Mol Med, Chicago, IL 60611 USA. [Horikoshi, Momoko; McCarthy, Mark I.] Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford OX1 2JD, England. [Horikoshi, Momoko; McCarthy, Mark I.; Morris, Andrew P.] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. [Myhre, Ronny; Jacobsson, Bo] Norwegian Inst Publ Hlth, Dept Genes & Environm, Div Epidemiol, Oslo, Norway. [Bradfield, Jonathan P.; Hakonarson, Hakon; Grant, Struan F. A.] Childrens Hosp Philadelphia, Ctr Appl Genom, Philadelphia, PA 19104 USA. [Kreiner-Moller, Eskil; Bisgaard, Hans] Univ Copenhagen, Fac Hlth Sci, COPSAC, Copenhagen, Denmark. [Kreiner-Moller, Eskil; Bisgaard, Hans] Copenhagen Univ Hosp, Danish Pediat Asthma Ctr, Gentofte, Denmark. [Huikari, Ville; Sebert, Sylvain; Jarvelin, Marjo-Riitta] Univ Oulu, Inst Hlth Sci, Oulu, Finland. [Painter, Jodie N.; Lind, Penelope A.; Medland, Sarah E.; Martin, Nicholas G.] Royal Brisbane Hosp, QIMR Berghofer Med Res Inst, Herston, Qld, Australia. [Hottenga, Jouke-Jan; Willemsen, Gonneke; de Geus, Eco J. C.] Vrije Univ Amsterdam Med Ctr, EMGO Inst Hlth & Care Res, Amsterdam, Netherlands. [Hottenga, Jouke-Jan; Willemsen, Gonneke; de Geus, Eco J. C.] Vrije Univ Amsterdam, Dept Biol Psychol, Amsterdam, Netherlands. [Allard, Catherine] Univ Sherbrooke, Dept Math, Quebec City, PQ, Canada. [Allard, Catherine; Bouchard, Luigi] CHU Sherbrooke, Ctr Rech, Quebec City, PQ, Canada. [Bouchard, Luigi] Chicoutimi Hosp, ECOGENE & Lipid Clin 21, Quebec City, PQ, Canada. [Bouchard, Luigi] Univ Sherbrooke, Dept Biochem, Quebec City, PQ, Canada. [Das, Shikta] Imperial Coll London, Dept Primary Care & Publ Hlth, London, England. [Evans, David M.] Univ Queensland, Diamantina Inst, Translat Res Inst, Brisbane, Qld, Australia. [Hakonarson, Hakon; Grant, Struan F. A.] Childrens Hosp Philadelphia, Div Human Genet, Philadelphia, PA 19104 USA. [Hakonarson, Hakon; Grant, Struan F. A.] Univ Penn, Perelman Sch Med, Dept Pediat, Philadelphia, PA 19104 USA. [Heikkinen, Jani] Univ Helsinki, FIMM Inst Mol Med Finland, Helsinki, Finland. [Hofman, Albert; Jaddoe, Vincent W.; Felix, Janine F.] Univ Med Ctr Rotterdam, Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [McCarthy, Mark I.] Churchill Hosp, Biomed Res Ctr, Oxford Natl Inst Hlth Res NIHR, Oxford OX3 7LJ, England. [Melbye, Mads] Stanford Univ, Sch Med, Dept Med, Stanford, CA 94305 USA. [Morris, Andrew P.] Univ Liverpool, Dept Biostat, Liverpool L69 3BX, Merseyside, England. [Reichetzeder, Christoph; Hocher, Berthold] Univ Potsdam, Inst Nutr Sci, Potsdam, Germany. [Reichetzeder, Christoph] Charite, Ctr Cardiovasc Res, Berlin, Germany. [Sebert, Sylvain; Jarvelin, Marjo-Riitta] Imperial Coll London, Fac Med, Hlth Protect Agcy Ctr Environm & Hlth, Med Res Council,Sch Publ Hlth,Dept Epidemiol & Bi, London, England. [Sengpiel, Verena; Jacobsson, Bo] Sahlgrens Univ Hosp, Dept Obstet & Gynecol, S-41345 Gothenburg, Sweden. [Sorensen, Thorkild I. A.] Bispebjerg & Frederiksberg Univ Hosp, Inst Prevent Med, Copenhagen, Denmark. [Sorensen, Thorkild I. A.] Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn, Ctr Basic Metabol Res, Copenhagen, Denmark. [Sorensen, Thorkild I. A.] Univ Copenhagen, Fac Hlth & Med Sci, Dept Publ Hlth, Copenhagen, Denmark. [Jarvelin, Marjo-Riitta] Natl Inst Hlth andWelfare, Dept Children & Young People & Families, Oulu, Finland. [Jarvelin, Marjo-Riitta] Univ Oulu, Bioctr Oulu, Oulu, Finland. [Jarvelin, Marjo-Riitta] Oulu Univ Hosp, Unit Primary Care, Oulu, Finland. [Nohr, Ellen A.] Univ So Denmark, Inst Clin Res, Res Unit Obstet & Gynecol, Odense, Denmark. [Jaddoe, Vincent W.; Felix, Janine F.] Univ Med Ctr Rotterdam, Erasmus MC, Dept Pediat, Rotterdam, Netherlands. [Murray, Jeffrey C.] Univ Iowa, Dept Pediat, Iowa City, IA 52242 USA. [Hocher, Berthold] Jinan Univ, Affiliated Hosp 1, Guangzhou, Guangdong, Peoples R China. [Hivert, Marie-France] Harvard Univ, Sch Med, Harvard Pilgrim Hlth Care Inst, Dept Populat Med, Boston, MA USA. [Hivert, Marie-France] Massachusetts Gen Hosp, Ctr Diabet, Boston, MA 02114 USA. [Hivert, Marie-France] Univ Sherbrooke, Dept Med, Quebec City, PQ, Canada. [Hypponen, Elina] Univ S Australia, Sch Hlth Sci, Ctr Populat Hlth Res, Adelaide, SA 5001, Australia. [Hypponen, Elina] Univ S Australia, Sansom Inst, Adelaide, SA 5001, Australia. [Hypponen, Elina] South Australian Hlth & Med Res Inst, Adelaide, SA, Australia. [Hofman, Albert] Harvard Univ, TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. RP Freathy, RM (reprint author), Royal Devon & Exeter Hosp, Inst Biomed & Clin Sci, Univ Exeter, Barrack Rd, Exeter EX2 5DW, Devon, England.; Lawlor, DA (reprint author), Univ Bristol, MRC Integrat Epidemiol Unit, Oakfield Rd, Bristol BS8 2BN, Avon, England. EM d.a.lawlor@bristol.ac.uk; r.freathy@ex.ac.uk RI Hypponen, Elina/B-2596-2014; Bisgaard, Hans/N-4761-2016; Davey Smith, George/A-7407-2013; OI Hypponen, Elina/0000-0003-3670-9399; Medland, Sarah/0000-0003-1382-380X; Lawlor, Debbie A/0000-0002-6793-2262; Bisgaard, Hans/0000-0003-4131-7592; Davey Smith, George/0000-0002-1407-8314; Hattersley, Andrew/0000-0001-5620-473X; de Geus, Eco/0000-0001-6022-2666; Palmer, Tom/0000-0003-4655-4511; Jarvelin, Marjo-Riitta/0000-0002-2149-0630; Evans, David/0000-0003-0663-4621 FU Canadian Institutes of Health Research; European Research Council [323195]; Medical Research Council [MR/J012165/1, G0500070, G0601261, G0701603, MC_PC_15018, MC_UU_1201/1, MC_UU_1201/1/5, MC_UU_1201/4, MC_UU_12013/1, MC_UU_12013/3, MC_UU_12013/4, MC_UU_12013/5]; NICHD NIH HHS [R01 HD056465]; NIDDK NIH HHS [R01 DK10324, R01 DK103246]; NIEHS NIH HHS [P30 ES013508]; Wellcome Trust [102215, 104150, 104150/Z/14/Z, WT083431MF, WT088806, WT094529MA, WT098017] NR 55 TC 22 Z9 23 U1 7 U2 17 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 MAR 15 PY 2016 VL 315 IS 11 BP 1129 EP 1140 DI 10.1001/jama.2016.1975 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA DG5ZB UT WOS:000372159800018 PM 26978208 ER PT J AU Goyal, RK AF Goyal, Raj K. TI CrossTalk opposing view: Interstitial cells are not involved and physiologically important in neuromuscular transmission in the gut SO JOURNAL OF PHYSIOLOGY-LONDON LA English DT Editorial Material ID LOWER ESOPHAGEAL SPHINCTER; V MUTANT MICE; ENTERIC MOTOR-NEURONS; SMOOTH-MUSCLE-CELLS; CHOLINERGIC NEUROTRANSMISSION; INHIBITORY NEUROTRANSMISSION; NITRIC-OXIDE; GASTROINTESTINAL-TRACT; GASTRIC FUNDUS; CAJAL C1 [Goyal, Raj K.] Harvard Univ, Sch Med, West Roxbury, MA 02132 USA. [Goyal, Raj K.] VA Boston Healthcare Syst, Cambridge, MA 02132 USA. RP Goyal, RK (reprint author), Harvard Univ, Sch Med, West Roxbury, MA 02132 USA.; Goyal, RK (reprint author), VA Boston Healthcare Syst, Cambridge, MA 02132 USA. EM raj_goyal@hms.harvard.edu FU BLRD VA [I01 BX002806] NR 30 TC 4 Z9 4 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3751 EI 1469-7793 J9 J PHYSIOL-LONDON JI J. Physiol.-London PD MAR 15 PY 2016 VL 594 IS 6 BP 1511 EP 1513 DI 10.1113/JP271587 PG 3 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA DH6SP UT WOS:000372922100003 PM 26842563 ER PT J AU Goyal, RK AF Goyal, Raj K. TI Rebuttal from Raj K Goyal SO JOURNAL OF PHYSIOLOGY-LONDON LA English DT Editorial Material ID NITRERGIC NEUROMUSCULAR-TRANSMISSION; CHOLINERGIC NEUROTRANSMISSION; INTERSTITIAL-CELLS; CAJAL; FUNDUS C1 [Goyal, Raj K.] Harvard Univ, Sch Med, West Roxbury, MA 02132 USA. [Goyal, Raj K.] VA Boston Healthcare Syst, West Roxbury, MA 02132 USA. RP Goyal, RK (reprint author), Harvard Univ, Sch Med, West Roxbury, MA 02132 USA.; Goyal, RK (reprint author), VA Boston Healthcare Syst, West Roxbury, MA 02132 USA. EM raj_goyal@hms.harvard.edu FU BLRD VA [I01 BX002806] 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 0022-3751 EI 1469-7793 J9 J PHYSIOL-LONDON JI J. Physiol.-London PD MAR 15 PY 2016 VL 594 IS 6 BP 1517 EP 1517 DI 10.1113/JP271972 PG 1 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA DH6SP UT WOS:000372922100005 PM 26841952 ER PT J AU Desch, AN Gibbings, SL Goyal, R Kolde, R Bednarek, J Bruno, T Slansky, JE Jacobelli, J Mason, R Ito, Y Messier, E Randolph, GJ Prabagar, M Atif, SM Segura, E Xavier, RJ Bratton, DL Janssen, WJ Henson, PM Jakubzick, CV AF Desch, A. Nicole Gibbings, Sophie L. Goyal, Rajni Kolde, Raivo Bednarek, Joe Bruno, Tullia Slansky, Jill E. Jacobelli, Jordan Mason, Robert Ito, Yoko Messier, Elise Randolph, Gwendalyn J. Prabagar, Miglena Atif, Shaikh M. Segura, Elodie Xavier, Ramnik J. Bratton, Donna L. Janssen, William J. Henson, Peter M. Jakubzick, Claudia V. TI Flow Cytometric Analysis of Mononuclear Phagocytes in Nondiseased Human Lung and Lung-Draining Lymph Nodes SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Article DE monocytes; dendritic cells; pulmonary; macrophages; mononuclear phagocytes ID PLASMACYTOID DENDRITIC CELLS; TISSUE-RESIDENT MACROPHAGES; T-CELLS; MANNOSE RECEPTOR; RABBIT LUNGS; TGF-BETA; EXPRESSION; MONOCYTES; DIFFERENTIATION; INFLAMMATION AB Rationale: The pulmonary mononuclear phagocyte system is a critical host defense mechanism composed of macrophages, monocytes, monocyte-derived cells, and dendritic cells. However, our current characterization of these cells is limited because it is derived largely from animal studies and analysis of human mononuclear phagocytes from blood and small tissue resections around tumors. Objectives: Phenotypic and morphologic characterization of mononuclear phagocytes that potentially access inhaled antigens in human lungs. Methods: We acquired and analyzed pulmonary mononuclear phagocytes from fully intact nondiseased human lungs (including the major blood vessels and draining lymph nodes) obtained en bloc from 72 individual donors. Differential labeling of hematopoietic cells via intrabronchial and intravenous administration of antibodies within the same lobe was used to identify extravascular tissue-resident mononuclear phagocytes and exclude cells within the vascular lumen. Multiparameter flow cytometry was used to identify mononuclear phagocyte populations among cells labeled by each route of antibody delivery. Measurements and Main Results: We performed a phenotypic analysis of pulmonary mononuclear phagocytes isolated from whole nondiseased human lungs and lung-draining lymph nodes. Five pulmonary mononuclear phagocytes were observed, including macrophages, monocyte-derived cells, and dendritic cells that were phenotypically distinct from cell populations found in blood. Conclusions: Different mononuclear phagocytes; particularly dendritic cells, were labeled by intravascular and intrabronchial antibody delivery, countering the notion that tissue and blood mononuclear phagocytes are equivalent systems. Phenotypic descriptions of the mononuclear phagocytes in nondiseased lungs provide a precedent for comparative studies in diseased lungs and potential targets for therapeutics. C1 [Desch, A. Nicole; Bruno, Tullia; Slansky, Jill E.; Jacobelli, Jordan; Henson, Peter M.; Jakubzick, Claudia V.] Univ Colorado, Dept Immunol & Microbiol, Anschutz Campus, Denver, CO 80202 USA. [Desch, A. Nicole; Kolde, Raivo; Xavier, Ramnik J.] Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Boston, MA 02114 USA. [Desch, A. Nicole; Kolde, Raivo; Xavier, Ramnik J.] Harvard Univ, Sch Med, Boston, MA USA. [Desch, A. Nicole; Kolde, Raivo; Xavier, Ramnik J.] Broad Inst Massachusetts Inst Technol & Harvard, Cambridge, MA USA. [Gibbings, Sophie L.; Goyal, Rajni; Bednarek, Joe; Prabagar, Miglena; Atif, Shaikh M.; Bratton, Donna L.; Henson, Peter M.; Jakubzick, Claudia V.] Natl Jewish Hlth, Dept Pediat, Denver, CO USA. [Mason, Robert; Ito, Yoko; Messier, Elise; Janssen, William J.] Natl Jewish Hlth, Dept Med, Anschutz Campus, Denver, CO USA. [Mason, Robert; Ito, Yoko; Messier, Elise; Janssen, William J.] Univ Colorado, Anschutz Campus, Denver, CO 80202 USA. [Randolph, Gwendalyn J.] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO USA. [Segura, Elodie] INSERM, U932, Paris, France. [Segura, Elodie] Inst Curie, Paris, France. RP Jakubzick, CV (reprint author), Natl Jewish Hlth, Dept Pediat & Immunol, 1400 Jackson St, Denver, CO 80206 USA. EM jakubzickc@njhealth.org OI segura, elodie/0000-0003-1795-1921 FU NIAID Training Grants [T32 A1007405, HL68864, HL88138, HL109517]; ACS grants [RSG-08-184-01-L1B, HL34303, AI110408, ANR-10-IDEX-0001-02 PSL, ANR-11-LABX-0043, CIC IGR-Curie 1428]; Natalie Zucker Award, Colorado Clinical Translational Sciences Institute and Bioscience Discovery Evaluation Grant Program [HL81151, R01 HL115334] FX Supported by NIAID Training Grants T32 A1007405 (A.N.D.), HL68864 and HL88138 (P.M.H.), and HL109517 (W.J.J.); ACS grants RSG-08-184-01-L1B (J.E.S.), HL34303 and AI110408 (D.L.B.), ANR-10-IDEX-0001-02 PSL, ANR-11-LABX-0043, and CIC IGR-Curie 1428 (E.S.); and Natalie Zucker Award, Colorado Clinical Translational Sciences Institute and Bioscience Discovery Evaluation Grant Program, Diversity Supplement HL81151 and R01 HL115334 (C.V.J.). NR 51 TC 12 Z9 12 U1 4 U2 4 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD MAR 15 PY 2016 VL 193 IS 6 BP 614 EP 626 DI 10.1164/rccm.201507-1376OC PG 13 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA DG9DF UT WOS:000372382300010 PM 26551758 ER PT J AU Krop, IE Modi, S LoRusso, PM Pegram, M Guardino, E Althaus, B Lu, D Strasak, A Elias, A AF Krop, Ian E. Modi, Shanu LoRusso, Patricia M. Pegram, Mark Guardino, Ellie Althaus, Betsy Lu, Dan Strasak, Alexander Elias, Anthony TI Phase 1b/2a study of trastuzumab emtansine (T-DM1), paclitaxel, and pertuzumab in HER2-positive metastatic breast cancer SO BREAST CANCER RESEARCH LA English DT Article ID PLUS DOCETAXEL; GROWTH; THERAPY; EFFICACY; COMPLEX; TRIAL; HER2 AB Background: In pre-clinical studies, the anti-tumor activity of T-DM1 was enhanced when combined with taxanes or pertuzumab. This phase 1b/2a study evaluated the safety/tolerability of T-DM1 + paclitaxel +/- pertuzumab in HER2-positive advanced breast cancer. Methods: In phase 1b (n = 60), a 3 + 3 dose-escalation approach was used to determine the maximum tolerated dose (MTD) of T-DM1 + paclitaxel +/- pertuzumab. The primary objective of phase 2a was feasibility, with 44 patients randomized to T-DM1 + paclitaxel +/- pertuzumab at the MTD identified in phase 1b. Results: The MTD was T-DM1 3.6 mg/kg every three weeks (q3w) or 2.4 mg/kg weekly + paclitaxel 80 mg/m(2) weekly +/- pertuzumab 840 mg loading dose followed by 420 mg q3w. Phase 2a patients had received a median of 5.0 (range: 0-10) prior therapies for advanced cancer. In phase 2a, 51.2 % received >= 12 paclitaxel doses within 15 weeks, and 14.0 % received 12 paclitaxel doses by week 12. Common all-grade adverse events (AEs) were peripheral neuropathy (90.9 %) and fatigue (79.5 %). A total of 77.3 % experienced grade >= 3 AEs, most commonly neutropenia (25.0 %) and peripheral neuropathy (18.2 %). Among the 42 phase 2a patients with measurable disease, the objective response rate (ORR) was 50.0 % (95 % confidence interval (CI) 34.6-65.4); the clinical benefit rate (CBR) was 56.8 % (95 % CI 41.6-71.0). No pharmacokinetic interactions were observed between T-DM1 and paclitaxel. Conclusions: This regimen showed clinical activity. Although there is potential for paclitaxel to be added to T-DM1 +/- pertuzumab, peripheral neuropathy was common in this heavily pretreated population. C1 [Krop, Ian E.] Dana Farber Canc Inst, Breast Oncol, 450 Brookline Ave, Boston, MA 02215 USA. [Modi, Shanu] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10065 USA. [Modi, Shanu] Weill Cornell Med Coll, 445 E 69th St, New York, NY 10021 USA. [LoRusso, Patricia M.] Yale Univ, 800 Howard Ave, New Haven, CT 06519 USA. [Pegram, Mark] Stanford Univ, Stanford Canc Inst, Sch Med, 900 Blake Wilbur, Stanford, CA 94305 USA. [Guardino, Ellie; Althaus, Betsy; Lu, Dan] Genentech Inc, 1 DNA Way, San Francisco, CA 94080 USA. [Strasak, Alexander] F Hoffmann La Roche & Co Ltd, Grenzacherstr 124, CH-4070 Basel, Switzerland. [Elias, Anthony] Univ Colorado, Ctr Canc, 1665 Aurora Ct, Aurora, CO 80045 USA. RP Krop, IE (reprint author), Dana Farber Canc Inst, Breast Oncol, 450 Brookline Ave, Boston, MA 02215 USA. EM Ian_Krop@dfci.harvard.edu FU Genentech, Inc. FX The authors wish to thank John Ning and David Ipe, MS, who are current and former employees of Genentech, Inc., respectively, for their contributions to this study. Genentech, Inc. sponsored the study and collaborated with the investigators in its design and subsequent data analysis. Third-party writing assistance for this manuscript was provided by CodonMedical, a division of Ashfield Healthcare Communications (a UDG Healthcare plc company), and funded by Genentech, Inc. NR 22 TC 2 Z9 2 U1 1 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1465-542X EI 1465-5411 J9 BREAST CANCER RES JI Breast Cancer Res. PD MAR 15 PY 2016 VL 18 AR 34 DI 10.1186/s13058-016-0691-7 PG 10 WC Oncology SC Oncology GA DH0RQ UT WOS:000372492000002 PM 26979312 ER PT J AU Min, PK Park, J Isaacs, S Taylor, BA Thompson, PD Troyanos, C D'Hemecourt, P Dyer, S Chan, SY Baggish, AL AF Min, Pil-Ki Park, Joseph Isaacs, Stephanie Taylor, Beth A. Thompson, Paul D. Troyanos, Chris D'Hemecourt, Pierre Dyer, Sophia Chan, Stephen Y. Baggish, Aaron L. TI Influence of statins on distinct circulating microRNAs during prolonged aerobic exercise SO JOURNAL OF APPLIED PHYSIOLOGY LA English DT Article DE microRNAs; hydroxymethylglutaryl-CoA reductase inhibitors; muscle contraction; exercise; skeletal muscle ID ACUTE MYOCARDIAL-INFARCTION; CREATINE-KINASE LEVELS; SKELETAL-MUSCLE CELLS; ENDURANCE EXERCISE; MARATHON RUN; PLASMA; EXPRESSION; MYOPATHY; BIOMARKERS; LOVASTATIN AB Statins exacerbate exercise-induced skeletal muscle injury. Muscle-specific microRNAs (myomiRs) increase in plasma after prolonged exercise, but the patterns of myomiRs release after statin-associated muscle injury have not been examined. We examined the relationships between statin exposure, in vitro and in vivo muscle contraction, and expression of candidate circulating myomiRs. We measured plasma levels of myomiRs, circulating microRNA-1 (c-miR-1), c-miR-133a, c-miR-206, and c-miR-499-5p from 28 statin-using and 28 nonstatin-using runners before (PRE), immediately after (FINISH), and 24 h after they ran a 42-km footrace (the 2011 Boston marathon) (POST-24). To examine these cellular-regulation myomiRs, we used contracting mouse C2C12 myotubes in culture with and without statin exposure to compare intracellular and extracellular expression of these molecules. In marathoners, c-miR-1, c-miR-133a, and c-miR-206 increased at FINISH, returned to baseline at POST-24, and were unaffected by statin use. In contrast, c-miR-499-5p was unchanged at FINISH but increased at POST-24 among statin users compared with PRE and runners who did not take statins. In cultured C2C12 myotubes, extracellular c-miR-1, c-miR-133a, and c-miR-206 were significantly increased by muscle contraction regardless of statin use. In contrast, extracellular miR-499-5p was unaffected by either isolated statin exposure or isolated carbachol exposure but it was increased when muscle contraction was combined with statin exposure. In summary, we found that statin-potentiated muscle injury during exercise is accompanied by augmented extracellular release of miR-499-5p. Thus c-miR-499-5p may serve as a biomarker of statin-potentiated muscle damage. C1 [Min, Pil-Ki; Park, Joseph; Chan, Stephen Y.] Harvard Univ, Sch Med, Dept Med, Div Cardiovasc Med,Brigham & Womens Hosp, Boston, MA USA. [Isaacs, Stephanie; Baggish, Aaron L.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiovasc Performance Program, Boston, MA USA. [Taylor, Beth A.; Thompson, Paul D.] Hartford Hosp, Div Cardiol, Henry Low Heart Ctr, Hartford, CT 06115 USA. [Troyanos, Chris; D'Hemecourt, Pierre; Dyer, Sophia; Baggish, Aaron L.] Boston Athlet Assoc, Boston, MA USA. [Min, Pil-Ki] Yonsei Univ, Coll Med, Gangnam Severance Hosp, Dept Internal Med,Div Cardiol, Seoul, South Korea. RP Chan, SY (reprint author), Univ Pittsburgh, Pittsburgh Heart Lung Blood & Vasc Med Inst, Med Ctr, BST1704-2,200 Lothrop St, Pittsburgh, PA 15261 USA. EM chansy@pitt.edu FU McArthur-Radovsky Fund; Lerner Fund; Harris Fund; Watkins Fund; Hassenfeld Scholars Fund FX This work was supported by the McArthur-Radovsky, Lerner, Harris, and Watkins Funds (to S.Y. Chan) and the Hassenfeld Scholars Fund (to A.L. Baggish). NR 58 TC 5 Z9 5 U1 2 U2 6 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 8750-7587 EI 1522-1601 J9 J APPL PHYSIOL JI J. Appl. Physiol. PD MAR 15 PY 2016 VL 120 IS 6 BP 711 EP 720 DI 10.1152/japplphysiol.00654.2015 PG 10 WC Physiology; Sport Sciences SC Physiology; Sport Sciences GA DG4RU UT WOS:000372061000022 PM 26472872 ER PT J AU Huang, XY Huang, ZL Yang, JH Xu, YH Sun, JS Zheng, Q Wei, CY Song, W Yuan, Z AF Huang, Xiu-yan Huang, Zi-li Yang, Ju-hong Xu, Yong-hua Sun, Jiu-song Zheng, Qi Wei, Chunyao Song, Wei Yuan, Zhou TI Pancreatic cancer cell-derived IGFBP-3 contributes to muscle wasting SO JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH LA English DT Article ID GROWTH-FACTOR-I; SKELETAL-MUSCLE; SIGNALING PATHWAY; GENE-EXPRESSION; ADIPOSE-TISSUE; CACHEXIA; DIFFERENTIATION; CARCINOMA; MYOSTATIN; BINDING AB Background: Progressive loss of skeletal muscle, termed muscle wasting, is a hallmark of cancer cachexia and contributes to weakness, reduced quality of life, as well as poor response to therapy. Previous studies have indicated that systemic host inflammatory response regarding tumor development results in muscle wasting. However, how tumor directly regulates muscle wasting via tumor-derived secreted proteins is still largely unknown. Methods: In this study, we performed bioinformatics analysis in two datasets of pancreatic ductal adenocarcinoma, which causes cancer cachexia and muscle wasting with the highest prevalence, and uncovered that IGFBP3, which encodes IGF-binding protein-3 (IGFBP-3), is dramatically up-regulated in pancreatic tumor samples. We also verified the wasting effect of IGFBP-3 on C2C12 muscle cells with biochemical and genetic assays. Results: IGFBP-3 potently leads to impaired myogenesis and enhanced muscle protein degradation, the major features of muscle wasting, via IGF signaling inhibition. Moreover, conditioned medium from Capan-1 pancreatic cancer cells, which contains abundant IGFBP-3, significantly induces muscle cell wasting. This wasting effect is potently alleviated by IGFBP3 knockdown in Capan-1 cells or IGFBP-3 antibody neutralization. Strikingly, compared to muscle cells, IGF signaling and proliferation rate of Capan-1 cells were rarely affected by IGFBP-3 treatment. Conclusions: Our results demonstrated that pancreatic cancer cells induce muscle wasting via IGFBP-3 production. C1 [Huang, Xiu-yan; Zheng, Qi; Yuan, Zhou] Shanghai Jiao Tong Univ, Affiliated Peoples Hosp 6, Dept Gen Surg, Shanghai 200233, Peoples R China. [Huang, Zi-li; Xu, Yong-hua] Xuhui Cent Hosp, Dept Radiol, Shanghai 200031, Peoples R China. [Yang, Ju-hong] Tianjin Med Univ, Metab Dis Hosp, Minist Hlth, Collaborat Innovat Ctr Tianjin Med Epigenet,Key L, Tianjin 300070, Peoples R China. [Yang, Ju-hong] Tianjin Med Univ, Tianjin Inst Endocrinol, Tianjin 300070, Peoples R China. [Sun, Jiu-song] Dana Farber Canc Inst, Dept Canc Immunol & AIDS, 450 Brookline Ave, Boston, MA 02215 USA. [Sun, Jiu-song] Harvard Univ, Sch Med, Dept Med, 25 Shattuck St, Boston, MA 02115 USA. [Wei, Chunyao] Massachusetts Gen Hosp, Dept Mol Biol, Howard Hughes Med Inst, Boston, MA 02114 USA. [Song, Wei] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. RP Huang, XY (reprint author), Shanghai Jiao Tong Univ, Affiliated Peoples Hosp 6, Dept Gen Surg, Shanghai 200233, Peoples R China. EM xyhuang1119@163.com; zhouyuan201414@163.com FU National Natural Science Foundation of China [81272401]; International Foundation of Translational Medicine for Abroad Scholars and Students, U.S. [UCTMP2015-03C001]; International Foundation of Translational Medicine for Abroad Scholars and Students, China [UCTMP2015-03C001]; Foundation of Shanghai Health Bureau, Shanghai, PR China [2012QJ001A, 2010L059A]; Foundation of 6th People's Hospital Affiliated to Shanghai Jiaotong University, Shanghai, PR China [1131] FX This study was supported by grants from the National Natural Science Foundation of China (No. 81272401), the International Foundation of Translational Medicine for Abroad Scholars and Students, U.S. and China (No. UCTMP2015-03C001), the Foundation of Shanghai Health Bureau, Shanghai, PR China (No. 2012QJ001A; No. 2010L059A), and the Foundation of 6th People's Hospital Affiliated to Shanghai Jiaotong University, Shanghai, PR China (Hospital, No. 1131). NR 56 TC 2 Z9 2 U1 4 U2 6 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1756-9966 J9 J EXP CLIN CANC RES JI J. Exp. Clin. Cancer Res. PD MAR 15 PY 2016 VL 35 AR 46 DI 10.1186/s13046-016-0317-z PG 13 WC Oncology SC Oncology GA DH1LM UT WOS:000372545500001 PM 26975989 ER PT J AU Zou, L Feng, Y Xu, GQ Jian, WL Chao, W AF Zou, Lin Feng, Yan Xu, Ganqiong Jian, Wenling Chao, Wei TI Splenic RNA and MicroRNA Mimics Promote Complement Factor B Production and Alternative Pathway Activation via Innate Immune Signaling SO JOURNAL OF IMMUNOLOGY LA English DT Article ID TOLL-LIKE RECEPTOR-3; SINGLE-STRANDED RNA; NF-KAPPA-B; CARDIOVASCULAR-DISEASE; INFLAMMATORY RESPONSE; POLYMICROBIAL SEPSIS; CARDIAC DYSFUNCTION; EXTRACELLULAR RNA; MESSENGER-RNA; SEPTIC SHOCK AB Complement factor B (cfB) is an essential component of the alternative pathway (AP) and plays an important role in the pathogenesis of polymicrobial sepsis. However, the mechanism leading to cfB production and AP activation during sepsis remains poorly understood. In this study, we found that plasma cell-free RNA was significantly increased following cecal ligation and puncture (CLP), an animal model of polymicrobial sepsis, and was closely associated with sepsis severity. Quantitative RT-PCR and microRNA (miRNA) array analysis revealed an increase in bacterial RNA and multiple host miRNAs (miR-145, miR-146a, miR-122, miR-210) in the blood following CLP. Treatment with tissue RNA or synthetic miRNA mimics (miR-145, miR-146a, miR-122, miR-34a) induced a marked increase in cfB production in cardiomyocytes or macrophages. The newly synthesized cfB released into medium was biologically active because it participated in AP activation initiated by cobra venom factor. Genetic deletion of TLR7 or MyD88, but not TLR3, and inhibition of the MAPKs (JNK and p38) or NF-kappa B abolished miR-146a-induced cfB production. In vivo, CLP led to a significant increase in splenic cfB expression that correlated with the plasma RNA or miRNA levels. Peritoneal injection of RNA or miR-146a led to an increase in cfB expression in the peritoneal space that was attenuated in MyD88-knockout or TLR7-knockout mice, respectively. These findings demonstrate that host cellular RNA and specific miRNAs are released into the circulation during polymicrobial sepsis and may function as extracellular mediators capable of promoting cfB production and AP activation through specific TLR7 and MyD88 signaling. C1 [Zou, Lin; Feng, Yan; Xu, Ganqiong; Jian, Wenling; Chao, Wei] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. [Zou, Lin; Feng, Yan; Chao, Wei] Univ Maryland, Sch Med, Dept Anesthesiol, 22 South Greene S11C00, Baltimore, MD 21201 USA. RP Chao, W (reprint author), Univ Maryland, Sch Med, Dept Anesthesiol, 22 South Greene S11C00, Baltimore, MD 21201 USA. EM wchao@anes.umm.edu FU National Institutes of Health [GM097259]; International Anesthesia Research Society FX This work was supported in part by National Institutes of Health Grant GM097259 (to W.C.) and a mentored research award from the International Anesthesia Research Society (to L.Z.). NR 52 TC 2 Z9 3 U1 0 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 MAR 15 PY 2016 VL 196 IS 6 BP 2788 EP 2798 DI 10.4049/jimmunol.1502106 PG 11 WC Immunology SC Immunology GA DG8MK UT WOS:000372338100035 PM 26889043 ER PT J AU Narayanan, PL Warton, C Boonzaier, NR Molteno, CD Joseph, J Jacobson, JL Jacobson, SW Zollei, L Meintjes, EM AF Narayanan, Priya Lakshmi Warton, Christopher Boonzaier, Natalie Rosella Molteno, Christopher D. Joseph, Jesuchristopher Jacobson, Joseph L. Jacobson, Sandra W. Zoellei, Lilla Meintjes, Ernesta M. TI Improved segmentation of cerebellar structures in children SO JOURNAL OF NEUROSCIENCE METHODS LA English DT Article DE Pediatric probabilistic atlas; Cerebellum; Multi atlas segmentation; CAPCA18 ID AUTOMATICALLY GENERATED TEMPLATES; MULTI-ATLAS SEGMENTATION; FETAL ALCOHOL SYNDROME; SURFACE-BASED ANALYSIS; IMAGE SEGMENTATION; BRAIN MRI; RECONSTRUCTION; RELIABILITY; SELECTION; FUSION AB Background: Consistent localization of cerebellar cortex in a standard coordinate system is important for functional studies and detection of anatomical alterations in studies of morphometry. To date, no pediatric cerebellar atlas is available. New method: The probabilistic Cape Town Pediatric Cerebellar Atlas (CAPCA18) was constructed in the age-appropriate National Institute of Health Pediatric Database asymmetric template space using manual tracings of 16 cerebellar compartments in 18 healthy children (9-13 years) from Cape Town, South Africa. The individual atlases of the training subjects were also used to implement multi atlas label fusion using multi atlas majority voting (MAMV) and multi atlas generative model (MAGM) approaches. Segmentation accuracy in 14 test subjects was compared for each method to 'gold standard' manual tracings. Results: Spatial overlap between manual tracings and CAPCA18 automated segmentation was 73% or higher for all lobules in both hemispheres, except VIIb and X. Automated segmentation using MAGM yielded the best segmentation accuracy over all lobules (mean Dice Similarity Coefficient 0.76; range 0.55-0.91; mean Hausdorff distance 0.9 mm; range 0.8-2.7 mm). Comparison with existing methods: In all lobules, spatial overlap of CAPCA18 segmentations with manual tracings was similar or higher than those obtained with SUIT (spatially unbiased infra-tentorial template), providing additional evidence of the benefits of an age appropriate atlas. MAGM segmentation accuracy was comparable to values reported recently by Park et al. (Neuroimage 2014;95(1):217) in adults (across all lobules mean DSC=0.73, range 0.40-0.89). Conclusions: CAPCA18 and the associated multi-subject atlases of the training subjects yield improved segmentation of cerebellar structures in children. (C) 2016 Elsevier B.V. All rights reserved. C1 [Narayanan, Priya Lakshmi; Warton, Christopher; Boonzaier, Natalie Rosella; Joseph, Jesuchristopher; Jacobson, Joseph L.; Jacobson, Sandra W.; Meintjes, Ernesta M.] Univ Cape Town, Fac Hlth Sci, Dept Human Biol, ZA-7925 Cape Town, South Africa. [Narayanan, Priya Lakshmi; Joseph, Jesuchristopher; Meintjes, Ernesta M.] Univ Cape Town, Div Biomed Engn, MRC UCT Med Imaging Res Unit, ZA-7925 Cape Town, South Africa. [Molteno, Christopher D.; Jacobson, Joseph L.; Jacobson, Sandra W.] Univ Cape Town, Fac Hlth Sci, Dept Psychiat & Mental Hlth, ZA-7925 Cape Town, South Africa. [Jacobson, Joseph L.; Jacobson, Sandra W.] Wayne State Univ, Sch Med, Dept Psychiat & Behav Neurosci, Detroit, MI USA. [Zoellei, Lilla] Massachusetts Gen Hosp, Martinos Ctr Biomed Imaging, Boston, MA 02114 USA. RP Narayanan, PL (reprint author), Univ Cape Town, Fac Hlth Sci, Dept Human Biol, ZA-7925 Cape Town, South Africa. EM priyalakshmi79@gmail.com OI Boonzaier, Natalie Rosella/0000-0003-1763-0896 FU NIH Fogarty International Research Collaboration (FIRCA) [R03 TW007030]; National Institute on Alcohol Abuse and Alcoholism (NIAAA) [R01AA016781]; NIAAA [R01AA09524]; NIH Office of Research on Minority Health; NIH FIRCA [R03 TW007030]; NIH/NIAAA [R21AA017410]; National Research Foundation of South Africa Focus Area grant [FA2005040800024]; South African Research Chairs Initiative of the Department of Science and Technology, Republic of South Africa; National Research Foundation of South Africa; Medical Research Council of South Africa; Office of the President of Wayne State University; University of Cape Town; State of Michigan; NICHD [1K99HD061485-01A1, R00 HD061485-03] FX Cerebellar neuroimaging data were collected with funding from NIH Fogarty International Research Collaboration (FIRCA; R03 TW007030) and National Institute on Alcohol Abuse and Alcoholism (NIAAA; R01AA016781). Recruitment of the Cape Town longitudinal cohort was funded by two administrative supplements from NIAAA to R01AA09524 and the NIH Office of Research on Minority Health; recruitment of the Cape Town cross-sectional cohort, by NIH FIRCA (R03 TW007030). This research was supported by funding from NIH/NIAAA (R21AA017410), a National Research Foundation of South Africa Focus Area grant (FA2005040800024), South African Research Chairs Initiative of the Department of Science and Technology, Republic of South Africa and National Research Foundation of South Africa, Medical Research Council of South Africa, Children's Bridge grant from the Office of the President of Wayne State University, a seed money grant from the University of Cape Town; and grants from the Joseph Young, Sr., Fund from the State of Michigan. LZ was supported for this research in part by NICHD grants 1K99HD061485-01A1 and R00 HD061485-03. We thank D. Viljoen, who collaborated on the recruitment of the longitudinal cohort; M. September, J. Croxford, and A.S. Marais for their work on recruitment and retention of the cohorts; the staff at the Cape Universities Brain Imaging Centre and our University of Cape Town research staff for collection of the neuroimaging data. We also express our gratitude to the mothers and children who have participated in the Cape Town Longitudinal Cohort Studies. NR 48 TC 0 Z9 0 U1 0 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0270 EI 1872-678X J9 J NEUROSCI METH JI J. Neurosci. Methods PD MAR 15 PY 2016 VL 262 BP 1 EP 13 DI 10.1016/j.jneumeth.2015.12.010 PG 13 WC Biochemical Research Methods; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA DG9CC UT WOS:000372379400001 PM 26743973 ER PT J AU Cavusoglu, E Marmur, JD Kassotis, JT Yanamadala, S Chopra, V Eng, C AF Cavusoglu, Erdal Marmur, Jonathan D. Kassotis, John T. Yanamadala, Sunitha Chopra, Vineet Eng, Calvin TI Usefulness of Plasma Matrix Metalloproteinase-3 Levels to Predict Myocardial Infarction in Men With and Without Acute Coronary Syndrome SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID ALL-CAUSE MORTALITY; ATHEROSCLEROTIC PLAQUES; STROMELYSIN-1 MMP-3; INDEPENDENT PREDICTOR; GENE-EXPRESSION; PROMOTER; MACROPHAGES; INSTABILITY; PROGRESSION; ACTIVATION AB Matrix metalloproteinase-3 (MMP-3), or stromelysin-1, is a matrix metalloproteinase which is expressed in atherosclerotic plaques and which has been implicated in the pathogenesis of acute coronary syndrome (ACS). Functional polymorphisms in the promoter region of the human MMP-3 gene resulting in an increased expression of MMP-3 have been shown to predict the risk of incident myocardial infarction (MI). However, there have been no studies that have specifically examined the utility of baseline plasma MMP-3 levels for the prediction of long-term MI. In this study, baseline plasma MMP-3 levels were measured in 355 male patients who were referred for coronary angiography and followed prospectively for the development of enzymatically confirmed MI out to 5 years. After adjustment for a variety of baseline clinical, angiographic, and laboratory parameters, plasma MMP-3 levels were an independent predictor of MI at 5 years (hazards ratio 1.42, 95% CI 1.13 to 1.79; p = 0.0023). Furthermore, in 5 additional multivariate models that included a variety of contemporary biomarkers associated with adverse outcomes and MI, MMP-3 remained an independent predictor of MI at 5 years. Similar results were obtained when the analyses were restricted to the subpopulation of patients presenting with ACS. In conclusion, elevated levels of MMP-3 are associated with an increased risk of long-term MI in patients with and without ACS referred for coronary angiography. Furthermore, this association is independent of a variety of clinical, angiographic, laboratory variables, including biomarkers with established prognostic efficacy for the prediction of MI. (c) 2016 Elsevier Inc. All rights reserved. C1 [Cavusoglu, Erdal; Chopra, Vineet; Eng, Calvin] Bronx Vet Affairs Med Ctr, Dept Med, Div Cardiol, Bronx, NY USA. [Cavusoglu, Erdal; Marmur, Jonathan D.; Kassotis, John T.; Yanamadala, Sunitha] Suny Downstate Med Ctr, Dept Med, Div Cardiol, Brooklyn, NY 11203 USA. RP Cavusoglu, E (reprint author), Bronx Vet Affairs Med Ctr, Dept Med, Div Cardiol, Bronx, NY USA.; Cavusoglu, E (reprint author), Suny Downstate Med Ctr, Dept Med, Div Cardiol, Brooklyn, NY 11203 USA. EM ECavusoglu@aol.com NR 30 TC 0 Z9 0 U1 1 U2 1 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 MAR 15 PY 2016 VL 117 IS 6 BP 881 EP 886 DI 10.1016/j.amjcard.2015.12.022 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DG5RH UT WOS:000372135800001 PM 26805660 ER PT J AU Giordano, S Zhao, XM Xing, D Hage, F Oparil, S Cooke, JP Lee, J Nakayama, KH Huang, NF Chen, YF AF Giordano, Samantha Zhao, Xiangmin Xing, Daisy Hage, Fadi Oparil, Suzanne Cooke, John P. Lee, Jieun Nakayama, Karina H. Huang, Ngan F. Chen, Yiu-Fai TI Targeted delivery of human iPS-ECs overexpressing IL-8 receptors inhibits neointimal and inflammatory responses to vascular injury in the rat SO AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY LA English DT Article DE targeted cell therapy; human induced pluripotent stem cells; endothelial cells; vascular injury; inflammation vascular injury; restenosis ID PLURIPOTENT STEM-CELLS; PERIPHERAL ARTERIAL-DISEASE; ENDOTHELIAL GROWTH-FACTOR; MYOCARDIAL-INFARCTION; CAROTID ARTERIES; BALLOON INJURY; INTERLEUKIN-8; ESTROGEN; PROLIFERATION; HYPERTENSION AB Interleukin-8 (IL8) is highly expressed by injured arteries in a variety of diseases and is a chemoattractant for neutrophils which express IL8 receptors IL8RA and RB (IL8RA/B) on their membranes. Neutrophils interact with the damaged endothelium and initiate an inflammatory cascade at the site of injury. We have generated a novel translational targeted cell therapy for acute vascular injury using adenoviral vectors to overexpress IL8RA/B and green fluorescent protein (GFP) on the surface of endothelial cells (ECs) derived from human induced pluripotent stem cells (HiPS-IL8RA/B-ECs). We hypothesize that HiPS-IL8RA/B-ECs transfused intravenously into rats with balloon injury of the carotid artery will target to the injured site and compete with neutrophils, thus inhibiting inflammation and neointima formation. Young adult male Sprague-Dawley rats underwent balloon injury of the right carotid artery and received intravenous transfusion of saline vehicle, 1.5 x 10(6) HiPS-ECs, 1.5 x 10(6) HiPS-Null-ECs, or 1.5 x 10(6) HiPS-IL8RA/B-ECs immediately after endoluminal injury. Tissue distribution of HiPS-IL8RA/B-ECs was analyzed by a novel GFP DNA qPCR method. Cytokine and chemokine expression and leukocyte infiltration were measured in injured and uninjured arteries at 24 h postinjury by ELISA and immunohistochemistry, respectively. Neointimal, medial areas, and reendothelialization were measured 14 days postinjury. HiPS-IL8RA/B-ECs homed to injured arteries, inhibited inflammatory mediator expression and inflammatory cell infiltration, accelerated reendothelialization, and attenuated neointima formation after endoluminal injury while control HiPS-ECs and HiPS-Null-ECs did not. HiPS-IL8RA/B-ECs transfused into rats with endoluminal carotid artery injury target to the injured artery and provide a novel strategy to treat vascular injury. C1 [Giordano, Samantha; Xing, Daisy; Hage, Fadi; Oparil, Suzanne; Chen, Yiu-Fai] Univ Alabama Birmingham, Dept Med, Div Cardiovasc Dis, Vasc Biol & Hypertens Program, Birmingham, AL 35294 USA. [Zhao, Xiangmin] Univ Illinois, Coll Med, Dept Pulm Crit Care Sleep & Allergy, Chicago, IL USA. [Hage, Fadi] Birmingham Vet Affairs Med Ctr, Div Cardiol, Birmingham, AL USA. [Cooke, John P.] Houston Methodist Res Inst, Houston, TX USA. [Lee, Jieun] Stanford Univ, Div Cardiovasc Med, Stanford, CA 94305 USA. [Nakayama, Karina H.; Huang, Ngan F.] Stanford Univ, Cardiovasc Inst, Stanford, CA 94305 USA. [Nakayama, Karina H.; Huang, Ngan F.] Vet Affairs Palo Alto Hlth Care Syst, Palo Alto, CA USA. [Huang, Ngan F.] Stanford Univ, Dept Cardiothorac Surg, Stanford, CA 94305 USA. RP Chen, YF (reprint author), Univ Alabama Birmingham, Dept Med, 1008 Zeigler Res Bldg,703 19th St South, Birmingham, AL 35294 USA. EM yfchen@uab.edu OI Cooke, John/0000-0003-0033-9138; Hage, Fadi/0000-0002-1397-4942 FU UAB CCVC William W. Featheringill Innovative Award; National Institutes of Health [RO1-HL-116727, RO1-HL-087980, T32-HL-07457, U01-HL-100397, RC2-HL-103400, R00-HL-098688]; American Heart Association [AHA-SDG-0930098N]; Veterans Affairs Biomedical Laboratory Research & Development Service Merit Award [OMB 4040-0001] FX This work was supported, in part, by UAB CCVC William W. Featheringill Innovative Award (Y. F. Chen); by National Institutes of Health Grants RO1-HL-116727 (Y. F. Chen), RO1-HL-087980 (S. Oparil), T32-HL-07457 (S. Oparil, S. Giordano); U01-HL-100397 and RC2-HL-103400 (J. P. Cooke), and R00-HL-098688 (N. F. Huang); by American Heart Association Grant AHA-SDG-0930098N (F. G. Hage); and by Veterans Affairs Biomedical Laboratory Research & Development Service Merit Award OMB 4040-0001 (F. G. Hage). NR 24 TC 1 Z9 1 U1 2 U2 6 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6135 EI 1522-1539 J9 AM J PHYSIOL-HEART C JI Am. J. Physiol.-Heart Circul. Physiol. PD MAR 15 PY 2016 VL 310 IS 6 BP H705 EP H715 DI 10.1152/ajpheart.00587.2015 PG 11 WC Cardiac & Cardiovascular Systems; Physiology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Physiology GA DG4ZX UT WOS:000372082900005 PM 26801304 ER PT J AU Schuetze, SM Wathen, JK Lucas, DR Choy, E Samuels, BL Staddon, AP Ganjoo, KN von Mehren, M Chow, WA Loeb, DM Tawbi, HA Rushing, DA Patel, SR Thomas, DG Chugh, R Reinke, DK Baker, LH AF Schuetze, Scott M. Wathen, J. Kyle Lucas, David R. Choy, Edwin Samuels, Brian L. Staddon, Arthur P. Ganjoo, Kristen N. von Mehren, Margaret Chow, Warren A. Loeb, David M. Tawbi, Hussein A. Rushing, Daniel A. Patel, Shreyaskumar R. Thomas, Dafydd G. Chugh, Rashmi Reinke, Denise K. Baker, Laurence H. TI SARC009: Phase 2 study of dasatinib in patients with previously treated, high-grade, advanced sarcoma SO CANCER LA English DT Article DE adaptive; Bayesian; Choi; dasatinib; phase 2; sarcoma ID CHRONIC MYELOID-LEUKEMIA; SOFT-TISSUE SARCOMAS; CLINICAL-TRIALS; CELL LINES; IN-VITRO; CANCER; INHIBITION; IMATINIB; PAZOPANIB; SUBTYPES AB BACKGROUNDDasatinib exhibited activity in preclinical models of sarcoma. The Sarcoma Alliance for Research through Collaboration (SARC) conducted a multicenter, phase 2 trial of dasatinib in patients with advanced sarcoma. METHODSPatients received dasatinib twice daily. The primary objective was to estimate the clinical benefit rate (CBR) (complete response or partial response within 6 months or stable disease duration of 6 months) with a target of 25%. Patients were enrolled into 1 of 7 different cohorts and assessed by imaging every 8 weeks using Choi criteria tumor response and a Bayesian hierarchical design. For each subtype, enrollment was stopped after a minimum of 9 patients were treated if there was a <1% chance the CBR was 25%. RESULTSA total of 200 patients were enrolled. Accrual was stopped early in 5 cohorts because of low CBR. The leiomyosarcoma (LMS) and undifferentiated pleomorphic sarcoma (UPS) cohorts fully accrued and 6 of 47 and 8 of 42 evaluable patients, respectively, exhibited clinical benefit. The probability that the CBR was 25% in the LMS and UPS cohorts was 0.008 and 0.10, respectively. The median progression-free survival ranged from 0.9 months in patients with rhabdomyosarcoma to 2.2 months in patients with LMS. The median overall survival was 8.6 months. The most frequent adverse events were constitutional, gastrointestinal, and respiratory, and 36% of patients required dose reduction for toxicity. Serious adverse events attributed to therapy occurred in 11% of patients. CONCLUSIONSDasatinib may have activity in patients with UPS but is inactive as a single agent in the other sarcoma subtypes included herein. The Bayesian design allowed for the early termination of accrual in 5 subtypes because of lack of drug activity. Cancer 2016;122:868-74. (c) 2015 American Cancer Society. Dasatinib, an inhibitor of multiple tyrosine kinases, was evaluated for anticancer activity in distinct histologic subtypes of sarcoma. Use of an adaptive Bayesian design allowed for the efficient estimation of clinical benefit from dasatinib and limited enrollment in subtypes in which no activity was observed. C1 [Schuetze, Scott M.; Chugh, Rashmi; Baker, Laurence H.] Univ Michigan, Div Hematol Oncol, Dept Med, Ann Arbor, MI 48109 USA. [Wathen, J. Kyle] Johnson & Johnson, Dept Biostat, New Brunswick, NJ USA. [Lucas, David R.] Univ Michigan, Anat Pathol, Ann Arbor, MI 48109 USA. [Choy, Edwin] Massachusetts Gen Hosp, Dept Med, Div Hematol Oncol, Boston, MA 02114 USA. [Samuels, Brian L.] Northwest Oncol, Post Falls, ID USA. [Staddon, Arthur P.] Univ Penn, Sch Med, Dept Med, Div Hematol Oncol, Philadelphia, PA 19104 USA. [Ganjoo, Kristen N.] Stanford Med Inst, Med Oncol, Stanford, CA USA. [von Mehren, Margaret] Fox Chase Canc Ctr, Div Med Oncol & Hematol, 7701 Burholme Ave, Philadelphia, PA 19111 USA. [Chow, Warren A.] City Hope Med Ctr, Dept Med Oncol & Therapeut Res, Duarte, CA USA. [Loeb, David M.] Johns Hopkins Univ, Sidney Kimmel Comprehens Canc Ctr, Div Pediat Oncol, Dept Oncol, Baltimore, MD USA. [Tawbi, Hussein A.] Univ Pittsburgh, Sch Med, Dept Med, Div Hematol Oncol, Pittsburgh, PA 15213 USA. [Rushing, Daniel A.] Indiana Univ, Dept Med, Div Hematol Oncol, Indianapolis, IN USA. [Patel, Shreyaskumar R.] Univ Texas MD Anderson Canc Ctr, Dept Sarcoma Med Oncol, Houston, TX 77030 USA. [Thomas, Dafydd G.] Univ Michigan, Mol Pathol, Ann Arbor, MI 48109 USA. [Reinke, Denise K.] Sarcoma Alliance Res Collaborat, Ann Arbor, MI USA. RP Schuetze, SM (reprint author), Univ Michigan, Div Hematol Oncol, C342 Med Inn,SPC 5848,1500 E Med Ctr Dr, Ann Arbor, MI 48109 USA. EM scotschu@med.umich.edu FU Sarcoma Alliance for Research through Collaboration (SARC); Bristol-Myers Squibb; SARC by Bristol-Myers Squibb FX Supported by the Sarcoma Alliance for Research through Collaboration (SARC) and Bristol-Myers Squibb. Dasatinib was provided by Bristol-Myers Squibb to the participating sites. Funding for the study was provided to SARC by Bristol-Myers Squibb. NR 24 TC 4 Z9 4 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 MAR 15 PY 2016 VL 122 IS 6 BP 868 EP 874 DI 10.1002/cncr.29858 PG 7 WC Oncology SC Oncology GA DG7QQ UT WOS:000372279200009 PM 26710211 ER PT J AU Thompson, D Vo, KT London, WB Fischer, M Ambros, PF Nakagawara, A Brodeur, GM Matthay, KK DuBois, SG AF Thompson, Daria Vo, Kieuhoa T. London, Wendy B. Fischer, Matthias Ambros, Peter F. Nakagawara, Akira Brodeur, Garrett M. Matthay, Katherine K. DuBois, Steven G. TI Identification of patient subgroups with markedly disparate rates of MYCN amplification in neuroblastoma: A report from the International Neuroblastoma Risk Group project SO CANCER LA English DT Article DE decision trees; gene amplification; neuroblastoma; neuroblastoma; genetics; oncogene proteins; genetics ID CHILDRENS ONCOLOGY GROUP; N-MYC; METASTATIC NEUROBLASTOMA; GENE AMPLIFICATION; PROGNOSTIC FACTORS; NEURO-BLASTOMA; CHROMOSOME 1P; STAGE; AGE; DIAGNOSIS AB BACKGROUNDMYCN gene amplification (MNA) is a hallmark of aggressive neuroblastoma. This study was performed to determine univariate and multivariate predictors of tumor MNA. METHODSData from the International Neuroblastoma Risk Group were analyzed for a subset of 7102 patients with known MYCN status. Chi-square testing and logistic regression were used to identify univariate and multivariate predictors of MYCN status. Recursive partitioning was used to identify groups of patients with maximal differences in rates of MNA. RESULTSAll clinical features (age18 months, high ferritin levels, high lactate dehydrogenase [LDH] levels, International Neuroblastoma Staging System stage 4, and adrenal sites) and pathological/biological features (DNA index1, high mitosis-karyorrhexis index [MKI], undifferentiated/poorly differentiated grade, unfavorable histology according to the International Neuroblastoma Pathology Classification, and segmental chromosomal aberrations [SCAs]) were significantly associated with MNA. LDH (odds ratio [OR], 8.4; P<.001) and chromosomal 1p loss of heterozygosity (OR, 19.8; P<.001) were the clinical and biological variables, respectively, most strongly associated with MNA. In logistic regression, all variables except chromosome 17q aberration and pooled SCAs were independently predictive of MNA. Recursive partitioning identified subgroups with disparate rates of MNA, including subgroups with 85.7% MNA (patients with high LDH levels who had poorly differentiated adrenal tumors with chromosome 1p deletion) and 0.6% MNA (localized tumors having hyperdiploidy and low MKIs and lacking chromosome 1p aberrations). CONCLUSIONSMNA is strongly associated with other clinical and biological variables in neuroblastoma. Recursive partitioning has identified subgroups of neuroblastoma patients with highly disparate rates of MNA. These findings can be used to inform investigations of molecular mechanisms of MNA. Cancer 2016;122:935-45. (c) 2015 American Cancer Society. MYCN amplification in neuroblastoma is strongly associated with biology/pathology variables and particularly segmental chromosomal aberrations. Recursive partitioning techniques using these variables alone or in conjunction with clinical variables can identify subgroups of patients with markedly disparate rates of MYCN amplification. C1 [Vo, Kieuhoa T.; London, Wendy B.; Matthay, Katherine K.; DuBois, Steven G.] Univ Calif San Francisco, Sch Med, Dept Pediat, Benioff Childrens Hosp, San Francisco, CA 94143 USA. [London, Wendy B.] Harvard Univ, Dana Farber Childrens Hosp, Canc & Blood Disorders Ctr, Sch Med, Boston, MA USA. [Fischer, Matthias] Univ Cologne, Childrens Hosp & Ctr Mol Med Cologne, Dept Pediat Oncol, D-50931 Cologne, Germany. [Ambros, Peter F.] St Anne Kinderkrebsforsch, Childrens Canc Res Inst, Vienna, Austria. [Nakagawara, Akira] Chiba Canc Ctr Res Inst, Dept Biochem, Chiba, Japan. [Nakagawara, Akira] Chiba Univ, Chiba, Japan. [Brodeur, Garrett M.] Univ Penn, Childrens Hosp Philadelphia, Dept Pediat, Philadelphia, PA 19104 USA. [Brodeur, Garrett M.] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. RP DuBois, SG (reprint author), Dana Farber Canc Inst, Pediat Oncol, 450 Brookline Ave,Dana 3, Boston, MA 02215 USA. EM steven_dubois@dfci.harvard.edu OI Ambros, Peter F./0000-0002-5507-7211 FU Alex's Lemonade Stand Foundation; Frank A. Campini Foundation; Edward Conner Fund; Dougherty Foundation; National Institutes of Health [CA039771]; Audrey Evans Endowed Chair; Mildred V. Strouss Chair; German Ministry of Science and Education as part of the e:Med initiative [01ZX1303A, 01ZX1307D]; Foerdergesellschaft Kinderkrebs-Neuroblastom-Forschung eV FX Support was provided in part by Alex's Lemonade Stand Foundation (to Kieuhoa T. Vo, Katherine K. Matthay, and Steven G. DuBois), the Frank A. Campini Foundation (to Katherine K. Matthay and Steven G. DuBois), the Edward Conner Fund (to Katherine K. Matthay), the Dougherty Foundation (to Katherine K. Matthay and Steven G. DuBois), the National Institutes of Health (grant CA039771) and the Audrey Evans Endowed Chair (to Garrett M. Brodeur), and the Mildred V. Strouss Chair (to Katherine K. Matthay). Matthias Fischer reports grants from the German Ministry of Science and Education as part of the e:Med initiative (01ZX1303A and 01ZX1307D) and from Foerdergesellschaft Kinderkrebs-Neuroblastom-Forschung eV during the conduct of the study. The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the funding sources listed here. NR 35 TC 3 Z9 3 U1 3 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X EI 1097-0142 J9 CANCER-AM CANCER SOC JI Cancer PD MAR 15 PY 2016 VL 122 IS 6 BP 935 EP 945 DI 10.1002/cncr.29848 PG 11 WC Oncology SC Oncology GA DG7QQ UT WOS:000372279200017 PM 26709890 ER PT J AU Lipshultz, SE Anderson, LM Miller, TL Gerschenson, M Stevenson, KE Neuberg, DS Franco, VI LiButti, DE Silverman, LB Vrooman, LM Sallan, SE AF Lipshultz, Steven E. Anderson, Lynn M. Miller, Tracie L. Gerschenson, Mariana Stevenson, Kristen E. Neuberg, Donna S. Franco, Vivian I. LiButti, Daniel E. Silverman, Lewis B. Vrooman, Lynda M. Sallan, Stephen E. CA Dana-Farber Canc Inst Acute Lympho TI Impaired mitochondrial function is abrogated by dexrazoxane in doxorubicin-treated childhood acute lymphoblastic leukemia survivors SO CANCER LA English DT Article DE childhood cancer survivors; dexrazoxane; doxorubicin; mitochondrial DNA; mitochondrial function ID HEART-FAILURE; INDUCED CARDIOTOXICITY; LIPID-PEROXIDATION; CANCER SURVIVORS; OXIDATIVE STRESS; CARDIAC STATUS; ONCOLOGY-GROUP; RISK-FACTORS; CHILDREN; THERAPY AB BACKGROUNDImpaired cardiac function in doxorubicin-treated childhood cancer survivors is partly mediated by the disruption of mitochondrial energy production. Doxorubicin intercalates into mitochondrial DNA (mtDNA) and disrupts genes encoding for polypeptides that make adenosine triphosphate. METHODSThis cross-sectional study examined mtDNA copy numbers per cell and oxidative phosphorylation (OXPHOS) in peripheral blood mononuclear cells (PBMCs) in 64 childhood survivors of high-risk acute lymphoblastic leukemia (ALL) who had been treated on Dana-Farber Cancer Institute childhood ALL protocols and had received doxorubicin alone (42%) or doxorubicin with the cardioprotectant dexrazoxane (58%). The number of mtDNA copies per cell and the OXPHOS enzyme activity of nicotinamide adenine dinucleotide dehydrogenase (complex I [CI]) and cytochrome c oxidase (complex IV [CIV]) were measured with quantitative real-time polymerase chain reaction immunoassays and thin-layer chromatography, respectively. RESULTSAt a median follow-up of 7.8 years after treatment, the median number of mtDNA copies per cell for patients treated with doxorubicin alone (1106.3) was significantly higher than the median number for those who had also received dexrazoxane (310.5; P=.001). No significant differences were detected between the groups for CI or CIV activity. CONCLUSIONSDoxorubicin-treated survivors had an increased number of PBMC mtDNA copies per cell, and concomitant use of dexrazoxane was associated with a lower number of mtDNA copies per cell. Because of a possible compensatory increase in mtDNA copies per cell to maintain mitochondrial function in the setting of mitochondrial dysfunction, overall OXPHOS activity was not different between the groups. The long-term sustainability of this compensatory response in these survivors at risk for cardiac dysfunction over their lifespan is concerning. Cancer 2016;122:946-53. (c) 2016 American Cancer Society. Impaired cardiac function in doxorubicin-treated childhood cancer survivors is partly mediated by the disruption of mitochondrial energy production. This study provides evidence supporting the idea that dexrazoxane adjuvant therapy in pediatric patients with high-risk acute lymphoblastic leukemia offers systemic mitochondrial protection as observed in peripheral blood mononuclear cells 7 years after treatment. C1 [Lipshultz, Steven E.; Franco, Vivian I.] Wayne State Univ, Sch Med, Dept Pediat, Childrens Hosp Michigan, Detroit, MI 48201 USA. [Lipshultz, Steven E.] Karmanos Canc Inst, Detroit, MI USA. [Anderson, Lynn M.; Gerschenson, Mariana; LiButti, Daniel E.] Univ Hawaii Manoa, Dept Cell & Mol Biol Cell & Mol Biol, John A Burns Sch Med, Honolulu, HI 96822 USA. [Miller, Tracie L.] Univ Miami, Miller Sch Med, Dept Pediat, Miami, FL 33136 USA. [Stevenson, Kristen E.; Neuberg, Donna S.; Silverman, Lewis B.; Vrooman, Lynda M.; Sallan, Stephen E.] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Silverman, Lewis B.; Vrooman, Lynda M.; Sallan, Stephen E.] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Silverman, Lewis B.; Vrooman, Lynda M.; Sallan, Stephen E.] Boston Childrens Hosp, Dept Med, Div Hematol Oncol, Boston, MA USA. RP Lipshultz, SE (reprint author), Childrens Hosp Michigan, Dept Pediat, 3901 Beaubien Blvd,Suite 1K40, Detroit, MI 48201 USA. EM slipshultz@med.wayne.edu FU National Institutes of Health [HL072705, HL078522, HL053392, CA127642, CA068484, HD052104, AI50274, HD052102, HL087708, HL079233, HL004537, HL087000, HL007188, HL094100, HL095127, HD80002]; Children's Cardiomyopathy Foundation; Women's Cancer Association; Lance Armstrong Foundation; STOP Children's Cancer Foundation; Parker Family Foundation; Scott Howard Fund; Michael Garil Fund; National Cancer Institute FX This study was supported in part by grants from the National Institutes of Health (HL072705, HL078522, HL053392, CA127642, CA068484, HD052104, AI50274, HD052102, HL087708, HL079233, HL004537, HL087000, HL007188, HL094100, HL095127, and HD80002), the Children's Cardiomyopathy Foundation, the Women's Cancer Association, the Lance Armstrong Foundation, the STOP Children's Cancer Foundation, the Parker Family Foundation, the Scott Howard Fund, and the Michael Garil Fund. Tracie L. Miller reports a grant from the National Cancer Institute. NR 52 TC 3 Z9 3 U1 1 U2 1 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 MAR 15 PY 2016 VL 122 IS 6 BP 946 EP 953 DI 10.1002/cncr.29872 PG 8 WC Oncology SC Oncology GA DG7QQ UT WOS:000372279200018 PM 26762648 ER PT J AU Marshall, CB Mays, DJ Beeler, JS Rosenbluth, JM Boyd, KL Guasch, GLS Shaver, TM Tang, LJ Liu, Q Shyr, Y Venters, BJ Magnuson, MA Pietenpol, JA AF Marshall, Clayton B. Mays, Deborah J. Beeler, J. Scott Rosenbluth, Jennifer M. Boyd, Kelli L. Guasch, Gabriela L. Santos Shaver, Timothy M. Tang, Lucy J. Liu, Qi Shyr, Yu Venters, Bryan J. Magnuson, Mark A. Pietenpol, Jennifer A. TI p73 Is Required for Multiciliogenesis and Regulates the Foxj1-Associated Gene Network SO CELL REPORTS LA English DT Article ID INTEGRATIVE GENOMICS VIEWER; TRACHEAL EPITHELIAL-CELLS; AIRWAY STEM-CELLS; WILD-TYPE P53; CENTRIOLE AMPLIFICATION; TRANSCRIPTIONAL CONTROL; P73-DEFICIENT MICE; LUNG REGENERATION; P63; MOUSE AB We report that p73 is expressed in multiciliated cells (MCCs), is required for MCC differentiation, and directly regulates transcriptional modulators of multiciliogenesis. Loss of ciliary biogenesis provides a unifying mechanism for many phenotypes observed in p73 knockout mice including hydrocephalus; hippocampal dysgenesis; sterility; and chronic inflammation/infection of lung, middle ear, and sinus. Through p73 and p63 ChIP-seq using murine tracheal cells, we identified over 100 putative p73 target genes that regulate MCC differentiation and homeostasis. We validated Foxj1, a transcriptional regulator of multiciliogenesis, and many other cilia-associated genes as direct target genes of p73 and p63. We show p73 and p63 are co-expressed in a subset of basal cells and suggest that p73 marks these cells for MCC differentiation. In summary, p73 is essential for MCC differentiation, functions as a critical regulator of a transcriptome required for MCC differentiation, and, like p63, has an essential role in development of tissues. C1 [Marshall, Clayton B.; Mays, Deborah J.; Beeler, J. Scott; Rosenbluth, Jennifer M.; Guasch, Gabriela L. Santos; Shaver, Timothy M.; Tang, Lucy J.; Pietenpol, Jennifer A.] Vanderbilt Univ, Dept Biochem, Nashville, TN 37232 USA. [Rosenbluth, Jennifer M.] Dana Farber Canc Inst, Dept Med, Boston, MA 02215 USA. [Boyd, Kelli L.] Vanderbilt Univ, Dept Pathol Microbiol & Immunol, Nashville, TN 37232 USA. [Boyd, Kelli L.; Shyr, Yu; Venters, Bryan J.; Magnuson, Mark A.; Pietenpol, Jennifer A.] Vanderbilt Univ, Vanderbilt Ingram Canc Ctr, Nashville, TN 37232 USA. [Liu, Qi; Shyr, Yu] Vanderbilt Univ, Ctr Quantitat Sci, Nashville, TN 37232 USA. [Venters, Bryan J.; Magnuson, Mark A.] Vanderbilt Univ, Dept Mol Physiol & Biophys, Nashville, TN 37232 USA. RP Pietenpol, JA (reprint author), Vanderbilt Univ, Dept Biochem, Nashville, TN 37232 USA.; Pietenpol, JA (reprint author), Vanderbilt Univ, Vanderbilt Ingram Canc Ctr, Nashville, TN 37232 USA. EM j.pietenpol@vanderbilt.edu FU NIH [CA105436, CA070856, CA068485, T90DA022873] FX We thank Vasiliy Polosukhin for technical assistance with ALI, Kimberly Johnson and Violeta Sanchez for help with histology, and Harold Moses for assistance with pathology analysis. This research was supported by NIH grants CA105436, CA070856, and CA068485 to J.A.P. and T90DA022873 to C.B.M. NR 67 TC 9 Z9 9 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2211-1247 J9 CELL REP JI Cell Reports PD MAR 15 PY 2016 VL 14 IS 10 BP 2289 EP 2300 DI 10.1016/j.celrep.2016.02.035 PG 12 WC Cell Biology SC Cell Biology GA DG3VN UT WOS:000371998700003 PM 26947080 ER PT J AU Chen, FJ Zhang, YQ Senbabaoglu, Y Ciriello, G Yang, LX Reznik, E Shuch, B Micevic, G De Velasco, G Shinbrot, E Noble, MS Lu, YL Covington, KR Xi, L Drummond, JA Muzny, D Kang, H Lee, J Tamboli, P Reuter, V Shelley, CS Kaipparettu, BA Bottaro, DP Godwin, AK Gibbs, RA Getz, G Kucherlapati, R Park, PJ Sander, C Henske, EP Zhou, JH Kwiatkowski, DJ Ho, TH Choueiri, TK Hsieh, JJ Akbani, R Mills, GB Hakimi, AA Wheeler, DA Creighton, CJ AF Chen, Fengju Zhang, Yiqun Senbabaoglu, Yasin Ciriello, Giovanni Yang, Lixing Reznik, Ed Shuch, Brian Micevic, Goran De Velasco, Guillermo Shinbrot, Eve Noble, Michael S. Lu, Yiling Covington, Kyle R. Xi, Liu Drummond, Jennifer A. Muzny, Donna Kang, Hyojin Lee, Junehawk Tamboli, Pheroze Reuter, Victor Shelley, Carl Simon Kaipparettu, Benny A. Bottaro, Donald P. Godwin, Andrew K. Gibbs, Richard A. Getz, Gad Kucherlapati, Raju Park, Peter J. Sander, Chris Henske, Elizabeth P. Zhou, Jane H. Kwiatkowski, David J. Ho, Thai H. Choueiri, Toni K. Hsieh, James J. Akbani, Rehan Mills, Gordon B. Hakimi, A. Ari Wheeler, David A. Creighton, Chad J. TI Multilevel Genomics-Based Taxonomy of Renal Cell Carcinoma SO CELL REPORTS LA English DT Article ID CANCER; EXPRESSION; EVEROLIMUS; MUTATIONS; LANDSCAPE; DISCOVERY; SURVIVAL; BAP1 AB On the basis of multidimensional and comprehensive molecular characterization (including DNA methalylation and copy number, RNA, and protein expression), we classified 894 renal cell carcinomas (RCCs) of various histologic types into nine major genomic subtypes. Site of origin within the nephron was one major determinant in the classification, reflecting differences among clear cell, chromophobe, and papillary RCC. Widespread molecular changes associated with TFE3 gene fusion or chromatin modifier genes were present within a specific subtype and spanned multiple subtypes. Differences in patient survival and in alteration of specific pathways (including hypoxia, metabolism, MAP kinase, NRF2-ARE, Hippo, immune checkpoint, and PI3K/AKT/mTOR) could further distinguish the subtypes. Immune checkpoint markers and molecular signatures of T cell infiltrates were both highest in the subtype associated with aggressive clear cell RCC. Differences between the genomic subtypes suggest that therapeutic strategies could be tailored to each RCC disease subset. C1 [Chen, Fengju; Zhang, Yiqun; Kaipparettu, Benny A.; Creighton, Chad J.] Baylor Coll Med, Dan L Duncan Comprehens Canc Ctr, Houston, TX 77030 USA. [Senbabaoglu, Yasin; Reznik, Ed; Sander, Chris] Mem Sloan Kettering Canc Ctr, Computat Biol Program, New York, NY 10065 USA. [Ciriello, Giovanni] Univ Lausanne, Dept Computat Biol, CH-1015 Lausanne, Switzerland. [Yang, Lixing; Park, Peter J.] Harvard Univ, Sch Med, Dept Biomed Informat, Boston, MA 02115 USA. [Shuch, Brian] Yale Univ, Sch Med, Dept Urol, New Haven, CT 06520 USA. [Micevic, Goran] Yale Univ, Dept Dermatol, New Haven, CT 06510 USA. [Micevic, Goran] Yale Univ, Dept Pathol, New Haven, CT 06510 USA. [De Velasco, Guillermo; Choueiri, Toni K.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Shinbrot, Eve; Covington, Kyle R.; Xi, Liu; Drummond, Jennifer A.; Muzny, Donna; Gibbs, Richard A.; Wheeler, David A.; Creighton, Chad J.] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA. [Noble, Michael S.; Getz, Gad; Henske, Elizabeth P.; Kwiatkowski, David J.] MIT, Eli & Edythe L Broad Inst, Cambridge, MA 02142 USA. [Noble, Michael S.; Getz, Gad; Henske, Elizabeth P.; Kwiatkowski, David J.] Harvard Univ, Cambridge, MA 02142 USA. [Lu, Yiling; Mills, Gordon B.] Univ Texas MD Anderson Canc Ctr, Dept Syst Biol, Houston, TX 77054 USA. [Kang, Hyojin; Lee, Junehawk] Korea Inst Sci & Technol Informat KAIST, Dept Convergence Technol Res, Daejeon 305806, South Korea. [Lee, Junehawk] Korea Adv Inst Sci & Technol, Dept Bio & Brain Engn, Daejeon 305806, South Korea. [Tamboli, Pheroze] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA. [Reuter, Victor] Mem Sloan Kettering Canc, Dept Pathol, New York, NY 10065 USA. [Shelley, Carl Simon] Univ Wisconsin, Sch Med & Publ Hlth, Dept Med, Madison, WI 53726 USA. [Kaipparettu, Benny A.; Gibbs, Richard A.; Wheeler, David A.] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. [Bottaro, Donald P.] NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. [Godwin, Andrew K.] Univ Kansas, Med Ctr, Dept Pathol & Lab Med, Kansas City, KS 66160 USA. [Getz, Gad] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Kucherlapati, Raju] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Kucherlapati, Raju; Henske, Elizabeth P.; Kwiatkowski, David J.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Kucherlapati, Raju; Henske, Elizabeth P.; Kwiatkowski, David J.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Zhou, Jane H.] Tufts Univ, Sch Med, Tufts Med Ctr, Dept Pathol & Lab Med, Boston, MA 02111 USA. [Ho, Thai H.] Mayo Clin, Div Hematol & Med Oncol, Scottsdale, AZ 85054 USA. [Hsieh, James J.] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10065 USA. [Akbani, Rehan; Creighton, Chad J.] Univ Texas MD Anderson Canc Ctr, Dept Bioinformat & Computat Biol, Houston, TX 77030 USA. [Hakimi, A. Ari] Mem Sloan Kettering Canc Ctr, Dept Surg, Urol Serv, New York, NY 10065 USA. [Creighton, Chad J.] Baylor Coll Med, Dept Med, Houston, TX 77030 USA. RP Creighton, CJ (reprint author), Baylor Coll Med, Dan L Duncan Comprehens Canc Ctr, Houston, TX 77030 USA.; Creighton, CJ (reprint author), Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA.; Creighton, CJ (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Bioinformat & Computat Biol, Houston, TX 77030 USA.; Creighton, CJ (reprint author), Baylor Coll Med, Dept Med, Houston, TX 77030 USA. EM creighto@bcm.edu OI Micevic, Goran/0000-0003-0329-1053 FU NIH grant [CA125123]; Cancer Prevention and Research Institute of Texas grant [RP120713] FX This work was supported in part by NIH grant CA125123 and Cancer Prevention and Research Institute of Texas grant RP120713. A full listing of supporting grants is included in Supplemental Experimental Procedures. NR 35 TC 18 Z9 18 U1 4 U2 10 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2211-1247 J9 CELL REP JI Cell Reports PD MAR 15 PY 2016 VL 14 IS 10 BP 2476 EP 2489 DI 10.1016/j.celrep.2016.02.024 PG 14 WC Cell Biology SC Cell Biology GA DG3VN UT WOS:000371998700018 PM 26947078 ER PT J AU Piantadosi, A Rubin, DB McQuillen, DP Hsu, LG Lederer, PA Ashbaugh, CD Duffalo, C Duncan, R Thon, J Bhattacharyya, S Basgoz, N Feske, SK Lyons, JL AF Piantadosi, Anne Rubin, Daniel B. McQuillen, Daniel P. Hsu, Liangge Lederer, Philip A. Ashbaugh, Cameron D. Duffalo, Chad Duncan, Robert Thon, Jesse Bhattacharyya, Shamik Basgoz, Nesli Feske, Steven K. Lyons, Jennifer L. TI Emerging Cases of Powassan Virus Encephalitis in New England: Clinical Presentation, Imaging, and Review of the Literature SO CLINICAL INFECTIOUS DISEASES LA English DT Review DE Powassan; deer tick virus; encephalitis; New England ID WEST-NILE VIRUS; EASTERN EQUINE ENCEPHALITIS; DEER TICK VIRUS; ARBOVIRAL DISEASES; IXODES-SCAPULARIS; UNITED-STATES; NEW-YORK AB Background. Powassan virus (POWV) is a rarely diagnosed cause of encephalitis in the United States. In the Northeast, it is transmitted by Ixodes scapularis, the same vector that transmits Lyme disease. The prevalence of POWV among animal hosts and vectors has been increasing. We present 8 cases of POWV encephalitis from Massachusetts and New Hampshire in 2013-2015. Methods. We abstracted clinical and epidemiological information for patients with POWV encephalitis diagnosed at 2 hospitals in Massachusetts from 2013 to 2015. We compared their brain imaging with those in published findings from Powassan and other viral encephalitides. Results. The patients ranged in age from 21 to 82 years, were, for the most part, previously healthy, and presented with syndromes of fever, headache, and altered consciousness. Infections occurred from May to September and were often associated with known tick exposures. In all patients, cerebrospinal fluid analyses showed pleocytosis with elevated protein. In 7 of 8 patients, brain magnetic resonance imaging demonstrated deep foci of increased T2/fluid-attenuation inversion recovery signal intensity. Conclusions. We describe 8 cases of POWV encephalitis in Massachusetts and New Hampshire in 2013-2015. Prior to this, there had been only 2 cases of POWV encephalitis identified in Massachusetts. These cases may represent emergence of this virus in a region where its vector, I. scapularis, is known to be prevalent or may represent the emerging diagnosis of an under-appreciated pathogen. We recommend testing for POWV in patients who present with encephalitis in the spring to fall in New England. C1 [Piantadosi, Anne; Lederer, Philip A.; Basgoz, Nesli] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Rubin, Daniel B.; Thon, Jesse; Bhattacharyya, Shamik; Feske, Steven K.; Lyons, Jennifer L.] Brigham & Womens Hosp, Dept Neurol, 75 Francis St, Boston, MA 02115 USA. [McQuillen, Daniel P.; Duncan, Robert] Tufts Univ, Sch Med, Lahey Hosp & Med Ctr, Dept Infect Dis, Burlington, MA USA. [Hsu, Liangge] Brigham & Womens Hosp, Dept Radiol, 75 Francis St, Boston, MA 02115 USA. [Ashbaugh, Cameron D.] Brigham & Womens Hosp, Div Infect Dis, 75 Francis St, Boston, MA 02115 USA. [Duffalo, Chad] Christiana Care Hlth Syst, Div Infect Dis, Newark, DC USA. RP Lyons, JL (reprint author), Brigham & Womens Hosp, Div Neurol Infect & Inflammatory Dis, 45 Francis St, Boston, MA 02115 USA. EM jlyons5@partners.org OI Bhattacharyya, Shamik/0000-0001-8047-3622 FU NIAID NIH HHS [T32 AI007387] NR 27 TC 5 Z9 6 U1 1 U2 10 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 EI 1537-6591 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD MAR 15 PY 2016 VL 62 IS 6 BP 707 EP 713 DI 10.1093/cid/civ1005 PG 7 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA DF9XU UT WOS:000371716700005 PM 26668338 ER PT J AU Girouard, MP Sax, PE Parker, RA Taiwo, B Freedberg, KA Gulick, RM Weinstein, MC Paltiel, AD Walensky, RP AF Girouard, Michael P. Sax, Paul E. Parker, Robert A. Taiwo, Babafemi Freedberg, Kenneth A. Gulick, Roy M. Weinstein, Milton C. Paltiel, A. David Walensky, Rochelle P. TI The Cost-effectiveness and Budget Impact of 2-Drug Dolutegravir-Lamivudine Regimens for the Treatment of HIV Infection in the United States SO CLINICAL INFECTIOUS DISEASES LA English DT Article DE HIV; ART; cost-effectiveness; dolutegravir; lamivudine ID ANTIRETROVIRAL-NAIVE ADULTS; NON-INFERIORITY TRIAL; RITONAVIR PLUS LAMIVUDINE; ONCE-DAILY DOLUTEGRAVIR; OPEN-LABEL; TRIPLE TREATMENT; DUAL TREATMENT; DOUBLE-BLIND; THERAPY; RALTEGRAVIR AB Background. Recommended human immunodeficiency virus (HIV) treatment regimens in the United States contain 3 antiretroviral agents, costing >$30 000/person/year. Pilot studies are evaluating the efficacy of dual therapy with dolutegravir (DTG) and lamivudine (3TC). We examined the potential cost-effectiveness and budget impact of DTG + 3TC regimens in the United States. Methods. Using a mathematical model, we projected the clinical and economic outcomes of antiretroviral therapy (ART)-naive patients under 4 strategies: (1) no ART (for modeling comparison); (2) 2-drug: initial regimen of DTG + 3TC; (3) induction-maintenance: 48-week induction regimen of 3 drugs (DTG/abacavir [ABC]/3TC), followed by DTG + 3TC maintenance if virologically suppressed; and (4) standard of care: 3-drug regimen of DTG/ABC/3TC. Strategy-dependent model inputs, varied widely in sensitivity analyses, included 48-week virologic suppression (88%-93%), subsequent virologic failure (0.1%-0.6%/month), and Medicaid-discounted ART costs ($15 200-$39 600/year). A strategy was considered cost-effective if its incremental cost-effectiveness ratio (ICER) was <$100 000/quality-adjusted life-year (QALY). Results. The 3 ART strategies had the same 5-year survival rates (90%). The ICER was $22 500/QALY for induction-maintenance and >$500 000/QALY for standard of care. Two-drug was the preferred strategy only when DTG + 3TC 48-week virologic suppression rate exceeded 90%. With 50% uptake of either induction-maintenance or 2-drug for ART-naive patients, cost savings totaled $550 million and $800 million, respectively, within 5 years; savings reached >$3 billion if 25% of currently suppressed patients were switched to DTG + 3TC maintenance. Conclusions. Should DTG + 3TC demonstrate high rates of virologic suppression, this regimen will be cost-effective and would save >$500 million in ART costs in the United States over 5 years. C1 [Girouard, Michael P.; Parker, Robert A.; Freedberg, Kenneth A.; Walensky, Rochelle P.] Massachusetts Gen Hosp, Med Practice Evaluat Ctr, 50 Staniford St,9th Flr, Boston, MA 02114 USA. [Girouard, Michael P.; Freedberg, Kenneth A.; Walensky, Rochelle P.] Massachusetts Gen Hosp, Div Gen Internal Med, Boston, MA 02114 USA. [Sax, Paul E.; Walensky, Rochelle P.] Brigham & Womens Hosp, Div Infect Dis, 75 Francis St, Boston, MA 02115 USA. [Parker, Robert A.; Freedberg, Kenneth A.; Walensky, Rochelle P.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Parker, Robert A.] Massachusetts Gen Hosp, Ctr Biostat, Boston, MA 02114 USA. [Taiwo, Babafemi] Northwestern Univ, Feinberg Sch Med, Div Infect Dis, Chicago, IL 60611 USA. [Freedberg, Kenneth A.; Walensky, Rochelle P.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Freedberg, Kenneth A.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Freedberg, Kenneth A.; Weinstein, Milton C.] Harvard Univ, TH Chan Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA 02115 USA. [Gulick, Roy M.] Cornell Univ, Weill Med Coll, Div Infect Dis, New York, NY 10021 USA. [Weinstein, Milton C.] Harvard Univ, TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Paltiel, A. David] Yale Univ, Sch Publ Hlth, New Haven, CT USA. RP Walensky, RP (reprint author), Massachusetts Gen Hosp, Med Practice Evaluat Ctr, 50 Staniford St,9th Flr, Boston, MA 02114 USA. EM rwalensky@partners.org FU National Institute of Allergy and Infectious Diseases at the NIH [R01 AI093269, UM1 AI068636, R37 AI042006, UM AI069419]; Massachusetts General Hospital Research Scholars Award FX This work was funded by the National Institute of Allergy and Infectious Diseases at the NIH (grant numbers R01 AI093269, UM1 AI068636, R37 AI042006, UM AI069419); and the Massachusetts General Hospital Research Scholars Award (Executive Committee on Research to R. P. W.). NR 37 TC 4 Z9 4 U1 1 U2 3 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 MAR 15 PY 2016 VL 62 IS 6 BP 784 EP 791 DI 10.1093/cid/civ981 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA DF9XU UT WOS:000371716700018 PM 26658053 ER PT J AU Evans, S Follmann, D Schoenfeld, D Fowler, VG Chambers, HF AF Evans, Scott Follmann, Dean Schoenfeld, David Fowler, Vance G., Jr. Chambers, Henry F. TI DOOR/RADAR: A Gateway Into the Unknown? Reply SO CLINICAL INFECTIOUS DISEASES LA English DT Letter C1 [Evans, Scott] Harvard Univ, Boston, MA 02115 USA. [Follmann, Dean] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Schoenfeld, David] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Fowler, Vance G., Jr.] Duke Univ, Durham, NC USA. [Chambers, Henry F.] Univ Calif San Francisco, San Francisco, CA 94143 USA. RP Evans, S (reprint author), Harvard Univ, Sch Publ Hlth, CBAR Biostat, FXB 513,651 Huntington Ave, Boston, MA 02115 USA. EM evans@sdac.harvard.edu FU NIAID NIH HHS [UM1 AI104681, K24 AI093969, K24-AI093969, UM1-AI104681] NR 2 TC 0 Z9 0 U1 0 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 MAR 15 PY 2016 VL 62 IS 6 BP 815 EP 816 DI 10.1093/cid/civ1003 PG 2 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA DF9XU UT WOS:000371716700029 PM 26658301 ER PT J AU Fuh, L Hays, H Brown, N Shirk, MB AF Fuh, Lanting Hays, Hannah Brown, Nicole Shirk, Mary Beth TI Characterization of drug overdoses in an Ohio incarcerated population SO CLINICAL TOXICOLOGY LA English DT Article ID HEALTH-CARE; PRISONERS C1 [Fuh, Lanting] Massachusetts Gen Hosp, Dept Pharm, Boston, MA 02114 USA. [Hays, Hannah] Cent Ohio Poison Ctr, Columbus, OH USA. [Hays, Hannah] Nationwide Childrens Hosp, Columbus, OH USA. [Hays, Hannah] Ohio State Univ, Coll Med, Columbus, OH 43210 USA. [Brown, Nicole] Ohio State Univ, Dept Biomed Informat, Columbus, OH 43210 USA. [Shirk, Mary Beth] Ohio State Univ, Dept Pharm, Wexner Med Ctr, 368 Doan Hall,410 W 10th Ave, Columbus, OH 43210 USA. [Shirk, Mary Beth] Ohio State Univ, Coll Pharm, 500 W 12Th Ave, Columbus, OH 43210 USA. RP Shirk, MB (reprint author), Ohio State Univ, Dept Pharm, Wexner Med Ctr, 368 Doan Hall,410 W 10th Ave, Columbus, OH 43210 USA. EM MaryBeth.Shirk@osumc.edu NR 11 TC 0 Z9 0 U1 1 U2 2 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1556-3650 EI 1556-9519 J9 CLIN TOXICOL JI Clin. Toxicol. PD MAR 15 PY 2016 VL 54 IS 3 BP 266 EP 270 PG 5 WC Toxicology SC Toxicology GA DG1WN UT WOS:000371858300009 PM 26795588 ER PT J AU Xue, XY Papusha, A Choi, KY Bonner, JN Kumar, S Niu, HY Kaur, H Zheng, XF Donnianni, RA Lu, L Lichten, M Zhao, XL Ira, G Sung, P AF Xue, Xiaoyu Papusha, Alma Choi, Koyi Bonner, Jaclyn N. Kumar, Sandeep Niu, Hengyao Kaur, Hardeep Zheng, Xiao-Feng Donnianni, Roberto A. Lu, Lucy Lichten, Michael Zhao, Xiaolan Ira, Grzegorz Sung, Patrick TI Differential regulation of the anti-crossover and replication fork regression activities of Mph1 by Mte1 SO GENES & DEVELOPMENT LA English DT Article DE Mph1; Mte1; MHF; homologous recombination; genome replication; crossover formation ID COMPLEMENTATION GROUP-M; RECOMBINATION INTERMEDIATE METABOLISM; FANCONI-ANEMIA PATHWAY; HISTONE-FOLD COMPLEX; STRAND BREAK REPAIR; SACCHAROMYCES-CEREVISIAE; LINK REPAIR; HOMOLOGOUS RECOMBINATION; BRANCH MIGRATION; CANCER GENOMICS AB We identified Mte1 (Mph1-associated telomere maintenance protein 1) as a multifunctional regulator of Saccharomyces cerevisiae Mph1, a member of the FANCM family of DNA motor proteins important for DNA replication fork repair and crossover suppression during homologous recombination. We show that Mte1 interacts with Mph1 and DNA species that resemble a DNA replication fork and the Dloop formed during recombination. Biochemically, Mte1 stimulates Mph1-mediated DNA replication fork regression and branch migration in a model substrate. Consistent with this activity, genetic analysis reveals that Mte1 functions with Mph1 and the associated MHF complex in replication fork repair. Surprisingly, Mte1 antagonizes the D-loop-dissociative activity of Mph1-MHF and exerts a procrossover role in mitotic recombination. We further show that the influence of Mte1 on Mph1 activities requires its binding to Mph1 and DNA. Thus, Mte1 differentially regulates Mph1 activities to achieve distinct outcomes in recombination and replication fork repair. C1 [Xue, Xiaoyu; Niu, Hengyao; Zheng, Xiao-Feng; Lu, Lucy; Sung, Patrick] Yale Univ, Dept Mol Biophys & Biochem, Sch Med, New Haven, CT 06520 USA. [Papusha, Alma; Kumar, Sandeep; Ira, Grzegorz] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. [Choi, Koyi; Bonner, Jaclyn N.; Zhao, Xiaolan] Mem Sloan Kettering Canc Ctr, Program Mol Biol, New York, NY 10065 USA. [Kaur, Hardeep; Lichten, Michael] NCI, Lab Biochem & Mol Biol, Ctr Canc Res, Bethesda, MD 20892 USA. [Donnianni, Roberto A.] Columbia Univ, Dept Microbiol & Immunol, Med Ctr, New York, NY 10032 USA. [Niu, Hengyao] Indiana Univ, Dept Mol & Cellular Biochem, Bloomington, IN 47405 USA. [Zheng, Xiao-Feng] Harvard Univ, Dept Radiat Oncol, Sch Med, Dana Farber Canc Inst, Boston, MA 02215 USA. RP Sung, P (reprint author), Yale Univ, Dept Mol Biophys & Biochem, Sch Med, New Haven, CT 06520 USA.; Ira, G (reprint author), Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA.; Zhao, XL (reprint author), Mem Sloan Kettering Canc Ctr, Program Mol Biol, New York, NY 10065 USA. EM zhaox1@mkscc.org; gira@bcm.edu; patrick.sung@yale.edu RI Lichten, Michael/C-5795-2013 OI Lichten, Michael/0000-0001-9707-2956 FU US National Institutes of Health [ES007061, ES015252, ES015632, GM057814, GM080600, GM080670]; Intramural Research Program of the National Institutes of Health through the Center for Cancer Research at the National Cancer Institute FX We acknowledge Dr. Kazuishi Kubota and Dr. Steven Gygi (Harvard Medical School) for their help in mass spectrometry. This study was supported by US National Institutes of Health grants ES007061, ES015252, ES015632, GM057814, GM080600, and GM080670 and the Intramural Research Program of the National Institutes of Health through the Center for Cancer Research at the National Cancer Institute. NR 51 TC 2 Z9 2 U1 1 U2 4 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 MAR 15 PY 2016 VL 30 IS 6 BP 687 EP 699 DI 10.1101/gad.276139.115 PG 13 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA DG3MU UT WOS:000371974500007 PM 26966246 ER PT J AU Morini, E Dietrich, P Salani, M Downs, HM Wojtkiewicz, GR Alli, S Brenner, A Nilbratt, M LeClair, JW Oaklander, AL Slaugenhaupt, SA Dragatsis, I AF Morini, Elisabetta Dietrich, Paula Salani, Monica Downs, Heather M. Wojtkiewicz, Gregory R. Alli, Shanta Brenner, Anthony Nilbratt, Mats LeClair, John W. Oaklander, Anne Louise Slaugenhaupt, Susan A. Dragatsis, Ioannis TI Sensory and autonomic deficits in a new humanized mouse model of familial dysautonomia SO HUMAN MOLECULAR GENETICS LA English DT Article ID TRANSFER-RNA MODIFICATION; DORSAL-ROOT GANGLION; ELONGATOR COMPLEX; SPLICING DEFECT; CELL-MIGRATION; SKIN BIOPSY; IKBKAP GENE; TRANSCRIPTION; EXPRESSION; MUTATION AB Familial dysautonomia (FD) is an autosomal recessive neurodegenerative disease that affects the development and survival of sensory and autonomic neurons. FD is caused by an mRNA splicing mutation in intron 20 of the IKBKAP gene that results in a tissue-specific skipping of exon 20 and a corresponding reduction of the inhibitor of kappaB kinase complex-associated protein (IKAP), also known as Elongator complex protein 1. To date, several promising therapeutic candidates for FD have been identified that target the underlying mRNA splicing defect, and increase functional IKAP protein. Despite these remarkable advances in drug discovery for FD, we lacked a phenotypic mouse model in which we could manipulate IKBKAP mRNA splicing to evaluate potential efficacy. We have, therefore, engineered a new mouse model that, for the first time, will permit to evaluate the phenotypic effects of splicing modulators and provide a crucial platform for preclinical testing of new therapies. This new mouse model, TgFD9; Ikbkap(Delta 20/flox) was created by introducing the complete human IKBKAP transgene with the major FD splice mutation (TgFD9) into a mouse that expresses extremely low levels of endogenous Ikbkap (Ikbkap(Delta 20/flox)). The TgFD9; Ikbkap(Delta 20/flox) mouse recapitulates many phenotypic features of the human disease, including reduced growth rate, reduced number of fungiform papillae, spinal abnormalities, and sensory and sympathetic impairments, and recreates the same tissue-specific mis-splicing defect seen in FD patients. This is the first mouse model that can be used to evaluate in vivo the therapeutic effect of increasing IKAP levels by correcting the underlying FD splicing defect. C1 [Morini, Elisabetta; Salani, Monica; Brenner, Anthony; Nilbratt, Mats; LeClair, John W.; Slaugenhaupt, Susan A.] Massachusetts Gen Hosp, Res Inst, Ctr Human Genet Res, Boston, MA 02114 USA. [Downs, Heather M.; Oaklander, Anne Louise] Massachusetts Gen Hosp, Res Inst, Nerve Unit, Dept Neurol, Boston, MA 02114 USA. [Downs, Heather M.; Oaklander, Anne Louise] Massachusetts Gen Hosp, Res Inst, Nerve Unit, Dept Pathol Neuropathol, Boston, MA 02114 USA. [Wojtkiewicz, Gregory R.] Massachusetts Gen Hosp, Res Inst, Ctr Syst Biol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. [Dietrich, Paula; Alli, Shanta; Dragatsis, Ioannis] Univ Tennessee, Hlth Sci Ctr, Dept Physiol, Memphis, TN 38163 USA. [Alli, Shanta] RxBio Inc, Memphis, TN USA. RP Slaugenhaupt, SA (reprint author), Massachusetts Gen Hosp, Res Inst, Ctr Human Genet Res, Boston, MA 02114 USA.; Dragatsis, I (reprint author), Univ Tennessee, Hlth Sci Ctr, Dept Physiol, Memphis, TN 38163 USA. EM slaugenhaupt@chgr.mgh.harvard.edu; idragatsis@uthsc.edu FU National Institute of Health [R01NS036326, R01NS061842]; Dysautonomia Foundation, Inc.; Rotary Foundation FX This work was supported by National Institute of Health grants (R01NS036326 to S.A.S., R01NS061842 to I.D.), and by the Dysautonomia Foundation, Inc. E.M. was recipient of a postdoctoral grant from the Rotary Foundation. NR 65 TC 5 Z9 5 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 MAR 15 PY 2016 VL 25 IS 6 BP 1116 EP 1128 DI 10.1093/hmg/ddv634 PG 13 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA DG5XD UT WOS:000372152900006 PM 26769677 ER PT J AU Pers, TH Timshel, P Ripke, S Lent, S Sullivan, PF O'Donovan, MC Franke, L Hirschhorn, JN AF Pers, Tune H. Timshel, Pascal Ripke, Stephan Lent, Samantha Sullivan, Patrick F. O'Donovan, Michael C. Franke, Lude Hirschhorn, Joel N. CA Schizophrenia Working Grp Psychiat TI Comprehensive analysis of schizophrenia-associated loci highlights ion channel pathways and biologically plausible candidate causal genes SO HUMAN MOLECULAR GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; PRESYNAPTIC ACTIVE ZONE; DE-NOVO MUTATIONS; VARIANTS; PROTEOME; DISEASES; BIOLOGY; RISK; INTEGRATION; DISORDERS AB Over 100 associated genetic loci have been robustly associated with schizophrenia. Gene prioritization and pathway analysis have focused on a priori hypotheses and thus may have been unduly influenced by prior assumptions and missed important causal genes and pathways. Using a data-driven approach, we show that genes in associated loci: (1) are highly expressed in cortical brain areas; (2) are enriched for ion channel pathways (false discovery rates <0.05); and (3) contain 62 genes that are functionally related to each other and hence represent promising candidates for experimental follow up. We validate the relevance of the prioritized genes by showing that they are enriched for rare disruptive variants and de novo variants from schizophrenia sequencing studies (odds ratio 1.67, P = 0.039), and are enriched for genes encoding members of mouse and human postsynaptic density proteomes (odds ratio 4.56, P = 5.00 x 10(-4); odds ratio 2.60, P = 0.049). The authors wish it to be known that, in their opinion, the first 2 authors should be regarded as joint First Author. C1 [Pers, Tune H.; Hirschhorn, Joel N.] Boston Childrens Hosp Boston, Div Endocrinol, Boston, MA 02115 USA. [Pers, Tune H.; Hirschhorn, Joel N.] Boston Childrens Hosp Boston, Ctr Basic & Translat Obes Res, Boston, MA 02115 USA. [Pers, Tune H.; Hirschhorn, Joel N.] Broad Inst MIT & Harvard, Med & Populat Genet Program, Cambridge, MA 02142 USA. [Ripke, Stephan] Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Cambridge, MA 02142 USA. [Pers, Tune H.; Timshel, Pascal] Univ Copenhagen, Fac Hlth & Med Sci, Sect Metab Genet, Novo Nordisk Fdn Ctr Basic Metab Res, Univ Pk 1, DK-2100 Copenhagen O, Denmark. [Pers, Tune H.; Timshel, Pascal] Statens Serum Inst, Dept Epidemiol Res, DK-2300 Copenhagen, Denmark. [Ripke, Stephan] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02142 USA. [Lent, Samantha] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA. [Sullivan, Patrick F.] Karolinska Inst, Dept Med Epidemiol & Biostat, SE-17177 Stockholm, Sweden. [Sullivan, Patrick F.] Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA. [Sullivan, Patrick F.] Univ N Carolina, Dept Psychiat, Chapel Hill, NC 27599 USA. [O'Donovan, Michael C.] Cardiff Univ, Sch Med, Inst Psychol Med & Clin Neurosci, MRC Ctr Neuropsychiat Genet & Genom, Cardiff CF24 4HQ, S Glam, Wales. [O'Donovan, Michael C.] Cardiff Univ, Natl Ctr Mental Hlth, Cardiff CF24 4HQ, S Glam, Wales. [Franke, Lude] Univ Groningen, Univ Med Ctr Groningen, Dept Genet, NL-9711 Groningen, Netherlands. [Hirschhorn, Joel N.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. RP Hirschhorn, JN (reprint author), Boston Childrens Hosp Boston, Div Endocrinol, Boston, MA 02115 USA.; Hirschhorn, JN (reprint author), Boston Childrens Hosp Boston, Ctr Basic & Translat Obes Res, Boston, MA 02115 USA.; Hirschhorn, JN (reprint author), Broad Inst MIT & Harvard, Med & Populat Genet Program, Cambridge, MA 02142 USA.; Hirschhorn, JN (reprint author), Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. EM joelh@broadinstitute.org RI Franke, Lude/P-7036-2016 OI Franke, Lude/0000-0002-5159-8802 FU Danish Council for Independent Research Medical Sciences (FSS); Alfred Benzon Foundation; Lundbeck Foundation; Novo Scholarship Programme; National Institute of Diabetes and Digestive and Kidney Diseases [2R01DK075787]; National Institute of Mental Health [U01 MH094421]; Netherlands Organization for Scientific Research (NWO) [916-10135, 917-14374]; Horizon Breakthrough grant from the Netherlands Genomics Initiative [92519031]; National Institute of General Medicine [T32GM074905]; European Community [259867] FX This work was supported by the Danish Council for Independent Research Medical Sciences (FSS) (to T.H.P.); the Alfred Benzon Foundation (to T.H.P.); the Lundbeck Foundation (to T.H.P.); the Novo Scholarship Programme (to P.T.); the National Institute of Diabetes and Digestive and Kidney Diseases (2R01DK075787 to J.N.H.); the National Institute of Mental Health (grant U01 MH094421 to P.G.C.); the Netherlands Organization for Scientific Research (NWO-VENI grant 916-10135 and NWO VIDI grant 917-14374 to L.F.); the Horizon Breakthrough grant from the Netherlands Genomics Initiative (92519031 to L.F.); the National Institute of General Medicine (T32GM074905 to S.L.); and the European Community's Health Seventh Framework Programme (FP7/2007-2013) under grant agreement no. 259867 (to L.F.). NR 48 TC 1 Z9 1 U1 0 U2 2 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 MAR 15 PY 2016 VL 25 IS 6 BP 1247 EP 1254 DI 10.1093/hmg/ddw007 PG 8 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA DG5XD UT WOS:000372152900017 PM 26755824 ER PT J AU Jordan, JT Mayans, D Schneider, L Adams, N Khawaja, AM Engstrom, J AF Jordan, Justin T. Mayans, David Schneider, Logan Adams, Nellie Khawaja, Ayaz M. Engstrom, John TI Education Research: Neurology resident education Trending skills, confidence, and professional preparation SO NEUROLOGY LA English DT Article ID AMERICAN ACADEMY; MILLENNIUM C1 [Jordan, Justin T.] Massachusetts Gen Hosp, Pappas Ctr Neurooncol, Boston, MA 02114 USA. [Mayans, David] Neurol Consultants Kansas, Wichita, KS USA. [Schneider, Logan] Stanford Univ, Sch Med, Dept Neurol, Stanford, CA 94305 USA. [Adams, Nellie] Amer Acad Neurol Staff, Minneapolis, MN USA. [Khawaja, Ayaz M.] Univ Alabama Birmingham, Med Ctr, Dept Neurol, Birmingham, AL USA. [Engstrom, John] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA. RP Jordan, JT (reprint author), Massachusetts Gen Hosp, Pappas Ctr Neurooncol, Boston, MA 02114 USA. EM jtjordan@mgh.harvard.edu FU NHLBI NIH HHS [T32 HL110952] NR 7 TC 1 Z9 1 U1 1 U2 2 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 MAR 15 PY 2016 VL 86 IS 11 BP e112 EP e117 PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA DG2HG UT WOS:000371887300002 PM 26976522 ER PT J AU Saadi, A Schmahmann, JD AF Saadi, Altaf Schmahmann, Jeremy D. TI Pearls & Oy-sters: Tacrolimus neurotoxicity presenting as an isolated brainstem lesion SO NEUROLOGY LA English DT Article ID LIVER-TRANSPLANTATION; PONTINE MYELINOLYSIS C1 [Saadi, Altaf] Harvard Univ, Massachusetts Gen Hosp, Brigham & Womens Hosp, Sch Med,Partners Neurology Residency, Boston, MA USA. [Schmahmann, Jeremy D.] Harvard Univ, Massachusetts Gen Hosp, Dept Neurol,Med Sch,Ataxia Unit, Cognit Behav Neurol Unit,Lab Neuroanat & Cerebell, Boston, MA USA. RP Schmahmann, JD (reprint author), Harvard Univ, Massachusetts Gen Hosp, Dept Neurol,Med Sch,Ataxia Unit, Cognit Behav Neurol Unit,Lab Neuroanat & Cerebell, Boston, MA USA. EM jschmahmann@partners.org NR 11 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 MAR 15 PY 2016 VL 86 IS 11 BP e109 EP e111 PG 3 WC Clinical Neurology SC Neurosciences & Neurology GA DG2HG UT WOS:000371887300001 PM 26976521 ER PT J AU He, Q Jing, HY Liaw, L Gower, L Vary, C Hua, SC Yang, XH AF He, Qing Jing, Hongyu Liaw, Lucy Gower, Lindsey Vary, Calvin Hua, Shucheng Yang, Xuehui TI Suppression of Spry1 inhibits triple-negative breast cancer malignancy by decreasing EGF/EGFR mediated mesenchymal phenotype SO SCIENTIFIC REPORTS LA English DT Article ID REPRESSES E-CADHERIN; CELL LUNG-CANCER; DOWN-REGULATION; TUMOR-SUPPRESSOR; PROSTATE-CANCER; GENE-EXPRESSION; UP-REGULATION; RAS GENE; TRANSITION; GROWTH AB Sprouty (Spry) proteins have been implicated in cancer progression, but their role in triple-negative breast cancer (TNBC), a subtype of lethal and aggressive breast cancer, is unknown. Here, we reported that Spry1 is significantly expressed in TNBC specimen and MDA-MB-231 cells. To understand Spry1 regulation of signaling events controlling breast cancer phenotype, we used lentiviral delivery of human Spry1 shRNAs to suppress Spry1 expression in MDA-MB-231, an established TNBC cell line. Spry1 knockdown MDA-MB-231 cells displayed an epithelial phenotype with increased membrane E-cadherin expression. Knockdown of Spry1 impaired MDA-MB-231 cell migration, Matrigel invasion, and anchorage-dependent and -independent growth. Tumor xenografts originating from Spry1 knockdown MDA-MB-231 cells grew slower, had increased E-cadherin expression, and yielded fewer lung metastases compared to control. Furthermore, suppressing Spry1 in MDA-MB-231 cells impaired the induction of Snail and Slug expression by EGF, and this effect was associated with increased EGFR degradation and decreased EGFR/Grb2/Shp2/Gab1 signaling complex formation. The same phenotype was also observed in the TNBC cell line MDA-MB-157. Together, our results show that unlike in some tumors, where Spry may mediate tumor suppression, Spry1 plays a selective role in at least a subset of TNBC to promote the malignant phenotype via enhancing EGF-mediated mesenchymal phenotype. C1 [He, Qing; Jing, Hongyu; Liaw, Lucy; Gower, Lindsey; Vary, Calvin; Yang, Xuehui] Maine Med Ctr, Ctr Mol Med, Res Inst, 81 Res Dr, Scarborough, ME USA. [Jing, Hongyu; Hua, Shucheng] Jinlin Univ, Hosp 1, Dept Resp Med, Changchun, Peoples R China. [He, Qing] Massachusetts Gen Hosp, Dept Med, Endocrine Unit, Boston, MA 02114 USA. [He, Qing] Harvard Univ, Sch Med, Boston, MA USA. RP Yang, XH (reprint author), Maine Med Ctr, Ctr Mol Med, Res Inst, 81 Res Dr, Scarborough, ME USA. EM yangx@mmc.org FU Maine Cancer Foundation Accelerate Grant; Maine Medical Center Research Program Grant FX We thank Dr. Robert Friesel for critical reading of the manuscript. We thank MMCRI histology core Armie Mangoba, Katrina Abramo and Dr. Volkhard Lindner for creating breast cancer tissue array (TMA) and histochemistry analysis. We thank MMC BioBank Robert Ackroyd, Dr. Ivette F. Emery and Dr. Anne Breggia for coordinating studies on clinical specimens. This study was supported by the Maine Cancer Foundation Accelerate Grant and a Maine Medical Center Research Program Grant to X.Y. NR 49 TC 1 Z9 1 U1 2 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 MAR 15 PY 2016 VL 6 AR 23216 DI 10.1038/srep23216 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DG4QE UT WOS:000372056000001 PM 26976794 ER PT J AU Ibrahim, A Ferachou, D Sharma, G Singh, K Kirouac-Turmel, M Ozaki, T AF Ibrahim, Akram Ferachou, Denis Sharma, Gargi Singh, Kanwarpal Kirouac-Turmel, Marie Ozaki, Tsuneyuki TI Ultra-high dynamic range electro-optic sampling for detecting millimeter and sub-millimeter radiation SO SCIENTIFIC REPORTS LA English DT Article ID SPECTRAL-DOMAIN INTERFEROMETRY; OPTICAL RECTIFICATION; TERAHERTZ TECHNOLOGY; THZ PULSE; SPECTROSCOPY; GENERATION; COMMUNICATION; TRANSITION; SYSTEM; NOISE AB Time-domain spectroscopy using coherent millimeter and sub-millimeter radiation (also known as terahertz radiation) is rapidly expanding its application, owing greatly to the remarkable advances in generating and detecting such radiation. However, many current techniques for coherent terahertz detection have limited dynamic range, thus making it difficult to perform some basic experiments that need to directly compare strong and weak terahertz signals. Here, we propose and demonstrate a novel technique based on cross-polarized spectral-domain interferometry to achieve ultra-high dynamic range electro-optic sampling measurement of coherent millimeter and sub-millimeter radiation. In our scheme, we exploit the birefringence in a single-mode polarization maintaining fiber in order to measure the phase change induced by the electric field of terahertz radiation in the detection crystal. With our new technique, we have achieved a dynamic range of 7 x 10(6), which is 4 orders of magnitude higher than conventional electro-optic sampling techniques, while maintaining comparable signal-to-noise ratio. The present technique is foreseen to have great impact on experiments such as linear terahertz spectroscopy of optically thick materials (such as aqueous samples) and nonlinear terahertz spectroscopy, where the higher dynamic range is crucial for proper interpretation of experimentally obtained results. C1 [Ibrahim, Akram; Ferachou, Denis; Kirouac-Turmel, Marie; Ozaki, Tsuneyuki] Univ Quebec, Adv Laser Light Source, INRS EMT, 1650 Boul Lionel Boulet, Varennes, PQ J3X 1S2, Canada. [Sharma, Gargi] Univ Massachusetts Lowell, 1 Univ Ave, Lowell, MA 01854 USA. [Singh, Kanwarpal] Harvard Univ, Massachusetts Gen Hosp, Sch Med, 40 Blossom St, Boston, MA 02114 USA. RP Ibrahim, A; Ozaki, T (reprint author), Univ Quebec, Adv Laser Light Source, INRS EMT, 1650 Boul Lionel Boulet, Varennes, PQ J3X 1S2, Canada. EM ibrahima@emt.inrs.ca; ozaki@emt.inrs.ca FU Natural Sciences and Engineering Research Council of Canada (NSERC); Fonds de recherche du Quebec - Nature et technologies (FRQNT) FX We are thankful to the technicians at the Advanced Laser Light Source (ALLS) -INRS-EMT, Universite du Quebec, for operating the Ti:sapphire laser system. We acknowledge the financial support from the Natural Sciences and Engineering Research Council of Canada (NSERC) and the Fonds de recherche du Quebec - Nature et technologies (FRQNT). NR 45 TC 4 Z9 4 U1 7 U2 9 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 MAR 15 PY 2016 VL 6 AR 23107 DI 10.1038/srep23107 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DG4OH UT WOS:000372051000002 PM 26976363 ER PT J AU Patel, MS Asch, DA Rosin, R Small, DS Bellamy, SL Heuer, J Sproat, S Hyson, C Haff, N Lee, SM Wesby, L Hoffer, K Shuttleworth, D Taylor, DH Hilbert, V Zhu, JS Yang, L Wang, XM Volpp, KG AF Patel, Mitesh S. Asch, David A. Rosin, Roy Small, Dylan S. Bellamy, Scarlett L. Heuer, Jack Sproat, Susan Hyson, Chris Haff, Nancy Lee, Samantha M. Wesby, Lisa Hoffer, Karen Shuttleworth, David Taylor, Devon H. Hilbert, Victoria Zhu, Jingsan Yang, Lin Wang, Xingmei Volpp, Kevin G. TI Framing Financial Incentives to Increase Physical Activity Among Overweight and Obese Adults A Randomized, Controlled Trial SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID AMERICAN-HEART-ASSOCIATION; LINEAR MIXED MODELS; ACTIVITY INTERVENTIONS; BEHAVIORAL ECONOMICS; WEARABLE DEVICES; HEALTH BEHAVIORS; IMPROVE HEALTH; OLDER-ADULTS; US ADULTS; INACTIVITY AB Background: Financial incentive designs to increase physical activity have not been well-examined. Objective: To test the effectiveness of 3 methods to frame financial incentives to increase physical activity among overweight and obese adults. Design: Randomized, controlled trial. (ClinicalTrials.gov: NCT 02030119) Setting: University of Pennsylvania. Participants: 281 adult employees (body mass index >= 27 kg/m(2)). Intervention: 13-week intervention. Participants had a goal of 7000 steps per day and were randomly assigned to a control group with daily feedback or 1 of 3 financial incentive programs with daily feedback: a gain incentive ($1.40 given each day the goal was achieved), lottery incentive (daily eligibility [expected value approximately $1.40] if goal was achieved), or loss incentive ($ 42 allocated monthly upfront and $1.40 removed each day the goal was not achieved). Participants were followed for another 13 weeks with daily performance feedback but no incentives. Measurements: Primary outcome was the mean proportion of participant-days that the 7000-step goal was achieved during the intervention. Secondary outcomes included the mean proportion of participant-days achieving the goal during follow-up and the mean daily steps during intervention and follow-up. Results: The mean proportion of participant-days achieving the goal was 0.30 (95% CI, 0.22 to 0.37) in the control group, 0.35 (CI, 0.28 to 0.42) in the gain-incentive group, 0.36 (CI, 0.29 to 0.43) in the lottery-incentive group, and 0.45 (CI, 0.38 to 0.52) in the loss-incentive group. In adjusted analyses, only the lossincentive group had a significantly greater mean proportion of participant-days achieving the goal than control (adjusted difference, 0.16 [CI, 0.06 to 0.26]; P = 0.001), but the adjusted difference in mean daily steps was not significant (861 [CI, 24 to 1746]; P = 0.056). During follow-up, daily steps decreased for all incentive groups and were not different from control. Limitation: Single employer. Conclusion: Financial incentives framed as a loss were most effective for achieving physical activity goals. C1 Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. Univ Penn, Wharton Sch, Penn Med Ctr Hlth Care Innovat, Philadelphia, PA 19104 USA. Univ Penn, Leonard Davis Inst, Ctr Hlth Incent & Behav Econ, Philadelphia, PA 19104 USA. Philadelphia Vet Affairs Med Ctr, Philadelphia, PA USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Columbia Univ, Med Ctr, New York, NY USA. RP Patel, MS (reprint author), Univ Penn, Perelman Sch Med, Div Gen Internal Med, 423 Guardian Dr,13th Floor Blockley Hall, Philadelphia, PA 19104 USA. EM mpatel@upenn.edu FU National Institute on Aging FX National Institute on Aging. NR 54 TC 14 Z9 14 U1 4 U2 16 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 MAR 15 PY 2016 VL 164 IS 6 BP 385 EP + DI 10.7326/M15-1635 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA DG6PG UT WOS:000372207200012 PM 26881417 ER PT J AU Saitz, R Wakeman, SE Kelly, JF AF Saitz, Richard Wakeman, Sarah E. Kelly, John F. TI The Integration of Care for Mental Health, Substance Abuse, and Other Behavioral Health Conditions Into Primary Care SO ANNALS OF INTERNAL MEDICINE LA English DT Letter ID INTERVENTION; ALCOHOL C1 [Saitz, Richard] Boston Univ, Sch Publ Hlth, Boston, MA USA. [Saitz, Richard] Boston Univ, Sch Med, Boston, MA 02118 USA. [Wakeman, Sarah E.; Kelly, John F.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Saitz, R (reprint author), Boston Univ, Sch Publ Hlth, Boston, MA USA.; Saitz, R (reprint author), Boston Univ, Sch Med, Boston, MA 02118 USA. NR 5 TC 1 Z9 1 U1 5 U2 9 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 MAR 15 PY 2016 VL 164 IS 6 BP 447 EP 447 DI 10.7326/L15-0525 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA DG6PG UT WOS:000372207200021 PM 26974721 ER PT J AU Nguyen, PL Ciezki, JP AF Nguyen, Paul L. Ciezki, Jay P. TI High-Dose-Rate Monotherapy for Localized Prostate Cancer-What More Will It Take to Make This a Standard Therapy? SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Editorial Material C1 [Nguyen, Paul L.] Harvard Univ, Dept Radiat Oncol, Sch Med, Dana Farber Brigham & Womens Canc Ctr, Boston, MA USA. [Ciezki, Jay P.] Cleveland Clin, Dept Radiat Oncol, Cleveland, OH 44106 USA. RP Nguyen, PL (reprint author), Dana Farber Brigham & Womens Hosp, 75 Francis St,L2, Boston, MA 02115 USA. EM pnguyen@lroc.harvard.edu NR 5 TC 2 Z9 2 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 EI 1879-355X J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD MAR 15 PY 2016 VL 94 IS 4 BP 655 EP 656 DI 10.1016/j.ijrobp.2015.12.375 PG 2 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA DF8BM UT WOS:000371581900004 PM 26972639 ER PT J AU Chen, YW Mahal, BA Muralidhar, V Nezolosky, M Beard, CJ Den, RB Feng, FY Hoffman, KE Martin, NE Orio, PF Nguyen, PL AF Chen, Yu-Wei Mahal, Brandon A. Muralidhar, Vinayak Nezolosky, Michelle Beard, Clair J. Den, Robert B. Feng, Felix Y. Hoffman, Karen E. Martin, Neil E. Orio, Peter F. Nguyen, Paul L. TI Association Between Treatment at a High-Volume Facility and Improved Survival for Radiation-Treated Men With High-Risk Prostate Cancer SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article ID RADICAL PROSTATECTOMY; UNITED-STATES; HOSPITAL VOLUME; BLADDER-CANCER; LUNG-CANCER; OUTCOME RELATIONSHIP; SURGEON VOLUME; DATA-BASE; CARE; IMPACT AB Purpose: Although the association between higher hospital volume and improved outcomes has been well-documented in surgery, there is little data about whether this effect exists for radiation-treated patients. We investigated whether treatment at a radiation facility that treats a high volume of prostate cancer patients is associated with improved survival for men with high-risk prostate cancer. Methods and Materials: We used the National Cancer Database (NCDB) to identity patients diagnosed with prostate cancer from 2004 to 2006. The radiation case volume (RCV) of each hospital was based on its number of radiation-treated prostate cancer patients. We used propensity-score based analysis to compare the overall survival (OS) of high-risk prostate cancer patients in high versus low RCV hospitals. Primary endpoint is overall survival. Covariates adjusted for were tumor characteristics, sociodemographic factors, radiation type, and use of androgen deprivation therapy (ADT). Results: A total of 19,565 radiation-treated high-risk patients were identified. Median follow-up was 81.0 months (range: 1-108 months). When RCV was coded as a continuous variable, each increment of 100 radiation-managed patients was associated with improved OS (adjusted hazard ratio [AHR]: 0.97; 95% confidence interval [CI]: 0.95-Inc0.98; P<. 0001) after adjusting for known confounders. For illustrative purposes, when RCV was dichotomized at the 80th percentile (43 patients/year), high RCV was associated with improved OS (7-year overall survival 76% vs 74%, log-rank test P=. 0005; AHR: 0.91, 95% CI: 0.86-0.96, P=. 0005). This association remained significant when RCV was dichotomized at 75th (37 patients/year), 90th (60 patients/year), and 95th (84 patients/year) percentiles but not the 50th (19 patients/year). Conclusions: Our results suggest that treatment at centers with higher prostate cancer radiation case volume is associated with improved OS for radiation-treated men with high-risk prostate cancer. (c) 2016 The Authors. Published by Elsevier Inc. C1 [Chen, Yu-Wei; Muralidhar, Vinayak; Nezolosky, Michelle; Beard, Clair J.; Martin, Neil E.; Orio, Peter F.; Nguyen, Paul L.] Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA. [Chen, Yu-Wei; Muralidhar, Vinayak; Nezolosky, Michelle; Beard, Clair J.; Martin, Neil E.; Orio, Peter F.; Nguyen, Paul L.] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. [Mahal, Brandon A.] Brigham & Womens Hosp, Dept Med, 75 Francis St, Boston, MA 02115 USA. [Mahal, Brandon A.; Muralidhar, Vinayak; Beard, Clair J.; Martin, Neil E.; Orio, Peter F.; Nguyen, Paul L.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Den, Robert B.] Thomas Jefferson Univ, Sidney Kimmel Med Coll, Dept Radiat Oncol, Philadelphia, PA 19107 USA. [Feng, Felix Y.] Univ Michigan, Med Ctr, Dept Radiat Oncol, Ann Arbor, MI 48109 USA. [Hoffman, Karen E.] Univ Texas MD Anderson Canc Ctr, Dept Radiat Oncol, Houston, TX 77030 USA. RP Nguyen, PL (reprint author), Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Radiat Oncol,Dana Farber Canc Inst, 75 Francis St, Boston, MA 02115 USA. EM pnguyen@LROC.harvard.edu NR 34 TC 3 Z9 3 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 EI 1879-355X J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD MAR 15 PY 2016 VL 94 IS 4 BP 683 EP 690 DI 10.1016/j.ijrobp.2015.12.008 PG 8 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA DF8BM UT WOS:000371581900008 PM 26972640 ER PT J AU Lin, CC Bruinooge, SS Kirkwood, MK Hershman, DL Jemal, A Guadagnolo, BA Yu, JB Hopkins, S Goldstein, M Bajorin, D Giordano, SH Kosty, M Arnone, A Hanley, A Stevens, S Olsen, C AF Lin, Chun Chieh Bruinooge, Suanna S. Kirkwood, M. Kelsey Hershman, Dawn L. Jemal, Ahmedin Guadagnolo, B. Ashleigh Yu, James B. Hopkins, Shane Goldstein, Michael Bajorin, Dean Giordano, Sharon H. Kosty, Michael Arnone, Anna Hanley, Amy Stevens, Stephanie Olsen, Christine TI Association Between Geographic Access to Cancer Care and Receipt of Radiation Therapy for Rectal Cancer SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article ID RADIOTHERAPY UTILIZATION RATE; COLORECTAL-CANCER; BREAST-CANCER; UNITED-STATES; TRAVEL-TIME; DATA-BASE; PREOPERATIVE RADIOTHERAPY; PROSTATE-CANCER; COLON-CANCER; IMPACT AB Purpose: Trimodality therapy (chemoradiation and surgery) is the standard of care for stage II/III rectal cancer but nearly one third of patients do not receive radiation therapy (RT). We examined the relationship between the density of radiation oncologists and the travel distance to receipt of RT. Methods and Materials: A retrospective study based on the National Cancer Data Base identified 26,845 patients aged 18 to 80 years with stage II/III rectal cancer diagnosed from 2007 to 2010. Radiation oncologists were identified through the Physician Compare dataset. Generalized estimating equations clustering by hospital service area was used to examine the association between geographic access and receipt of RT, controlling for patient sociodemographic and clinical characteristics. Results: Of the 26,845 patients, 70% received RT within 180 days of diagnosis or within 90 days of surgery. Compared with a travel distance of <12.5 miles, patients diagnosed at a reporting facility who traveled >= 50 miles had a decreased likelihood of receipt of RT (50-249 miles, adjusted odds ratio 0.75, P<. 001; >= 250 miles, adjusted odds ratio 0.46; P=. 002), all else being equal. The density level of radiation oncologists was not significantly associated with the receipt of RT. Patients who were female, nonwhite, and aged >= 50 years and had comorbidities were less likely to receive RT (P<. 05). Patients who were uninsured but self-paid for their medical services, initially diagnosed elsewhere but treated at a reporting facility, and resided in Midwest had an increased the likelihood of receipt of RT (P<. 05). Conclusions: An increased travel burden was associated with a decreased likelihood of receiving RT for patients with stage II/III rectal cancer, all else being equal; however, radiation oncologist density was not. Further research of geographic access and establishing transportation assistance programs or lodging services for patients with an unmet need might help decrease geographic barriers and improve the quality of rectal cancer care. (c) 2016 Elsevier Inc. All rights reserved. C1 [Lin, Chun Chieh; Jemal, Ahmedin] Amer Canc Soc, 250 Williams St, Atlanta, GA 30303 USA. [Bruinooge, Suanna S.; Kirkwood, M. Kelsey; Hanley, Amy] Amer Soc Clin Oncol, Alexandria, VA USA. [Hershman, Dawn L.] Columbia Univ, Med Ctr, New York, NY USA. [Guadagnolo, B. Ashleigh; Giordano, Sharon H.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Yu, James B.] Yale Univ, Sch Med, New Haven, CT USA. [Hopkins, Shane] William R Bliss Canc Ctr, Ames, IA USA. [Goldstein, Michael] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Bajorin, Dean] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. [Kosty, Michael] Scripps Clin, San Diego, CA USA. [Arnone, Anna; Stevens, Stephanie] Amer Soc Radiat Oncol, Fairfax, VA USA. [Olsen, Christine] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Lin, CC (reprint author), Amer Canc Soc, 250 Williams St, Atlanta, GA 30303 USA. EM anna.lin@cancer.org FU NCI NIH HHS [P30 CA008748] NR 38 TC 4 Z9 4 U1 2 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 EI 1879-355X J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD MAR 15 PY 2016 VL 94 IS 4 BP 719 EP 728 DI 10.1016/j.ijrobp.2015.12.012 PG 10 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA DF8BM UT WOS:000371581900012 PM 26972644 ER PT J AU Kleinberg, LR Catalano, PJ Forastiere, AA Keller, SM Mitchel, EP Anne, PR Benson, AB AF Kleinberg, Lawrence R. Catalano, Paul J. Forastiere, Arlene A. Keller, Steven M. Mitchel, Edith P. Anne, Pramila Rani Benson, Al B., III TI Eastern Cooperative Oncology Group and American College of Radiology Imaging Network Randomized Phase 2 Trial of Neoadjuvant Preoperative Paclitaxel/Cisplatin/Radiation Therapy (RT) or Irinotecan/Cisplatin/RT in Esophageal Adenocarcinoma: Long-Term Outcome and Implications for Trial Design SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article ID CELL LUNG-CANCER; II TRIAL; ESOPHAGOGASTRIC JUNCTION; CONCURRENT RADIOTHERAPY; SURGERY; CHEMORADIOTHERAPY; CARCINOMA; CISPLATIN; IRINOTECAN; DISEASE AB Purpose: Toxicity, pathologic complete response, and long-term outcomes are reported for the neoadjuvant therapies assessed in a randomized phase 2 Eastern Cooperative Oncology Group and American College of Radiology Imaging Network trial for operable esophageal adenocarcinoma, staged as II-IVa by endoscopy/ultrasonography (EUS). Methods and Materials: A total of 86 eligible patients began treatment. For arm A, preoperative chemotherapy was cisplatin, 30 mg/m(2), and irinotecan, 50 mg/m(2), on day 1, 8, 22, 29 during 45 Gy radiation therapy (RT), 1.8 Gy per day over 5 weeks. Adjuvant therapy was cisplatin, 30 mg/m(2), and irinotecan, 65 mg/m(2) day 1, 8 every 21 days for 3 cycles. Arm B therapy was cisplatin, 30 mg/m(2), and paclitaxel, 50 mg/m(2), day 1, 8, 15, 22, 29 with RT, followed by adjuvant cisplatin, 75 mg/m(2), and paclitaxel, 175 mg/m(2), day 1 every 21 days for 3 cycles. Stratification included EUS stage and performance status. Results: In arm A, median overall survival was 35 months, and 5-, 6-, and 7-year survival rates were 46%, 39%, and 35%, respectively, whereas for arm B, they were 21 months and 27%, 27%, and 23%, respectively. Median progression-or recurrence-free survival (PFS) was 39.8 months with a 3-year PFS of 50% for arm A and 12.4 months (P=. 046) with 3-year PFS of 28% for arm B. Eighty percent of the observed incidents of progression occurred within 19 months. Survival did not differ significantly by EUS and performance status strata. Conclusions: Long-term survival was similar for both arms and did not appear superior to results achieved with other standard regimens. (c) 2016 Elsevier Inc. All rights reserved. C1 [Kleinberg, Lawrence R.] Johns Hopkins Univ, Dept Radiat Oncol & Mol Radiat Sci, 401 N Broadway,Ste 1440, Baltimore, MD 21231 USA. [Catalano, Paul J.] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Catalano, Paul J.] Harvard Univ, TH Chan Sch Publ Hlth, Boston, MA 02115 USA. [Forastiere, Arlene A.] Johns Hopkins Univ, Dept Oncol, Baltimore, MD 21231 USA. [Keller, Steven M.] Montefiore Med Ctr, Dept Cardiovasc & Thorac Surg, 111 E 210th St, Bronx, NY 10467 USA. [Mitchel, Edith P.] Thomas Jefferson Univ, Dept Med Oncol, Philadelphia, PA 19107 USA. [Anne, Pramila Rani] Thomas Jefferson Univ, Dept Radiat Oncol, Philadelphia, PA 19107 USA. [Benson, Al B., III] Northwestern Univ, Dept Med Hematol Oncol, Lurie Canc Ctr, Chicago, IL 60611 USA. RP Kleinberg, LR (reprint author), Johns Hopkins Univ, Dept Radiat Oncol & Mol Radiat Sci, 401 N Broadway,Ste 1440, Baltimore, MD 21231 USA. EM kleinla@jhmi.edu FU NCI NIH HHS [U10 CA017145, CA66636, U10 CA016116, CA23318, CA180820, U10 CA013650, U10 CA180820, U10 CA066636, U10 CA023318, P30 CA006973, U10 CA021115, P30 CA060553, U10 CA014958, U10 CA180794, CA21115, CA16116, CA180794] NR 42 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 EI 1879-355X J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD MAR 15 PY 2016 VL 94 IS 4 BP 738 EP 746 DI 10.1016/j.ijrobp.2015.12.009 PG 9 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA DF8BM UT WOS:000371581900014 PM 26972646 ER PT J AU Rose, BS Jee, KW Niemierko, A Murphy, JE Blaszkowsky, LS Allen, JN Lee, LK Wang, YB Drapek, LC Hong, TS Wo, JY AF Rose, Brent S. Jee, Kyung-Wook Niemierko, Andrzej Murphy, Janet E. Blaszkowsky, Lawrence S. Allen, Jill N. Lee, Leslie K. Wang, Yingbing Drapek, Lorraine C. Hong, Theodore S. Wo, Jennifer Y. TI Irradiation of FDG-PET-Defined Active Bone Marrow Subregions and Acute Hematologic Toxicity in Anal Cancer Patients Undergoing Chemoradiation SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article ID INTENSITY-MODULATED RADIOTHERAPY; SQUAMOUS-CELL CARCINOMA; RADIATION-THERAPY; CERVICAL-CANCER; CONCURRENT CHEMORADIATION; DOSIMETRIC PREDICTORS; PELVIC RADIOTHERAPY; RANDOMIZED-TRIAL; CHEMOTHERAPY; MITOMYCIN AB Purpose: Irradiation of pelvic bone marrow (BM) has been correlated with hematologic toxicity (HT) in patients undergoing chemoradiation for anal cancer. We hypothesized that irradiation of hematologically active bone marrow (ABM) subregions defined by fluorodeoxyglucose (FDG) positron emission tomography (PET) is a principal cause of radiation-associated HT. Methods and Materials: The cohort included 45 patients with nonmetastatic anal cancer who underwent FDG-PET imaging prior to definitive chemoradiation with mitomycin-C and 5-fluorouracil. Total bone marrow (TBM) was defined as the external contour of the pelvic bones from the top of lumbar 5 (L5) to the bottom of the ischial tuberosity. Standardized uptake values (SUV) for all voxels within the TBM were quantified and normalized by comparison to normal liver SUV. Subvolumes of the TBM that exhibited the highest and lowest 50% of the SUVs were designated ABM(50) and IBM50, respectively. The primary endpoint was the absolute neutrophil count (ANC) nadir during or within 2 weeks of completion of treatment. equivalent uniform doses (EUD) with an a value of 0.5, 1 (equivalent to mean dose), 3, 7, and 12 to the BM structures and the ANC. Results: Mean +/- SD ANC nadir was 0.77 x 10(9) /L (+/- 0.66 x 10(9) /L). Grades 3 and 4 ANC toxicity occurred in 26.7% and 44.4% of patients, respectively. The EUD a parameter of 0.5 was optimal for all BM models indicating high radiation sensitivity. EUD of TBM and ABM(50) and IBM50 were all significantly associated with ANC nadir. However, model performance for ABM(50) was not superior to that of the TBM and IBM50 models. Conclusions: Irradiation of pelvic BM was associated with HT. However, FDG-PET-defined ABM models failed to improve model performance compared to the TBM model. (c) 2016 Elsevier Inc. All rights reserved. C1 [Rose, Brent S.] Massachusetts Gen Hosp, Harvard Radiat Oncol Program, Lunder Bldg,LL3,55 Fruit St, Boston, MA 02114 USA. [Jee, Kyung-Wook; Niemierko, Andrzej; Drapek, Lorraine C.; Hong, Theodore S.; Wo, Jennifer Y.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Murphy, Janet E.; Blaszkowsky, Lawrence S.; Allen, Jill N.] Massachusetts Gen Hosp, Div Hematol Oncol, Boston, MA 02114 USA. [Lee, Leslie K.; Wang, Yingbing] Massachusetts Gen Hosp, Div Nucl Med & Mol Imaging, Boston, MA 02114 USA. RP Rose, BS (reprint author), Massachusetts Gen Hosp, Harvard Radiat Oncol Program, Lunder Bldg,LL3,55 Fruit St, Boston, MA 02114 USA. EM bsrose@lroc.harvard.edu NR 28 TC 2 Z9 2 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 EI 1879-355X J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD MAR 15 PY 2016 VL 94 IS 4 BP 747 EP 754 DI 10.1016/j.ijrobp.2015.12.006 PG 8 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA DF8BM UT WOS:000371581900015 PM 26972647 ER PT J AU Sridharan, V Margalit, DN Curreri, SA Severgnini, M Hodi, FS Haddad, RI Tishler, RB Schoenfeld, JD AF Sridharan, V. Margalit, D. N. Curreri, S. A. Severgnini, M. Hodi, F. S. Haddad, R. I. Tishler, R. B. Schoenfeld, J. D. TI Systemic Immunologic Effects of Definitive Radiation in Head and Neck Cancer SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Meeting Abstract CT Multidisciplinary Head and Neck Cancer Symposium CY FEB 18-20, 2016 CL Scottsdale, AZ SP Amer Head & Neck Soc, Amer Soc Clin Oncol, ASTRO C1 [Sridharan, V.] Harvard Univ, Sch Med, Boston, MA USA. [Margalit, D. N.; Curreri, S. A.; Severgnini, M.; Hodi, F. S.; Tishler, R. B.; Schoenfeld, J. D.] Brigham & Womens Hosp, Dana Farber Canc Inst, 75 Francis St, Boston, MA 02115 USA. [Haddad, R. I.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 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 0360-3016 EI 1879-355X J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD MAR 15 PY 2016 VL 94 IS 4 MA 2 BP 864 EP 864 PG 1 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA DF8BM UT WOS:000371581900033 ER PT J AU Cohen, E Licitra, L Burtness, B Fayette, J Gauler, T Clement, PM Grau, JJ del Campo, JM Mailliez, A Haddad, RI Vermorken, JB Tahara, M Guigay, J Geoffrois, L Merlano, MC Cong, XJ Gibson, N Solca, F Ehrnrooth, E Machiels, JPH AF Cohen, E. Licitra, L. Burtness, B. Fayette, J. Gauler, T. Clement, P. M. Grau, J. J. del Campo, J. M. Mailliez, A. Haddad, R. I. Vermorken, J. B. Tahara, M. Guigay, J. Geoffrois, L. Merlano, M. C. Cong, X. J. Gibson, N. Solca, F. Ehrnrooth, E. Machiels, J. P. H. TI Tumor Biomarker Association With Clinical Outcomes in Recurrent and/or Metastatic Head and Neck Squamous Cell Carcinoma (R/M HNSCC) Patients (Pts) Treated With Afatinib Versus Methotrexate (MTX): LUX-Head & Neck 1 (LHN1) SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Meeting Abstract CT Multidisciplinary Head and Neck Cancer Symposium CY FEB 18-20, 2016 CL Scottsdale, AZ SP Amer Head & Neck Soc, Amer Soc Clin Oncol, ASTRO C1 [Cohen, E.] Univ Calif San Diego, La Jolla, CA 92093 USA. [Licitra, L.] Fdn IRCCS Ist Nazl Tumori, Milan, Italy. [Burtness, B.] Yale Univ, Sch Med, New Haven, CT USA. [Fayette, J.] Univ Lyon, Leon Berard Ctr, Lyon, France. [Fayette, J.] Univ Lyon, Hosp Civils Lyon, Lyon, France. [Gauler, T.] Univ Hosp Essen, West German Canc Ctr, Essen, Germany. [Clement, P. M.] Katholieke Univ Leuven, Dept Oncol, KU Leuven, Leuven, Belgium. [Grau, J. J.] Univ Barcelona, Hosp Clin Barcelona, Barcelona, Spain. [del Campo, J. M.] Hosp Univ Vall DHebron, Dept Med Oncol, Barcelona, Spain. [Mailliez, A.] Ctr Oscar Lambret, F-59020 Lille, France. [Haddad, R. I.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, 44 Binney St, Boston, MA 02115 USA. [Haddad, R. I.] Brigham & Womens Hosp, Dept Med, 75 Francis St, Boston, MA 02115 USA. [Vermorken, J. B.] Univ Antwerp Hosp, Edegem, Belgium. [Tahara, M.] Natl Canc Ctr Hosp East, Kashiwa, Chiba, Japan. [Guigay, J.] Gustave Roussy, Villejuif, France. [Guigay, J.] Ctr Antoine Lacassagne, 36 Voie Romaine, F-06054 Nice, France. [Geoffrois, L.] Inst Cancerol Lorraine, Vandoeuvre Les Nancy, France. [Merlano, M. C.] Azienda Osped Santa Croce & Carle, Cuneo, Italy. [Cong, X. J.] Boehringer Ingelheim Pharmaceut Inc, 90 E Ridge POB 368, Ridgefield, CT 06877 USA. [Gibson, N.] Boehringer Ingelheim Pharma GmbH & Co KG, Biberach, Germany. [Solca, F.] Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria. [Ehrnrooth, E.] Danmark AS, Boehringer Ingelheim, Copenhagen, Denmark. [Machiels, J. P. H.] Clin Univ St Luc, Serv Oncol Med, Inst Roi Albert 2, B-1200 Brussels, Belgium. [Machiels, J. P. H.] Catholic Univ Louvain, Inst Rech Clin & Expt, Pole MIRO, B-1200 Brussels, Belgium. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 EI 1879-355X J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD MAR 15 PY 2016 VL 94 IS 4 MA 10 BP 868 EP 869 PG 2 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA DF8BM UT WOS:000371581900042 ER PT J AU Margalit, DN Puzanov, M Rawal, B Haddad, RI Schoenfeld, JD Rabinowits, G Chau, N Lorch, J Goguen, LA Annino, DJ Thomas, T Catalano, PJ Tishler, RB AF Margalit, D. N. Puzanov, M. Rawal, B. Haddad, R. I. Schoenfeld, J. D. Rabinowits, G. Chau, N. Lorch, J. Goguen, L. A. Annino, D. J. Thomas, T. Catalano, P. J. Tishler, R. B. TI Variability in Outcome Based on Type of Concurrent Chemotherapy for Treatment of Squamous Cell Carcinoma of the Oropharynx SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Meeting Abstract CT Multidisciplinary Head and Neck Cancer Symposium CY FEB 18-20, 2016 CL Scottsdale, AZ SP Amer Head & Neck Soc, Amer Soc Clin Oncol, ASTRO C1 [Margalit, D. N.; Schoenfeld, J. D.; Goguen, L. A.; Annino, D. J.; Thomas, T.; Tishler, R. B.] Brigham & Womens Hosp, Dana Farber Canc Inst, 75 Francis St, Boston, MA 02115 USA. [Puzanov, M.] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. [Rawal, B.; Rabinowits, G.; Chau, N.; Lorch, J.; Catalano, P. J.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Haddad, R. I.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, 44 Binney St, Boston, MA 02115 USA. [Haddad, R. I.] Brigham & Womens Hosp, Dept Med, 75 Francis St, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 EI 1879-355X J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD MAR 15 PY 2016 VL 94 IS 4 MA 102 BP 872 EP 872 PG 1 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA DF8BM UT WOS:000371581900047 ER PT J AU Marta, GN Riera, R Haddad, RI Cohen, E Rabinowits, G Kowalski, LP AF Marta, G. N., Sr. Riera, R. Haddad, R. I. Cohen, E. Rabinowits, G. Kowalski, L. P. TI Induction Chemotherapy Followed by Concurrent Chemoradiation Therapy Versus Concurrent Chemoradiation Therapy Upfront in Locally Advanced Oral Cavity Cancer: Systematic Review and Meta-Analysis of Individual Data SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Meeting Abstract CT Multidisciplinary Head and Neck Cancer Symposium CY FEB 18-20, 2016 CL Scottsdale, AZ SP Amer Head & Neck Soc, Amer Soc Clin Oncol, ASTRO C1 [Marta, G. N., Sr.] Univ Sao Paulo, Hosp Siriolibanes, Dept Radiat Oncol, Sao Paulo, Brazil. [Marta, G. N., Sr.] Univ Sao Paulo, Fac Med, Inst Canc Estado Sao Paulo, Sao Paulo, Brazil. [Riera, R.] Univ Fed Sao Paulo, Escola Paulista Med UNIFESP EPM, Brazilian Cochrane Ctr, Sao Paulo, Brazil. [Riera, R.] Univ Fed Sao Paulo, Escola Paulista Med UNIFESP EPM, Discipline Emergency Med & Evidence Based Med, Sao Paulo, Brazil. [Haddad, R. I.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, 44 Binney St, Boston, MA 02115 USA. [Haddad, R. I.] Brigham & Womens Hosp, Dept Med, 75 Francis St, Boston, MA 02115 USA. [Cohen, E.] Univ Calif San Diego, La Jolla, CA 92093 USA. [Rabinowits, G.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Head & Neck Oncol Program, 44 Binney St, Boston, MA 02115 USA. [Kowalski, L. P.] AC Camargo Canc Ctr, Dept Head & Neck Surg & Otorhinolaryngol, Sao Paulo, Brazil. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 EI 1879-355X J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD MAR 15 PY 2016 VL 94 IS 4 MA 129 BP 882 EP 883 PG 2 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA DF8BM UT WOS:000371581900073 ER PT J AU Margalit, DN Schoenfeld, JD Rawal, B Puzanov, M Haddad, RI Rabinowits, G Chau, N Lorch, J Lavigne, A Goguen, LA Annino, DJ Thomas, T Catalano, PJ Tishler, RB AF Margalit, D. N. Schoenfeld, J. D. Rawal, B. Puzanov, M. Haddad, R. I. Rabinowits, G. Chau, N. Lorch, J. Lavigne, A. Goguen, L. A. Annino, D. J. Thomas, T. Catalano, P. J. Tishler, R. B. TI Patient Immunosuppression and the Association With Cancer-Specific Outcomes After Treatment of Squamous Cell Carcinoma of the Oropharynx SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Meeting Abstract CT Multidisciplinary Head and Neck Cancer Symposium CY FEB 18-20, 2016 CL Scottsdale, AZ SP Amer Head & Neck Soc, Amer Soc Clin Oncol, ASTRO C1 [Margalit, D. N.; Schoenfeld, J. D.; Goguen, L. A.; Annino, D. J.; Thomas, T.; Tishler, R. B.] Brigham & Womens Hosp, Dana Farber Canc Inst, 75 Francis St, Boston, MA 02115 USA. [Rawal, B.; Rabinowits, G.; Chau, N.; Lorch, J.; Catalano, P. J.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Puzanov, M.; Lavigne, A.] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. [Haddad, R. I.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, 44 Binney St, Boston, MA 02115 USA. [Haddad, R. I.] Brigham & Womens Hosp, Dept Med, 75 Francis St, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 EI 1879-355X J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD MAR 15 PY 2016 VL 94 IS 4 MA 208 BP 913 EP 913 PG 1 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA DF8BM UT WOS:000371581900149 ER PT J AU Finegersh, A Kulich, S Duvvuri, U AF Finegersh, A. Kulich, S. Duvvuri, U. TI DNA Methylation Regulates ANO1 Expression Through Alternate Mechanisms at 3 Distinct CpG Islands in Head and Neck Squamous Cell Carcinoma SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Meeting Abstract CT Multidisciplinary Head and Neck Cancer Symposium CY FEB 18-20, 2016 CL Scottsdale, AZ SP Amer Head & Neck Soc, Amer Soc Clin Oncol, ASTRO C1 [Finegersh, A.] Univ Pittsburgh, Sch Med, Pittsburgh, PA USA. [Kulich, S.] VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. [Duvvuri, U.] Univ Pittsburgh, Med Ctr, Pittsburgh, PA USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 EI 1879-355X J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD MAR 15 PY 2016 VL 94 IS 4 MA 283 BP 942 EP 942 PG 1 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA DF8BM UT WOS:000371581900220 ER PT J AU Hanna, GJ Grote, HJ Vergara, V Brunkhorst, B Rabinowits, G Thakuria, M LeBoeuf, NR Cuillerot, JM DeCaprio, JA Lorch, J AF Hanna, G. J. Grote, H. J. Vergara, V. Brunkhorst, B. Rabinowits, G. Thakuria, M. LeBoeuf, N. R. Cuillerot, J. M. DeCaprio, J. A. Lorch, J. TI Characterizing Programmed Death Ligand 1 (PD-1L) Expression in Merkel Cell Carcinoma SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Meeting Abstract CT Multidisciplinary Head and Neck Cancer Symposium CY FEB 18-20, 2016 CL Scottsdale, AZ SP Amer Head & Neck Soc, Amer Soc Clin Oncol, ASTRO C1 [Hanna, G. J.; Vergara, V.; Rabinowits, G.; Thakuria, M.; LeBoeuf, N. R.; DeCaprio, J. A.; Lorch, J.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Grote, H. J.] Merck Pharmaceut, Darmstadt, Germany. [Brunkhorst, B.; Cuillerot, J. M.] EMD Serono, Rockland, MA USA. NR 0 TC 0 Z9 0 U1 3 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 EI 1879-355X J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD MAR 15 PY 2016 VL 94 IS 4 MA 307 BP 951 EP 952 PG 2 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA DF8BM UT WOS:000371581900244 ER PT J AU Springer, TA Sen, M AF Springer, Timothy A. Sen, Mehmet TI Leukocyte integrin alpha(L)beta(2) headpiece structures: The alpha I domain, the pocket for the internal ligand, and concerted movements of its loops SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID FUNCTION-ASSOCIATED ANTIGEN-1; CRYSTAL-STRUCTURE; BETA-SUBUNIT; ADHESION; RECEPTOR; RESOLUTION; COMPLEX; LFA-1; MODEL; RECOGNITION AB High-resolution crystal structures of the headpiece of lymphocyte function-associated antigen-1 (integrin alpha(L)beta(2)) reveal how the alpha I domain interacts with its platform formed by the alpha-subunit beta-propeller and beta-subunit beta I domains. The alpha(L)beta(2) structures compared with alpha(X)beta(2) structures show that the aI domain, tethered through its N-linker and a disulfide to a stable beta-ribbon pillar near the center of the platform, can undergo remarkable pivoting and tilting motions that appear buffered by N-glycan decorations that differ between alpha(L) and alpha(X) subunits. Rerefined beta(2) integrin structures reveal details including pyroglutamic acid at the beta(2) N terminus and bending within the EGF1 domain. Allostery is relayed to the alpha I domain by an internal ligand that binds to a pocket at the interface between the alpha-propeller and beta I domains. Marked differences between the alpha(L) and beta(X) subunit beta-propeller domains concentrate near the binding pocket and aI domain interfaces. Remarkably, movement in allostery in the beta I domain of specificity determining loop 1 (SDL1) causes concerted movement of SDL2 and thereby tightens the binding pocket for the internal ligand. C1 [Springer, Timothy A.; Sen, Mehmet] Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA. [Springer, Timothy A.; Sen, Mehmet] Harvard Univ, Sch Med, Dept Biol Chem, Boston, MA 02115 USA. [Springer, Timothy A.; Sen, Mehmet] Harvard Univ, Sch Med, Dept Mol Pharmacol, Boston, MA 02115 USA. [Springer, Timothy A.; Sen, Mehmet] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Sen, Mehmet] Univ Houston, Dept Biol & Biochem, Houston, TX 77204 USA. RP Springer, TA (reprint author), Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA.; Springer, TA (reprint author), Harvard Univ, Sch Med, Dept Biol Chem, Boston, MA 02115 USA.; Springer, TA (reprint author), Harvard Univ, Sch Med, Dept Mol Pharmacol, Boston, MA 02115 USA.; Springer, TA (reprint author), Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. EM Timothy.Springer@childrens.harvard.edu FU NIH [NCI CA031798]; GlaxoSmithKline fellowship FX We thank Adem Koksal, Nathan Hudson, and Travis Moore for critical reading of this manuscript; Xianchi Dong for help with X-ray data acquisition; and the staff at Advanced Photon Source beamline 23-ID (GM/CA-CAT). This work was supported by NIH Grant NCI CA031798 and a GlaxoSmithKline fellowship. NR 37 TC 3 Z9 3 U1 3 U2 7 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAR 15 PY 2016 VL 113 IS 11 BP 2940 EP 2945 DI 10.1073/pnas.1601379113 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DG4BF UT WOS:000372014200052 ER PT J AU Menachery, VD Yount, BL Sims, AC Debbink, K Agnihothram, SS Gralinski, LE Graham, RL Scobey, T Plante, JA Royal, SR Swanstrom, J Sheahan, TP Pickles, RJ Corti, D Randell, SH Lanzavecchia, A Marasco, WA Baric, RS AF Menachery, Vineet D. Yount, Boyd L., Jr. Sims, Amy C. Debbink, Kari Agnihothram, Sudhakar S. Gralinski, Lisa E. Graham, Rachel L. Scobey, Trevor Plante, Jessica A. Royal, Scott R. Swanstrom, Jesica Sheahan, Timothy P. Pickles, Raymond J. Corti, Davide Randell, Scott H. Lanzavecchia, Antonio Marasco, Wayne A. Baric, Ralph S. TI SARS-like WIV1-CoV poised for human emergence SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE SARS; CoV; emergence; Spike; WIV1 ID ACUTE RESPIRATORY SYNDROME; HUMAN MONOCLONAL-ANTIBODIES; CROSS-SPECIES TRANSMISSION; SYNDROME CORONAVIRUS; NEUTRALIZATION; DETERMINANTS; DISEASE; CELLS; HOST; MICE AB Outbreaks from zoonotic sources represent a threat to both human disease as well as the global economy. Despite a wealth of metagenomics studies, methods to leverage these datasets to identify future threats are underdeveloped. In this study, we describe an approach that combines existing metagenomics data with reverse genetics to engineer reagents to evaluate emergence and pathogenic potential of circulating zoonotic viruses. Focusing on the severe acute respiratory syndrome (SARS)-like viruses, the results indicate that the WIV1-coronavirus (CoV) cluster has the ability to directly infect and may undergo limited transmission in human populations. However, in vivo attenuation suggests additional adaptation is required for epidemic disease. Importantly, available SARS monoclonal antibodies offered success in limiting viral infection absent from available vaccine approaches. Together, the data highlight the utility of a platform to identify and prioritize prepandemic strains harbored in animal reservoirs and document the threat posed by WIV1-CoV for emergence in human populations. C1 [Menachery, Vineet D.; Yount, Boyd L., Jr.; Sims, Amy C.; Debbink, Kari; Gralinski, Lisa E.; Graham, Rachel L.; Scobey, Trevor; Plante, Jessica A.; Royal, Scott R.; Swanstrom, Jesica; Sheahan, Timothy P.; Baric, Ralph S.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27599 USA. [Debbink, Kari] Univ N Carolina, Dept Microbiol & Immunol, Chapel Hill, NC 27599 USA. [Agnihothram, Sudhakar S.; Pickles, Raymond J.; Baric, Ralph S.] Natl Ctr Toxicol Res, Div Microbiol, Food & Drug Adm, Jefferson, AR 72079 USA. [Pickles, Raymond J.; Randell, Scott H.] Univ N Carolina, Dept Cell Biol & Physiol, Cyst Fibrosis Ctr, Chapel Hill, NC 27599 USA. [Pickles, Raymond J.; Randell, Scott H.] Univ N Carolina, Marsico Lung Inst, Cyst Fibrosis Ctr, Chapel Hill, NC 27599 USA. [Corti, Davide; Lanzavecchia, Antonio] Inst Biomed Res, Bellinzona, Switzerland. [Corti, Davide; Lanzavecchia, Antonio] ETH, Inst Microbiol, CH-8092 Zurich, Switzerland. [Corti, Davide] Humabs BioMed SA, Bellinzona, Switzerland. [Marasco, Wayne A.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Immunol & AIDS,Dept Med, 44 Binney St, Boston, MA 02115 USA. RP Baric, RS (reprint author), Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27599 USA.; Baric, RS (reprint author), Natl Ctr Toxicol Res, Div Microbiol, Food & Drug Adm, Jefferson, AR 72079 USA. EM rbaric@email.unc.edu FU National Institute of Allergy and Infectious Disease; National Institute of Aging of the NIH [U19AI109761, U19AI107810, AI1085524, F32AI102561, K99AG049092]; National Institute of Diabetes and Digestive and Kidney Disease [NIH DK065988]; NIH [AI076159, AI079521] FX We thank Dr. Zhengli-Li Shi of the Wuhan Institute of Virology for access to bat CoV sequences and plasmid of WIV1-CoV spike protein. Research was supported by the National Institute of Allergy and Infectious Disease and the National Institute of Aging of the NIH under Awards U19AI109761 and U19AI107810 (to R.S.B.), AI1085524 (to W.A.M.), and F32AI102561 and K99AG049092 (to V.D.M.). Human airway epithelial cell cultures were supported by the National Institute of Diabetes and Digestive and Kidney Disease under Award NIH DK065988 (to S.H.R.). Support for the generation of the mice expressing human ACE2 was provided by NIH Grants AI076159 and AI079521 (to A.C.S.). NR 27 TC 9 Z9 9 U1 3 U2 6 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAR 15 PY 2016 VL 113 IS 11 BP 3048 EP 3053 DI 10.1073/pnas.1517719113 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DG4BF UT WOS:000372014200070 PM 26976607 ER PT J AU Armstrong, MM Freedman, CJ Jung, JE Zheng, Y Kalyanaraman, C Jacobson, MP Simeonov, A Maloney, DJ van Leyen, K Jadhav, A Holman, TR AF Armstrong, Michelle M. Freedman, Cody J. Jung, Joo Eun Zheng, Yi Kalyanaraman, Chakrapani Jacobson, Matthew P. Simeonov, Anton Maloney, David J. van Leyen, Klaus Jadhav, Ajit Holman, Theodore R. TI A potent and selective inhibitor targeting human and murine 12/15-LOX SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article DE Inhibitor; Selective; High-throughput; Lipoxygenase; Human; Murine ID 15-LIPOXYGENASE INHIBITORS; 5-LIPOXYGENASE INHIBITORS; LIPOXYGENASE; STROKE; 12/15-LIPOXYGENASE; DERIVATIVES; PATHWAYS AB Human reticulocyte 12/15-lipoxygenase (h12/15-LOX) is a lipid-oxidizing enzyme that can directly oxidize lipid membranes in the absence of a phospholipase, leading to a direct attack on organelles, such as the mitochondria. This cytotoxic activity of h12/15-LOX is up-regulated in neurons and endothelial cells after a stroke and thought to contribute to both neuronal cell death and blood-brain barrier leakage. The discovery of inhibitors that selectively target recombinant h12/15-LOX in vitro, as well as possessing activity against the murine ortholog ex vivo, could potentially support a novel therapeutic strategy for the treatment of stroke. Herein, we report a new family of inhibitors discovered in a High Throughput Screen ( HTS) that are selective and potent against recombinant h12/15-LOX and cellular mouse 12/15-LOX ( m12/15-LOX). MLS000099089 ( compound 99089), the parent molecule, exhibits an IC50 potency of 3.4 +/- 0.5 mu M against h12/15-LOX in vitro and an ex vivo IC50 potency of approximately 10 mu M in a mouse neuronal cell line, HT-22. Compound 99089 displays greater than 30-fold selectivity versus h5-LOX and COX-2, 15-fold versus h15-LOX-2 and 10-fold versus h12-LOX, when tested at 20 mu M inhibitor concentration. Steady-state inhibition kinetics reveals that the mode of inhibition of 99089 against h12/15-LOX is that of a mixed inhibitor with a K-ic of 1.0 +/- 0.08 lM and a K-iu of 6.0 +/- 3.3 mu M. These data indicate that 99089 and related derivatives may serve as a starting point for the development of anti-stroke therapeutics due to their ability to selectively target h12/15-LOX in vitro and m12/15-LOX ex vivo. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Armstrong, Michelle M.; Freedman, Cody J.; Holman, Theodore R.] Univ Calif Santa Cruz, Dept Chem & Biochem, Santa Cruz, CA 95060 USA. [Jung, Joo Eun; Zheng, Yi; van Leyen, Klaus] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Neuroprotect Res Lab,Dept Radiol, Charlestown, MA 02129 USA. [Kalyanaraman, Chakrapani; Jacobson, Matthew P.] Univ Calif San Francisco, Sch Pharm, Dept Pharmaceut Chem, San Francisco, CA 94143 USA. [Simeonov, Anton; Maloney, David J.; Jadhav, Ajit] Natl Inst Hlth, Natl Ctr Adv Translat Sci, 9800 Med Ctr Dr,MSC 3370, Bethesda, MD 20892 USA. RP Holman, TR (reprint author), Univ Calif Santa Cruz, Dept Chem & Biochem, Santa Cruz, CA 95060 USA. EM holman@ucsc.edu FU NIH - United States [NS081180] FX This work was supported by the NIH - United States NS081180. NR 33 TC 1 Z9 1 U1 3 U2 11 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0968-0896 EI 1464-3391 J9 BIOORGAN MED CHEM JI Bioorg. Med. Chem. PD MAR 15 PY 2016 VL 24 IS 6 BP 1183 EP 1190 DI 10.1016/j.bmc.2016.01.042 PG 8 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA DE7MZ UT WOS:000370822700003 PM 26899595 ER PT J AU Durazzo, TC Meyerhoff, DJ Mon, A Abe, C Gazdzinski, S Murray, DE AF Durazzo, Timothy C. Meyerhoff, Dieter J. Mon, Anderson Abe, Christoph Gazdzinski, Stefan Murray, Donna E. TI Chronic Cigarette Smoking in Healthy Middle-Aged Individuals Is Associated With Decreased Regional Brain N-acetylaspartate and Glutamate Levels SO BIOLOGICAL PSYCHIATRY LA English DT Article DE Brain metabolites; Cigarette smoking; Decision making and impulsivity; Magnetic resonance; Neurocognition; Spectroscopy ID MAGNETIC-RESONANCE-SPECTROSCOPY; ALCOHOL-DEPENDENT INDIVIDUALS; RISK TASK BART; EARLY ABSTINENCE; SMOKERS; NEUROCOGNITION; VOLUMES; IMPULSIVENESS; NEUROBIOLOGY; METABOLITES AB BACKGROUND: Cigarette smoking is associated with metabolite abnormalities in anterior brain regions, but it is unclear if these abnormalities are apparent in other regions. Additionally, relationships between regional brain metabolite levels and measures of decision making, risk taking, and impulsivity in smokers and nonsmokers have not been investigated. METHODS: In young to middle-aged (predominately male) nonsmokers (n = 30) and smokers (n = 35), N-acetylaspartate (NAA), choline-containing compounds, creatine-containing compounds (Cr), myo-inositol (mI), and glutamate (Glu) levels in the anterior cingulate cortex and right dorsolateral prefrontal cortex (DLPFC) were compared via 4-tesla proton single volume magnetic resonance spectroscopy. Groups also were compared on NAA, choline-containing compounds, Cr, and mI concentrations in the gray matter and white matter of the four cerebral lobes and subcortical nuclei/regions with 1.5-tesla proton magnetic resonance spectroscopy. Associations of regional metabolite levels with neurocognitive, decision-making, risk-taking, and self-reported impulsivity measures were examined. RESULTS: Smokers showed lower DLPFC NAA, Cr, mI and Glu concentrations and lower lenticular nuclei NAA level; smokers also demonstrated greater age-related decreases of DLPFC NAA and anterior cingulate cortex and DLPFC Glu levels. Smokers exhibited poorer decision making and greater impulsivity. Across the sample, higher NAA and Glu in the DLPFC and NAA concentrations in multiple lobar gray matter and white matter regions and subcortical nuclei were associated with better neurocognition and lower impulsivity. CONCLUSIONS: This study provides additional novel evidence that chronic smoking in young and middle-aged individuals is associated with significant age-related neurobiological abnormalities in anterior frontal regions implicated in the development and maintenance of addictive disorders. C1 San Francisco Vet Adm Med Ctr, Ctr Imaging Neurodegenerat Dis, San Francisco, CA USA. Univ Calif San Francisco, Dept Radiol & Biomed Imaging, San Francisco, CA 94143 USA. RP Durazzo, TC (reprint author), San Francisco Vet Adm Med Ctr, Ctr Imaging Neurodegenerat Dis 114M, 4150 Clement St 114M, San Francisco, CA 94121 USA. EM timothy.durazzo@ucsf.edu OI Abe, Christoph/0000-0002-1680-8480 FU National Institutes of Health/National Institute on Drug Abuse Grant [DA24136]; National Institutes of Health/National Institute on Alcohol Abuse and Alcoholism Grant [AA10788] FX This work was supported by National Institutes of Health/National Institute on Drug Abuse Grant No. DA24136 (to TCD) and National Institutes of Health/National Institute on Alcohol Abuse and Alcoholism Grant No. AA10788 (to DJM), with resources and the use of facilities at the San Francisco Veterans Administration Medical Center, San Francisco CA. NR 58 TC 7 Z9 7 U1 0 U2 8 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 MAR 15 PY 2016 VL 79 IS 6 BP 481 EP 488 DI 10.1016/j.biopsych.2015.03.029 PG 8 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA DD6GY UT WOS:000370023900010 PM 25979621 ER PT J AU Schmidt, B Wei, L DePeralta, DK Hoshida, Y Tan, PS Sun, XC Sventek, JP Lanuti, M Tanabe, KK Fuchs, BC AF Schmidt, Benjamin Wei, Lan DePeralta, Danielle K. Hoshida, Yujin Tan, Poh Seng Sun, Xiaochen Sventek, Janelle P. Lanuti, Michael Tanabe, Kenneth K. Fuchs, Bryan C. TI Molecular subclasses of hepatocellular carcinoma predict sensitivity to fibroblast growth factor receptor inhibition SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE liver cancer; FGFR; MAPK; BGJ398; AZD4547 ID KINASE INHIBITOR; EXPRESSION; CANCER; FIBROBLAST-GROWTH-FACTOR-19; RECURRENCE; SIGNATURE; DISCOVERY AB A recent gene expression classification of hepatocellular carcinoma (HCC) includes a poor survival subclass termed S2 representing about one-third of all HCC in clinical series. S2 cells express E-cadherin and c-myc and secrete AFP. As the expression of fibroblast growth factor receptors (FGFRs) differs between S2 and non-S2 HCC, this study investigated whether molecular subclasses of HCC predict sensitivity to FGFR inhibition. S2 cell lines were significantly more sensitive (p < 0.001) to the FGFR inhibitors BGJ398 and AZD4547. BGJ398 decreased MAPK signaling in S2 but not in non-S2 cell lines. All cell lines expressed FGFR1 and FGFR2, but only S2 cell lines expressed FGFR3 and FGFR4. FGFR4 siRNA decreased proliferation by 44% or more in all five S2 cell lines (p < 0.05 for each cell line), a significantly greater decrease than seen with knockdown of FGFR1-3 with siRNA transfection. FGFR4 knockdown decreased MAPK signaling in S2 cell lines, but little effect was seen with knockdown of FGFR1-3. In conclusion, the S2 molecular subclass of HCC is sensitive to FGFR inhibition. FGFR4-MAPK signaling plays an important role in driving proliferation of a molecular subclass of HCC. This classification system may help to identify those patients who are most likely to benefit from inhibition of this pathway. C1 [Schmidt, Benjamin; Wei, Lan; DePeralta, Danielle K.; Sventek, Janelle P.; Tanabe, Kenneth K.; Fuchs, Bryan C.] Massachusetts Gen Hosp, Ctr Canc, Div Surg Oncol, Boston, MA 02114 USA. [Schmidt, Benjamin; Wei, Lan; DePeralta, Danielle K.; Sventek, Janelle P.; Lanuti, Michael; Tanabe, Kenneth K.; Fuchs, Bryan C.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Hoshida, Yujin; Tan, Poh Seng; Sun, Xiaochen] Icahn Sch Med Mt Sinai, Liver Canc Program, Tisch Canc Inst, Div Liver Dis,Dept Med, New York, NY 10029 USA. [Tan, Poh Seng] Natl Univ Hlth Syst, Univ Med Cluster, Div Gastroenterol & Hepatol, Singapore, Singapore. [Lanuti, Michael] Massachusetts Gen Hosp, Div Thorac Surg, Boston, MA 02114 USA. RP Fuchs, BC (reprint author), Massachusetts Gen Hosp, 55 Fruit St,WRN 401, Boston, MA 02114 USA. EM bfuchs@mgh.harvard.edu FU National Institutes of Health [T32 CA071345, R01 DK099558, K01 CA140861]; Massachusetts General Hospital Department of Surgery FX Grant sponsor: National Institutes of Health; Grant numbers: T32 CA071345, R01 DK099558, K01 CA140861; Grant sponsor: Massachusetts General Hospital Department of Surgery NR 55 TC 3 Z9 3 U1 1 U2 20 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 MAR 15 PY 2016 VL 138 IS 6 BP 1494 EP 1505 DI 10.1002/ijc.29893 PG 12 WC Oncology SC Oncology GA DD7CI UT WOS:000370080900020 PM 26481559 ER PT J AU Baek, JH Heo, JY Fava, M Mischoulon, D Nierenberg, A Hong, JP Roh, SW Jeon, HJ AF Baek, Ji Hyun Heo, Jung-Yoon Fava, Maurizio Mischoulon, David Nierenberg, Andrew Hong, Jin-Pyo Roh, Sung-Won Jeon, Hong Jin TI Anxiety symptoms are linked to new -onset suicidal ideation after six months of follow-up in outpatients with major depressive disorder (vol 187, pg 183, 2015) SO JOURNAL OF AFFECTIVE DISORDERS LA English DT Correction C1 [Baek, Ji Hyun; Heo, Jung-Yoon; Hong, Jin-Pyo; Jeon, Hong Jin] Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Dept Psychiat,Depress Ctr, Seoul, South Korea. [Jeon, Hong Jin] SAIHST, Dept Clin Res Design & Evaluat, Dept Hlth Sci & Technol, Seoul, South Korea. [Jeon, Hong Jin] SAIHST, Dept Med Device Management & Res, Seoul, South Korea. [Fava, Maurizio; Mischoulon, David; Jeon, Hong Jin] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Depress Clin & Res Program, Boston, MA USA. [Baek, Ji Hyun; Nierenberg, Andrew] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Bipolar Clin, Boston, MA USA. [Baek, Ji Hyun; Nierenberg, Andrew] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Res Program, Boston, MA USA. [Roh, Sung-Won] Seoul Natl Hosp, Seoul, South Korea. RP Jeon, HJ (reprint author), Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Dept Psychiat,Depress Ctr, Seoul, South Korea. EM jeonhj@skku.edu NR 1 TC 0 Z9 0 U1 2 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0327 EI 1573-2517 J9 J AFFECT DISORDERS JI J. Affect. Disord. PD MAR 15 PY 2016 VL 193 BP 185 EP 186 DI 10.1016/j.jad.2016.12.001 PG 2 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA DD0BT UT WOS:000369586000027 ER PT J AU Maguen, S Hoerster, KD Littman, AJ Klingaman, EA Evans-Hudnall, G Holleman, R Kim, HM Goodrich, DE AF Maguen, Shira Hoerster, Katherine D. Littman, Alyson J. Klingaman, Elizabeth A. Evans-Hudnall, Gina Holleman, Rob Kim, H. Myra Goodrich, David E. TI Iraq and Afghanistan veterans with PTSD participate less in VA's weight loss program than those without PTSD SO JOURNAL OF AFFECTIVE DISORDERS LA English DT Article DE Weight loss; Care engagement; Veterans; Mental health; Comorbidity; Sex; Obesity ID MENTAL-HEALTH DISORDERS; SERVICES TASK-FORCE; POSTTRAUMATIC-STRESS; MILITARY PERSONNEL; OBESITY; CARE; ADULTS; MANAGEMENT; HOME AB Background: Three-quarters of Iraq and Afghanistan veterans enrolled in Veterans Health Administration (VHA) care are overweight or obese. The VHA MOVE! weight management program can mitigate the risks of obesity-related morbidity. However, many Iraq and Afghanistan veterans experience barriers to VHA services, which may affect participation, especially among those with posttraumatic stress disorder (PTSD) and/or depression. Little is known about MOVE! engagement among recent veterans. We describe a retrospective evaluation of MOVE! participation among Iraq and Afghanistan veterans with and without mental health problems. Methods: As part of a national VHA mental health evaluation study, we accessed VHA patient care databases to identify Iraq and Afghanistan veterans receiving care from 2008-2013 who had >= 1 MOVE! visit(s) and >= 1 weight measurements (N=24,899). We used logistic regression to determine whether mental health conditions were associated with having 12 visits/year (desirable dose of care), adjusting for demographic, health, and utilization factors. Results: Among Iraq and Afghanistan veterans enrolled in MOVE!, 4% had a desirable dose of participation. In adjusted models, desirable MOVE! participation was more likely among those without PTSD; those who were older, female, and unmarried; and those who had higher baseline weight, more medical comorbidities, no pain, psychotropic medication use, higher disability ratings, and more mental health visits. Limitations: We used administrative ICD-9 codes. Sample only included veterans in VHA care. Conclusions: Iraq and Afghanistan veterans, particularly those with PTSD, had low participation in VHA weight management programming. Correlates of MOVE! participation were identified, highlighting opportunities to tailor MOVE! to improve participation for these veterans. Published by Elsevier B.V. C1 [Maguen, Shira] San Francisco VA Med Ctr, 4150 Clement St, San Francisco, CA 94121 USA. [Maguen, Shira] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Hoerster, Katherine D.; Littman, Alyson J.] VA Puget Sound Healthcare Syst, Seattle Div, Seattle, WA USA. [Hoerster, Katherine D.] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. [Littman, Alyson J.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Klingaman, Elizabeth A.] VA Maryland Healthcare Syst, Baltimore, MD USA. [Klingaman, Elizabeth A.] Univ Maryland, Sch Med, Dept Psychiat, Baltimore, MD USA. [Evans-Hudnall, Gina] Houston VA Med Ctr, Houston, TX USA. [Holleman, Rob; Kim, H. Myra; Goodrich, David E.] VA Ann Arbor Healthcare Syst, Ctr Clin Management Res, Ann Arbor, MI USA. RP Maguen, S (reprint author), San Francisco VA Med Ctr, 4150 Clement St, San Francisco, CA 94121 USA. EM Shira.Maguen@va.gov FU VA Health Services Research and Development Quality Enhancement Research Initiative (QUERI) [QLP 55-017]; VA Rehabilitation Research & Development Career Development Award [6982]; VA Health Services Research & Development Career Development Award [12-263]; Department of Veterans Affairs Office of Academic Affiliations Advanced Fellowship Program in Mental Illness Research and Treatment FX This analysis is part of a larger quality improvement evaluation of MOVE! requested by the VHA Center for Health Promotion & Disease Prevention (NCP) and conducted by VA National Serious Mental Illness Treatment and Evaluation Center (SMITREC). Funding for this study was provided by VA Health Services Research and Development Quality Enhancement Research Initiative (QUERI) programs for Diabetes and Mental Health research as a locally initiated project (QLP 55-017). Dr. Littman's time was supported in part through a VA Rehabilitation Research & Development Career Development Award (#6982). Dr. Hoerster's time was supported in part through a VA Health Services Research & Development Career Development Award (#12-263). Dr. Klingaman's time was supported by the Department of Veterans Affairs Office of Academic Affiliations Advanced Fellowship Program in Mental Illness Research and Treatment. NR 24 TC 0 Z9 0 U1 1 U2 9 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0327 EI 1573-2517 J9 J AFFECT DISORDERS JI J. Affect. Disord. PD MAR 15 PY 2016 VL 193 BP 289 EP 294 DI 10.1016/j.jad.2015.12.078 PG 6 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA DD0BT UT WOS:000369586000041 PM 26774516 ER PT J AU Venkataramani, AS Bor, J Jena, AB AF Venkataramani, Atheendar S. Bor, Jacob Jena, Anupam B. TI Regression discontinuity designs in healthcare research SO BMJ-BRITISH MEDICAL JOURNAL LA English DT Article ID CAUSAL-INFERENCE; IMPROVE; ONTARIO; TRIALS AB Clinical decisions are often driven by decision rules premised around specific thresholds. Specific laboratory measurements, dates, or policy eligibility criteria create cut-offs at which people become eligible for certain treatments or health services. The regression discontinuity design is a statistical approach that utilizes threshold based decision making to derive compelling causal estimates of different interventions. In this review, we argue that regression discontinuity is underutilized in healthcare research despite the ubiquity of threshold based decision making as well as the design's simplicity and transparency. Moreover, regression discontinuity provides evidence of "real world" therapeutic and policy effects, circumventing a major limitation of randomized controlled trials. We discuss the implementation, strengths, and weaknesses of regression discontinuity and review several examples from clinical medicine, public health, and health policy. We conclude by discussing the wide array of open research questions for which regression discontinuity stands to provide meaningful insights to clinicians and policymakers. C1 [Venkataramani, Atheendar S.] Massachusetts Gen Hosp, Div Gen Internal Med, Boston, MA 02114 USA. [Venkataramani, Atheendar S.] Harvard Ctr Populat & Dev Studies, Cambridge, MA USA. [Bor, Jacob] Boston Univ, Sch Publ Hlth, Dept Global Hlth, Boston, MA USA. [Jena, Anupam B.] Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. [Jena, Anupam B.] Massachusetts Gen Hosp, Dept Med, Cambridge, MA USA. [Jena, Anupam B.] Natl Bur Econ Res, Cambridge, MA 02138 USA. RP Jena, AB (reprint author), Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. EM jena@hcp.med.harvard.edu FU Office of the Director, National Institutes of Health (NIH) [1DP5OD017897-01] FX All authors have read and understood the BMJ policy on declaration of interests and declare the following: ABJ had support from the Office of the Director, National Institutes of Health (NIH early independence award, grant 1DP5OD017897-01) for the submitted work. NR 31 TC 2 Z9 2 U1 0 U2 1 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 MAR 14 PY 2016 VL 352 AR i1216 DI 10.1136/bmj.i1216 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA DH1XO UT WOS:000372578500001 PM 26977086 ER PT J AU Goel, S Wang, Q Watt, AC Tolaney, SM Dillon, DA Li, W Ramm, S Palmer, AC Yuzugullu, H Varadan, V Tuck, D Harris, LN Wong, KK Liu, XS Sicinski, P Winer, EP Krop, IE Zhao, JJ AF Goel, Shom Wang, Qi Watt, April C. Tolaney, Sara M. Dillon, Deborah A. Li, Wei Ramm, Susanne Palmer, Adam C. Yuzugullu, Haluk Varadan, Vinay Tuck, David Harris, Lyndsay N. Wong, Kwok-Kin Liu, X. Shirley Sicinski, Piotr Winer, Eric P. Krop, Ian E. Zhao, Jean J. TI Overcoming Therapeutic Resistance in HER2-Positive Breast Cancers with CDK4/6 Inhibitors SO CANCER CELL LA English DT Article ID TRASTUZUMAB RESISTANCE; ONCOGENE; MICE; LAPATINIB; CYCLINS; PHASE; CELLS AB Using transgenic mouse models, cell line-based functional studies, and clinical specimens, we show that cyclin D1/CDK4 mediate resistance to targeted therapy for HER2-positive breast cancer. This is overcome using CDK4/6 inhibitors. Inhibition of CDK4/6 not only suppresses Rb phosphorylation, but also reduces TSC2 phosphorylation and thus partially attenuates mTORC1 activity. This relieves feedback inhibition of upstream EGFR family kinases, resensitizing tumors to EGFR/HER2 blockade. Consequently, dual inhibition of EGFR/HER2 and CDK4/6 invokes a more potent suppression of TSC2 phosphorylation and hence mTORC1/S6K/ S6RP activity. The suppression of both Rb and S6RP enhances G1 arrest and a phenotype resembling cellular senescence. In vivo, CDK4/6 inhibitors sensitize patient-derived xenograft tumors to HER2-targeted therapies and delay tumor recurrence in a transgenic model of HER2-positive breast cancer. C1 [Goel, Shom; Tolaney, Sara M.; Wong, Kwok-Kin; Winer, Eric P.; Krop, Ian E.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Wang, Qi; Watt, April C.; Yuzugullu, Haluk; Sicinski, Piotr; Zhao, Jean J.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA. [Dillon, Deborah A.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Li, Wei; Liu, X. Shirley] Boston Univ, Sch Publ Hlth, Dept Biostat & Computat Biol, Dana Farber Canc Inst, Boston, MA 02215 USA. [Li, Wei; Liu, X. Shirley] Dana Farber Canc Inst, Ctr Funct Epigenet, Boston, MA 02215 USA. [Ramm, Susanne; Palmer, Adam C.] Harvard Univ, Sch Med, Harvard Program Therapeut Sci, Lab Syst Pharmacol, Boston, MA 02115 USA. [Ramm, Susanne] Brigham & Womens Hosp, Dept Med, Div Renal, Boston, MA 02115 USA. [Palmer, Adam C.] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA 02115 USA. [Palmer, Adam C.] Univ New S Wales, Sch Biotechnol & Biomol Sci, Sydney, NSW 2052, Australia. [Varadan, Vinay] Case Western Reserve Univ, Case Comprehens Canc Ctr, Cleveland, OH 44106 USA. [Tuck, David] Yale Univ, Dept Pathol, New Haven, CT 06520 USA. [Harris, Lyndsay N.] Case Western Reserve Sch Med, Cleveland, OH 44106 USA. [Sicinski, Piotr] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Zhao, Jean J.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Zhao, Jean J.] Broad Inst & Harvard, Cambridge, MA 02142 USA. [Wang, Qi] Med Univ S Carolina, Dept Pathol & Lab Med, Charleston, SC 29425 USA. [Tuck, David] Curis Inc, Lexington, MA 02421 USA. RP Goel, S (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA.; Zhao, JJ (reprint author), Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA.; Zhao, JJ (reprint author), Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA.; Zhao, JJ (reprint author), Broad Inst & Harvard, Cambridge, MA 02142 USA. EM shom_goel@dfci.harvard.edu; jean_zhao@dfci.harvard.edu OI Palmer, Adam/0000-0001-5028-7028; Ramm, Susanne/0000-0003-1108-5620 FU NIH [P50 CA168504, CA172461, U01CA180980, R01 CA083688, P01 CA080111]; Susan G. Komen grant [SAC 10005]; Breast Cancer Research Foundation; Institutional Research Grant of Hollings Cancer Center; Medical University of South Carolina; National Health and Medical Research Council of Australia; Eli Lilly; Genentech; AstraZeneca; Acetylon; Gilead Pharmaceuticals; Novartis FX A.C.W. and Q.W. contributed equally to this work. We thank Dr Roderick Bronson from the Rodent Histopathology Core Facility at Harvard Medical School (HMS) for helpful discussions regarding mouse pathology, and Dr Peter Sorger from the Department of Systems Biology at HMS for his advice and support. We also thank Mayuko Segawa for technical assistance. We thank Neil O'Brien (UCLA) for the gift of trastuzumab-resistant BT474 and SKBR3 cell lines. This study was supported by NIH P50 CA168504 (to E.P.W.) and CA172461 (to J.J.Z.), a Susan G. Komen grant SAC 10005 (to I.E.K.), the Breast Cancer Research Foundation (to E.P.W. and J.J.Z.), and Aid for Cancer Research (to E.P.W.). Q.W. is supported by the Institutional Research Grant of Hollings Cancer Center and the Medical University of South Carolina. W.L. and X.S.L. are supported by NIH grant U01CA180980. A.C.P. is supported by the National Health and Medical Research Council of Australia. P.S. is supported by NIH grants R01 CA083688 and P01 CA080111. S.G. conducts research sponsored by Eli Lilly. S.T. receives research funding from Genentech. K.K.W conducts research sponsored by AstraZeneca, Acetylon, and Gilead Pharmaceuticals, performs consultancy for G1 Therapeutics and Array Therapeutics, and is a founder and equity holder of G1 Therapeutics. P.S. receives research funding and serves as a consultant for Novartis. NR 29 TC 16 Z9 16 U1 8 U2 22 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 MAR 14 PY 2016 VL 29 IS 3 BP 255 EP 269 DI 10.1016/j.ccell.2016.02.006 PG 15 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DG8JB UT WOS:000372329000006 PM 26977878 ER PT J AU Smith, MP Brunton, H Rowling, EJ Ferguson, J Arozarena, I Miskolczi, Z Lee, JL Girotti, MR Marais, R Levesque, MP Dummer, R Frederick, DT Flaherty, KT Cooper, ZA Wargo, JA Wellbrock, C AF Smith, Michael P. Brunton, Holly Rowling, Emily J. Ferguson, Jennifer Arozarena, Imanol Miskolczi, Zsofia Lee, Jessica L. Girotti, Maria R. Marais, Richard Levesque, Mitchell P. Dummer, Reinhard Frederick, Dennie T. Flaherty, Keith T. Cooper, Zachary A. Wargo, Jennifer A. Wellbrock, Claudia TI Inhibiting Drivers of Non-mutational Drug Tolerance Is a Salvage Strategy for Targeted Melanoma Therapy SO CANCER CELL LA English DT Article ID HIV PROTEASE INHIBITOR; METASTATIC MELANOMA; CONFERS RESISTANCE; CUTANEOUS MELANOMA; BRAF INHIBITION; UP-REGULATION; IN-VIVO; NELFINAVIR; MITF; GROWTH AB Once melanomas have progressed with acquired resistance to mitogen-activated protein kinase (MAPK)targeted therapy, mutational heterogeneity presents a major challenge. We therefore examined the therapy phase before acquired resistance had developed and discovered the melanoma survival oncogene MITF as a driver of an early non-mutational and reversible drug-tolerance state, which is induced by PAX3-mediated upregulation of MITF. A drug-repositioning screen identified the HIV1-protease inhibitor nelfinavir as potent suppressor of PAX3 and MITF expression. Nelfinavir profoundly sensitizes BRAF and NRAS mutant melanoma cells to MAPK-pathway inhibitors. Moreover, nelfinavir is effective in BRAF and NRAS mutant melanoma cells isolated from patients progressed on MAPK inhibitor (MAPKi) therapy and in BRAF/NRAS/PTEN mutant tumors. We demonstrate that inhibiting a driver of MAPKi-induced drug tolerance could improve current approaches of targeted melanoma therapy. C1 [Smith, Michael P.; Brunton, Holly; Rowling, Emily J.; Ferguson, Jennifer; Arozarena, Imanol; Miskolczi, Zsofia; Lee, Jessica L.; Wellbrock, Claudia] Univ Manchester, Manchester Canc Res Ctr, Wellcome Trust Ctr Cell Matrix Res, Michael Smith Bldg,Oxford Rd, Manchester M13 9PT, Lancs, England. [Girotti, Maria R.; Marais, Richard] CRUK Manchester Inst Canc Res, Manchester Canc Res Ctr, Mol Oncol Grp, Wilmslow Rd, Manchester M20 4BX, Lancs, England. [Levesque, Mitchell P.; Dummer, Reinhard] Univ Zurich, Univ Spital Zurich, Dept Dermatol, Gloriastr 31, CH-8091 Zurich, Switzerland. [Frederick, Dennie T.; Flaherty, Keith T.] Massachusetts Gen Hosp, Ctr Canc, Dept Med, 55 Fruit St, Boston, MA 02114 USA. [Cooper, Zachary A.; Wargo, Jennifer A.] Univ Texas MD Anderson Canc Ctr, Div Surg Oncol, 1400 Pressler St, Houston, TX 77030 USA. RP Wellbrock, C (reprint author), Univ Manchester, Manchester Canc Res Ctr, Wellcome Trust Ctr Cell Matrix Res, Michael Smith Bldg,Oxford Rd, Manchester M13 9PT, Lancs, England. EM claudia.wellbrock@manchester.ac.uk OI Smith, Michael/0000-0002-5980-7840; Cooper, Zachary/0000-0003-1059-0940 FU Cancer Research UK (CRUK) [C11591/A16416]; AICR/Worldwide Cancer Research grant [12-0235]; Wellcome Trust; CRUK [C5759/A12328, C5759/A20971, A12985]; NCI/NIH [U54CA163125, K08CA160692]; DAVA Oncology; Illumina; BMS FX We thank Edward Stavnezer (Cleveland, OH) for SKI expression plasmids, Helen Young, Adam Hurlstone and Brian Telfer (University of Manchester) for help with the in vivo work and Stephen Taylor (University of Manchester) for the non-melanoma cell lines. C.W. acknowledges the support of Cancer Research UK (CRUK) (grant C11591/A16416) and AICR/Worldwide Cancer Research (grant 12-0235). This work was also supported by Wellcome Trust institutional grants to the University of Manchester, by CRUK grants C5759/A12328 and C5759/A20971 to R.M. and A12985 to Z.M., by an NCI/NIH U54CA163125 grant to J.A.W. and K.T.F and a K08CA160692 grant to J.A.W. Jennifer A. Wargo is a paid speaker for DAVA Oncology, Illumina and BMS, and has served on advisory boards for Roche Genentech, GSK, and Novartis. NR 42 TC 16 Z9 16 U1 5 U2 9 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 MAR 14 PY 2016 VL 29 IS 3 BP 270 EP 284 DI 10.1016/j.ccell.2016.02.003 PG 15 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DG8JB UT WOS:000372329000007 PM 26977879 ER PT J AU Hannawi, Y Abers, MS Geocadin, RG Mirski, MA AF Hannawi, Yousef Abers, Michael S. Geocadin, Romergryko G. Mirski, Marek A. TI Abnormal movements in critical care patients with brain injury: a diagnostic approach SO CRITICAL CARE LA English DT Review ID NEUROLEPTIC MALIGNANT SYNDROME; NONCONVULSIVE STATUS EPILEPTICUS; QUALITY STANDARDS SUBCOMMITTEE; CARDIAC-ARREST; ILL PATIENTS; THERAPEUTIC HYPOTHERMIA; CLINICAL-DIAGNOSIS; COMATOSE SURVIVORS; NEUROCRITICAL CARE; AMERICAN ACADEMY AB Abnormal movements are frequently encountered in patients with brain injury hospitalized in intensive care units (ICUs), yet characterization of these movements and their underlying pathophysiology is difficult due to the comatose or uncooperative state of the patient. In addition, the available diagnostic approaches are largely derived from outpatients with neurodegenerative or developmental disorders frequently encountered in the outpatient setting, thereby limiting the applicability to inpatients with acute brain injuries. Thus, we reviewed the available literature regarding abnormal movements encountered in acutely ill patients with brain injuries. We classified the brain injury into the following categories: anoxic, vascular, infectious, inflammatory, traumatic, toxic-metabolic, tumor-related and seizures. Then, we identified the abnormal movements seen in each category as well as their epidemiologic, semiologic and clinicopathologic correlates. We propose a practical paradigm that can be applied at the bedside for diagnosing abnormal movements in the ICU. This model seeks to classify observed abnormal movements in light of various patient-specific factors. It begins with classifying the patient's level of consciousness. Then, it integrates the frequency and type of each movement with the availability of ancillary diagnostic tests and the specific etiology of brain injury. C1 [Hannawi, Yousef; Geocadin, Romergryko G.; Mirski, Marek A.] Johns Hopkins Univ, Neurosci Crit Care Div, Dept Anesthesiol & Crit Care Med, Baltimore, MD USA. [Hannawi, Yousef; Geocadin, Romergryko G.; Mirski, Marek A.] Johns Hopkins Univ, Dept Neurol, Baltimore, MD 21218 USA. [Hannawi, Yousef] Ohio State Univ, Dept Neurol, Div Cerebrovasc Dis & Neurocrit Care, Columbus, OH 43210 USA. [Abers, Michael S.] Harvard Univ, Sch Med, Dept Med, Massachusetts Gen Hosp, Boston, MA USA. [Geocadin, Romergryko G.; Mirski, Marek A.] Johns Hopkins Univ, Dept Neurosurg, Baltimore, MD USA. RP Hannawi, Y (reprint author), Johns Hopkins Univ, Neurosci Crit Care Div, Dept Anesthesiol & Crit Care Med, Baltimore, MD USA.; Hannawi, Y (reprint author), Johns Hopkins Univ, Dept Neurol, Baltimore, MD 21218 USA.; Hannawi, Y (reprint author), Ohio State Univ, Dept Neurol, Div Cerebrovasc Dis & Neurocrit Care, Columbus, OH 43210 USA. EM yousefhannawi@yahoo.com NR 98 TC 0 Z9 0 U1 2 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1466-609X EI 1364-8535 J9 CRIT CARE JI Crit. Care PD MAR 14 PY 2016 VL 20 AR 60 DI 10.1186/s13054-016-1236-2 PG 10 WC Critical Care Medicine SC General & Internal Medicine GA DG8EI UT WOS:000372314800001 PM 26975183 ER PT J AU Nahrendorf, M Swirski, FK AF Nahrendorf, Matthias Swirski, Filip K. TI Innate immune cells in ischaemic heart disease: does myocardial infarction beget myocardial infarction? SO EUROPEAN HEART JOURNAL LA English DT Review DE Atherosclerosis; Myocardial infarction; Haematopoiesis; Monocyte; Macrophage; Bone marrow; Spleen; Proliferation ID ACUTE CORONARY SYNDROME; HEMATOPOIETIC STEM-CELLS; PROGENITOR CELLS; BONE-MARROW; LY-6C(HIGH) MONOCYTES; CARDIAC MACROPHAGES; SPLENIC RESERVOIR; MESENCHYMAL STEM; DENDRITIC CELLS; STEADY-STATE AB Knowledge of macrophages in steady-state and diseased tissue is rapidly expanding, propelled by improved diagnostic capacity to detect and monitor cells in their native environments. In this review, we discuss implications for ischaemic heart disease and examine innate immune cell pathways that increase systemic leucocyte supply after myocardial infarction (MI). Acute MI alters the macrophage phenotype and supply chain from tissue resident to blood monocytes sourced from haematopoietic organs. That blood leucocytosis closely associates with cardiovascular mortality provides a strong motivation to understand why and how organ ischaemia alters cellular immunity. C1 [Nahrendorf, Matthias; Swirski, Filip K.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. RP Nahrendorf, M (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. EM mnahrendorf@mgh.harvard.edu; fswirski@mgh.harvard.edu FU US National Institutes of Health [R01HL117829, R01NS084863]; MGH Research Scholar Award [R01HL095612, R56AI104695]; Howard M. Goodman Fellowship FX This work was supported by grants from the US National Institutes of Health R01HL117829, R01NS084863, the MGH Research Scholar Award (to M.N.), and R01HL095612, R56AI104695, and the Howard M. Goodman Fellowship (to F.K.S.). NR 62 TC 8 Z9 8 U1 3 U2 4 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 MAR 14 PY 2016 VL 37 IS 11 BP 868 EP + DI 10.1093/eurheartj/ehv453 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DG9KD UT WOS:000372400400009 PM 26351395 ER PT J AU Villain, H Benkahoul, A Drougard, A Lafragette, M Muzotte, E Pech, S Bui, E Brunet, A Birmes, P Roullet, P AF Villain, Helene Benkahoul, Aicha Drougard, Anne Lafragette, Marie Muzotte, Elodie Pech, Stephane Bui, Eric Brunet, Alain Birmes, Philippe Roullet, Pascal TI Effects of Propranolol, a beta-noradrenergic Antagonist, on Memory Consolidation and Reconsolidation in Mice SO FRONTIERS IN BEHAVIORAL NEUROSCIENCE LA English DT Article DE PTSD; consolidation; reconsolidation; propranolol; noradrenergic system; aversive memory; emotional valence ID POSTTRAUMATIC-STRESS-DISORDER; OBJECT RECOGNITION MEMORY; INHIBITORY AVOIDANCE MEMORY; DRIVEN TRAUMATIC IMAGERY; SPATIAL MEMORY; PROTEIN-SYNTHESIS; FEAR MEMORY; ADRENERGIC-BLOCKADE; CONDITIONED FEAR; EMOTIONAL MEMORY AB Memory reconsolidation impairment using the beta-noradrenergic receptor blocker propranolol is a promising novel treatment avenue for patients suffering from pathogenic memories, such as post traumatic stress disorder (PTSD). However, in order to better inform targeted treatment development, the effects of this compound on memory need to be better characterized via translational research. We examined the effects of systemic propranolol administration in mice undergoing a wide range of behavioral tests to determine more specifically which aspects of the memory consolidation and reconsolidation are impaired by propranolol. We found that propranolol (10 mg/kg) affected memory consolidation in non-aversive tasks (object recognition and object location) but not in moderately (Morris water maze (MWM) to highly (passive avoidance, conditioned taste aversion) aversive tasks. Further, propranolol impaired memory reconsolidation in the most and in the least aversive tasks, but not in the moderately aversive task, suggesting its amnesic effect was not related to task aversion. Moreover, in aquatic object recognition and location tasks in which animals were forced to behave (contrary to the classic versions of the tasks); propranolol did not impair memory reconsolidation. Taken together our results suggest that the memory impairment observed after propranolol administration may result from a modification of the emotional valence of the memory rather than a disruption of the contextual component of the memory trace. This is relevant to the use of propranolol to block memory reconsolidation in individuals with PTSD, as such a treatment would not erase the traumatic memory but only reduce the emotional valence associated with this event. C1 [Villain, Helene; Benkahoul, Aicha; Drougard, Anne; Lafragette, Marie; Muzotte, Elodie; Pech, Stephane; Roullet, Pascal] Univ Toulouse 3, CNRS, Ctr Biol integrat, Ctr Rech Cognit Anim,Univ Toulouse, F-31062 Toulouse, France. [Bui, Eric] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Bui, Eric] Harvard Univ, Sch Med, Boston, MA USA. [Brunet, Alain] Douglas Mental Hlth Univ Inst, Dept Psychiat, Montreal, PQ, Canada. [Brunet, Alain] McGill Univ, Montreal, PQ, Canada. [Birmes, Philippe] Univ Toulouse 3, INSERM, Univ Toulouse, Toulouse Neuro maging Ctr, F-31062 Toulouse, France. RP Roullet, P (reprint author), Univ Toulouse 3, CNRS, Ctr Biol integrat, Ctr Rech Cognit Anim,Univ Toulouse, F-31062 Toulouse, France. EM pascal.roullet@univ-tise3.fr FU Center National de la Recherche Scientifique (CNRS); University Paul Sabatier Toulouse III; Highland Street Foundation; Red Sox Foundation; Massachusetts General Hospital Home Base Program FX This study was supported by Center National de la Recherche Scientifique (CNRS) and by the University Paul Sabatier Toulouse III. LB research effort was supported by the Highland Street Foundation, and the Red Sox Foundation and Massachusetts General Hospital Home Base Program. Mice were housed in the ABC Facility of ANEXPLO Toulouse. NR 72 TC 2 Z9 2 U1 6 U2 14 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1662-5153 J9 FRONT BEHAV NEUROSCI JI Front. Behav. Neurosci. PD MAR 14 PY 2016 VL 10 AR 49 DI 10.3389/fnbeh.2016.00049 PG 14 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA DG3MX UT WOS:000371974800001 PM 27014009 ER PT J AU Weinrich, S Hardin, S Glaser, D Barger, M Bormann, J Lizarraga, C Terry, M Criscenzo, J Allard, CB AF Weinrich, Sally Hardin, Sally Glaser, Dale Barger, Mary Bormann, Jill Lizarraga, Cabiria Terry, Micheal Criscenzo, Jeeni Allard, Carolyn B. TI Assessing sexual trauma histories in homeless women SO JOURNAL OF TRAUMA & DISSOCIATION LA English DT Article DE Homeless women; sexual trauma; military sexual trauma ID VETERANS; MILITARY; PREVALENCE; ASSAULT AB Almost 1 out of every 3 homeless women (32%) in the United States, United Kingdom, and Australia has experienced childhood sexual trauma. We assessed lifetime sexual trauma histories among 29 homeless women from three Southern California community sites: one residential safe house and two safe parking areas. More than half of the women (54%) reported a history of sexual trauma. That rate was higher (86%) among women living at the safe home than among women staying at the safe parking sites (only 42%). All four of the women who had served in the military reported having experienced military sexual trauma. The high percentages of sexual trauma found in homeless women highlight the need for effective interventions for sexual trauma. C1 [Weinrich, Sally; Hardin, Sally; Glaser, Dale; Barger, Mary; Bormann, Jill; Terry, Micheal] Univ San Diego, Hahn Sch Nursing & Hlth Sci, 5998 Alcala Pk, San Diego, CA 92110 USA. [Weinrich, Sally; Hardin, Sally; Glaser, Dale; Barger, Mary; Bormann, Jill; Terry, Micheal] Univ San Diego, Betty & Bob Beyster Inst Nursing Res Adv Practice, 5998 Alcala Pk, San Diego, CA 92110 USA. [Bormann, Jill] US Dept Vet Affairs, Ctr Excellence Stress & Mental Hlth, San Diego, CA USA. [Lizarraga, Cabiria] Sharp Grossmont Hosp, La Mesa, CA USA. [Criscenzo, Jeeni] Amikas, San Diego, CA USA. [Allard, Carolyn B.] Univ Calif San Diego, Vet Affairs San Diego Healthcare Syst, Mil Sexual Trauma & Interpersonal Trauma Clin, San Diego, CA 92110 USA. RP Weinrich, S (reprint author), Univ San Diego, Hahn Sch Nursing & Hlth Sci, 5998 Alcala Pk, San Diego, CA 92110 USA.; Weinrich, S (reprint author), Univ San Diego, Betty & Bob Beyster Inst Nursing Res Adv Practice, 5998 Alcala Pk, San Diego, CA 92110 USA. EM sallyweinrich@sandiego.edu FU Jonas Center for Nursing and Veterans Healthcare; University of San Diego Hahn School of Nursing and Health Science Faculty Research Fund FX Funding was received from the Jonas Center for Nursing and Veterans Healthcare and the University of San Diego Hahn School of Nursing and Health Science Faculty Research Fund. NR 22 TC 1 Z9 1 U1 1 U2 3 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 1529-9732 EI 1529-9740 J9 J TRAUMA DISSOCIATIO JI J. Trauma Dissociation PD MAR 14 PY 2016 VL 17 IS 2 BP 237 EP 243 DI 10.1080/15299732.2015.1089968 PG 7 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA DG6MA UT WOS:000372197700009 PM 26583457 ER PT J AU Moye, J Gallagher-Thompson, D Thompson, LW AF Moye, Jennifer Gallagher-Thompson, Dolores Thompson, Larry Wolford TI Clinical Gerontologist: Reflections on its Past, Present, and Future SO CLINICAL GERONTOLOGIST LA English DT Editorial Material C1 [Moye, Jennifer] VA Boston Healthcare Syst, Boston, MA 02301 USA. [Moye, Jennifer] Harvard Univ, Sch Med, Boston, MA USA. [Gallagher-Thompson, Dolores; Thompson, Larry Wolford] Stanford Univ, Sch Med, Stanford, CA 94305 USA. RP Moye, J (reprint author), VA Boston Healthcare Syst, Brockton Div, 940 Belmont St, Brockton, MA 02301 USA. EM Jennifer.moye@va.gov RI Moye, Jennifer/F-2240-2017 OI Moye, Jennifer/0000-0002-3434-347X NR 5 TC 0 Z9 0 U1 0 U2 1 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 0731-7115 EI 1545-2301 J9 CLIN GERONTOLOGIST JI Clin. Gerontol. PD MAR 14 PY 2016 VL 39 IS 2 BP 85 EP 89 DI 10.1080/07317115.2015.1123209 PG 5 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA DE3ZZ UT WOS:000370570300001 ER PT J AU Olszewski, AJ Castillo, JJ AF Olszewski, Adam J. Castillo, Jorge J. TI Outcomes of HIV-associated Hodgkin lymphoma in the era of antiretroviral therapy SO AIDS LA English DT Article DE survival; HIV; National Cancer Data Base; chemotherapy; Hodgkin lymphoma; healthcare disparities; epidemiology ID HUMAN-IMMUNODEFICIENCY-VIRUS; CANCER DATA-BASE; AIDS-DEFINING CANCERS; UNITED-STATES; CLINICAL CHARACTERISTICS; GENERAL-POPULATION; INFECTED PATIENTS; ADVANCED-STAGE; RISK; VINBLASTINE AB Objectives: Clinical series suggest favorable outcomes of HIV-associated Hodgkin lymphoma, in conflict with population-based statistics. Our objective was to investigate the proportion of Americans who received curative chemotherapy for this disease, and compare their survival with HIV-negative cases using population data. Methods: We selected cases of HIV-associated Hodgkin lymphoma diagnosed in 2004-2012 from the National Cancer Data Base. Factors associated with receipt of chemotherapy were analyzed by logistic regression. Overall survival was compared in proportional hazard models adjusting for available confounding factors. Results: Among 2090 HIV-positive patients, 81% received chemotherapy, but 16% received no treatment. Advanced age, male sex, nonwhite race, poor socioeconomic status, and undetermined histologic subtype were associated with higher risk of nontreatment. In 2012, 49% of HIV-positive patients were black, and 15% were Hispanic. Unadjusted 5-year overall survival was significantly lower for HIV-positive (66%) than for HIV-negative (80%) populations. However, among patients who received chemotherapy, HIV-positive status was not significantly associated with higher mortality in classical histologic subtypes, including nodular sclerosis (hazard ratio, HR, 1.08; 95% confidence interval, CI, 0.88-1.33) and mixed cellularity (HR, 1.06; 95% CI, 0.80-1.40). In contrast, prognosis remained significantly worse for cases with undetermined histology (HR, 1.56; 95% CI, 1.31-1.85), suggesting a more aggressive biology or other high-risk characteristics in this subgroup. Conclusion: Worse survival statistics for HIV-associated Hodgkin lymphoma are driven by lower rates of chemotherapy administration. The disparity in treatment delivery needs attention because a majority of HIV-positive Americans with Hodgkin lymphoma are now black or Hispanic, and this proportion is increasing. C1 [Olszewski, Adam J.] Brown Univ, Alpert Med Sch, Providence, RI 02912 USA. [Olszewski, Adam J.] Brown Univ, Mem Hosp Rhode Isl, Dept Med, Pawtucket, RI 02860 USA. [Castillo, Jorge J.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Div Hematol Malignancies, 44 Binney St, Boston, MA 02115 USA. RP Olszewski, AJ (reprint author), Brown Univ, Alpert Med Sch, Ctr Canc, Mem Hosp Rhode Isl, 111 Brewster St, Pawtucket, RI 02860 USA. EM adam_olszewski@brown.edu OI Castillo, Jorge/0000-0001-9490-7532 FU American Society of Hematology; American Cancer Society [RSG-15-211-01-CPHPS] FX A.J.O. is currently supported by the American Society of Hematology Research Scholar Award, and the American Cancer Society Research Scholar Award (grant number RSG-15-211-01-CPHPS). NR 39 TC 4 Z9 4 U1 0 U2 1 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 MAR 13 PY 2016 VL 30 IS 5 BP 787 EP 796 DI 10.1097/QAD.0000000000000986 PG 10 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA DF4IH UT WOS:000371310700001 PM 26730566 ER PT J AU Janssen, A Shaw, T Bradbury, L Moujaber, T Norrelykke, AM Zerillo, JA LaCasce, A Co, JPT Robinson, T Starr, A Harnett, P AF Janssen, Anna Shaw, Tim Bradbury, Lauren Moujaber, Tania Norrelykke, Anne Mette Zerillo, Jessica A. LaCasce, Ann Co, John Patrick T. Robinson, Tracy Starr, Alison Harnett, Paul TI A mixed methods approach to developing and evaluating oncology trainee education around minimization of adverse events and improved patient quality and safety SO BMC MEDICAL EDUCATION LA English DT Article ID RESIDENTS; KNOWLEDGE; STUDENTS; HEALTH; TRIAL; LEARN AB Background: Adverse events are a significant quality and safety issue in the hospital setting due to their direct impact on patients. Additionally, such events are often handled by junior doctors due to their direct involvement with patients. As such, it is important for health care organizations to prioritize education and training for junior doctors on identifying adverse events and handling them when they occur. The Cancer Cup Challenge is an educational program focuses on quality improvement and adverse event awareness targeting for junior oncology doctors across three international sites. Methods: A mixed methodology was used to develop and evaluate the program. The Qstream spaced learning platform was used to disseminate information to participants, as it has been demonstrated to impact on both knowledge and behavior. Eight short case based scenarios with expert feedback were developed by a multidisciplinary advisory committee containing representatives from the international sites. At the conclusion of the course impact on participant knowledge was evaluated using analysis of the metrics collected by the Qstream platform. Additionally, an online survey and semi-structured interviews were used to evaluate engagement and perceived value by participants. Results: A total of 35 junior doctors registered to undertake the Qstream program, with 31 (88.57 %) successfully completing it. Analysis of the Qstream metrics revealed 76.57 % of cases were answered correctly on first attempt. The post-program survey received 17 responses, with 76.47 % indicating cases for the course were interesting and 82.35 % feeling cases were relevant. Finally, 14 participants consented to participate in semi-structured interviews about the program, with feedback towards the course being generally very positive. Conclusions: Our study demonstrates that an online game is well accepted by junior doctors as a method to increase their quality improvement awareness. Developing effective and sustainable training for doctors is important to ensure positive patient outcomes are maintained in the hospital setting. This is particularly important for junior doctors as they are working closely with patients and learning skills and behaviors, which will influence their practice throughout their careers. C1 [Janssen, Anna] Univ Sydney, Sydney West Translat Canc Res Ctr, Res Implementat Sci & E Hlth Grp RISe, Fac Hlth Sci, Sydney, NSW 2006, Australia. [Shaw, Tim] Univ Sydney, Fac Hlth Sci, Res Implementat Sci & E Hlth Grp RISe, Sydney, NSW 2006, Australia. [Bradbury, Lauren; Moujaber, Tania; Norrelykke, Anne Mette; Harnett, Paul] Westmead Hosp, Crown Princess Mary Canc Care Ctr, Westmead, NSW 2145, Australia. [Zerillo, Jessica A.; LaCasce, Ann] Dana Farber Canc Inst, Boston, MA 02115 USA. [Co, John Patrick T.] Partners HealthCare, Boston, MA USA. [Robinson, Tracy] Univ Canberra, Fac Hlth Disciplines Nursing & Midwifery, Canberra, ACT 2601, Australia. [Robinson, Tracy] Westmead Hosp, Sydney West Translat Canc Res Ctr, Sydney, NSW, Australia. [Starr, Alison] Western Sydney Local Hlth Dist, Westmead, NSW, Australia. RP Janssen, A (reprint author), Univ Sydney, Sydney West Translat Canc Res Ctr, Res Implementat Sci & E Hlth Grp RISe, Fac Hlth Sci, Sydney, NSW 2006, Australia. EM anna.janssen@sydney.edu.au RI Harnett, Paul/D-4090-2014; OI Harnett, Paul/0000-0001-7021-0642; Janssen, Anna/0000-0001-6611-9651 FU Sydney West Translational Cancer Research Centre grant from the Cancer Institute New South Wales FX This study was financed through the Sydney West Translational Cancer Research Centre grant from the Cancer Institute New South Wales. NR 23 TC 0 Z9 0 U1 2 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1472-6920 J9 BMC MED EDUC JI BMC Med. Educ. PD MAR 12 PY 2016 VL 16 AR 91 DI 10.1186/s12909-016-0609-1 PG 9 WC Education & Educational Research; Education, Scientific Disciplines SC Education & Educational Research GA DG0PC UT WOS:000371766300001 PM 26968519 ER PT J AU Hou, LP Heilbronner, U Degenhardt, F Adli, M Akiyama, K Akula, N Ardau, R Arias, B Backlund, L Banzato, CEM Benabarre, A Bengesser, S Bhattacharjee, AK Biernacka, JM Birner, A Brichant-Petitjean, C Bui, ET Cervantes, P Chen, GB Chen, HC Chillotti, C Cichon, S Clark, SR Colom, F Cousins, DA Cruceanu, C Czerski, PM Dantas, CR Dayer, A Eacute;tain, B Falkai, P Forstner, AJ Frisen, L Fullerton, JM Gard, S Garnham, JS Goes, FS Grof, P Gruber, O Hashimoto, R Hauser, J Herms, S Hoffmann, P Hofmann, A Jamain, S Jimenez, E Kahn, JP Kassem, L Kittel-Schneider, S Kliwicki, S Konig, B Kusumi, I Lackner, N Laje, G Landen, M Lavebratt, C Leboyer, M Leckband, SG Jaramillo, CAL MacQueen, G Manchia, M Martinsson, L Mattheisen, M McCarthy, MJ McElroy, SL Mitjans, M Mondimore, FM Monteleone, P Nievergelt, CM Nothen, MM Ouml;sby, U Ozaki, N Perlis, RH Pfennig, A Reich-Erkelenz, D Rouleau, GA Schofield, PR Schubert, KO Schweizer, BW Seemuller, F Severino, G Shekhtman, T Shilling, PD Shimoda, K Simhandl, C Slaney, CM Smoller, JW Squassina, A Stamm, T Stopkova, P Tighe, SK Tortorella, A Turecki, G Volkert, J Witt, S Wright, A Young, LT Zandi, PP Potash, JB DePaulo, JR Bauer, M Reininghaus, EZ Novak, T Aubry, JM Maj, M Baune, BT Mitchell, PB Vieta, E Frye, MA Rybakowski, JK Kuo, PH Kato, T Grigoroiu-Serbanescu, M Reif, A Del Zompo, M Bellivier, F Schalling, M Wray, NR Kelsoe, JR Alda, M Rietschel, M McMahon, FJ Schulze, TG AF Hou, Liping Heilbronner, Urs Degenhardt, Franziska Adli, Mazda Akiyama, Kazufumi Akula, Nirmala Ardau, Raffaella Arias, Barbara Backlund, Lena Banzato, Claudio E. M. Benabarre, Antoni Bengesser, Susanne Bhattacharjee, Abesh Kumar Biernacka, Joanna M. Birner, Armin Brichant-Petitjean, Clara Bui, Elise T. Cervantes, Pablo Chen, Guo-Bo Chen, Hsi-Chung Chillotti, Caterina Cichon, Sven Clark, Scott R. Colom, Francesc Cousins, David A. Cruceanu, Cristiana Czerski, Piotr M. Dantas, Clarissa R. Dayer, Alexandre Etain, Bruno Falkai, Peter Forstner, Andreas J. Frisen, Louise Fullerton, Janice M. Gard, Sebastien Garnham, Julie S. Goes, Fernando S. Grof, Paul Gruber, Oliver Hashimoto, Ryota Hauser, Joanna Herms, Stefan Hoffmann, Per Hofmann, Andrea Jamain, Stephane Jimenez, Esther Kahn, Jean-Pierre Kassem, Layla Kittel-Schneider, Sarah Kliwicki, Sebastian Koenig, Barbara Kusumi, Ichiro Lackner, Nina Laje, Gonzalo Landen, Mikael Lavebratt, Catharina Leboyer, Marion Leckband, Susan G. Lopez Jaramillo, Carlos A. MacQueen, Glenda Manchia, Mirko Martinsson, Lina Mattheisen, Manuel McCarthy, Michael J. McElroy, Susan L. Mitjans, Marina Mondimore, Francis M. Monteleone, Palmiero Nievergelt, Caroline M. Noethen, Markus M. Oesby, Urban Ozaki, Norio Perlis, Roy H. Pfennig, Andrea Reich-Erkelenz, Daniela Rouleau, Guy A. Schofield, Peter R. Schubert, K. Oliver Schweizer, Barbara W. Seemueller, Florian Severino, Giovanni Shekhtman, Tatyana Shilling, Paul D. Shimoda, Kazutaka Simhandl, Christian Slaney, Claire M. Smoller, Jordan W. Squassina, Alessio Stamm, Thomas Stopkova, Pavla Tighe, Sarah K. Tortorella, Alfonso Turecki, Gustavo Volkert, Julia Witt, Stephanie Wright, Adam Young, L. Trevor Zandi, Peter P. Potash, James B. DePaulo, J. Raymond Bauer, Michael Reininghaus, Eva Z. Novak, Tomas Aubry, Jean-Michel Maj, Mario Baune, Bernhard T. Mitchell, Philip B. Vieta, Eduard Frye, Mark A. Rybakowski, Janusz K. Kuo, Po-Hsiu Kato, Tadafumi Grigoroiu-Serbanescu, Maria Reif, Andreas Del Zompo, Maria Bellivier, Frank Schalling, Martin Wray, Naomi R. Kelsoe, John R. Alda, Martin Rietschel, Marcella McMahon, Francis J. Schulze, Thomas G. TI Genetic variants associated with response to lithium treatment in bipolar disorder: a genome-wide association study SO LANCET LA English DT Article ID PROPHYLACTIC LITHIUM; GENOTYPE IMPUTATION; I DISORDER; THERAPY; PHARMACOGENETICS; GADL1 AB Background Lithium is a first-line treatment in bipolar disorder, but individual response is variable. Previous studies have suggested that lithium response is a heritable trait. However, no genetic markers of treatment response have been reproducibly identified. Methods Here, we report the results of a genome-wide association study of lithium response in 2563 patients collected by 22 participating sites from the International Consortium on Lithium Genetics (ConLiGen). Data from common single nucleotide polymorphisms (SNPs) were tested for association with categorical and continuous ratings of lithium response. Lithium response was measured using a well established scale (Alda scale). Genotyped SNPs were used to generate data at more than 6 million sites, using standard genomic imputation methods. Traits were regressed against genotype dosage. Results were combined across two batches by meta-analysis. Findings A single locus of four linked SNPs on chromosome 21 met genome-wide significance criteria for association with lithium response (rs79663003, p= 1.37 x 10(-8); rs78015114, p= 1.31 x 10(-8); rs74795342, p= 3.31 x 10(-9); and rs75222709, p= 3.50 x 10(-9)). In an independent, prospective study of 73 patients treated with lithium monotherapy for a period of up to 2 years, carriers of the response-associated alleles had a significantly lower rate of relapse than carriers of the alternate alleles (p= 0.03268, hazard ratio 3.8, 95% CI 1.1-13.0). Interpretation The response-associated region contains two genes for long, non-coding RNAs (lncRNAs), AL157359.3 and AL157359.4. LncRNAs are increasingly appreciated as important regulators of gene expression, particularly in the CNS. Confirmed biomarkers of lithium response would constitute an important step forward in the clinical management of bipolar disorder. Further studies are needed to establish the biological context and potential clinical utility of these findings. C1 [Hou, Liping; Akula, Nirmala; Bui, Elise T.; Kassem, Layla; Laje, Gonzalo; McMahon, Francis J.; Schulze, Thomas G.] NIMH, Intramural Res Program, NIH, US Dept HHS, Bethesda, MD 20892 USA. [Heilbronner, Urs; Reich-Erkelenz, Daniela; Schulze, Thomas G.] Univ Munich, Inst Psychiat Phen & Genom, Munich, Germany. [Falkai, Peter; Seemueller, Florian] Univ Munich, Dept Psychiat & Psychotherapy, Munich, Germany. [Heilbronner, Urs; Gruber, Oliver; Schulze, Thomas G.] Univ Gottingen, Univ Med Ctr UMG, Dept Psychiat & Psychotherapy, D-37073 Gottingen, Germany. [Degenhardt, Franziska; Cichon, Sven; Forstner, Andreas J.; Herms, Stefan; Hoffmann, Per; Hofmann, Andrea; Noethen, Markus M.] Univ Bonn, Inst Human Genet, Bonn, Germany. [Degenhardt, Franziska; Cichon, Sven; Forstner, Andreas J.; Herms, Stefan; Hoffmann, Per; Hofmann, Andrea; Noethen, Markus M.] Life & Brain Ctr, Dept Genom, Bonn, Germany. [Adli, Mazda; Stamm, Thomas] Charite, Dept Psychiat & Psychotherapy, Campus Charite Mitte, D-13353 Berlin, Germany. [Adli, Mazda] Fliedner Klin Berlin, Ctr Psychiat Psychotherapy & Psychosomat Med, Berlin, Germany. [Akiyama, Kazufumi] Dokkyo Med Univ, Dept Biol Psychiat & Neurosci, Sch Med, Mibu, Tochigi, Japan. [Ardau, Raffaella; Chillotti, Caterina; Del Zompo, Maria] Hosp Univ Agcy Cagliari, Clin Pharmacol Unit, Cagliari, Italy. [Arias, Barbara; Mitjans, Marina] Univ Barcelona, CIBERSAM, Fac Biol, Dept Biol Anim,Unitat Antropol Dp Biol Anim, Barcelona, Catalonia, Spain. [Arias, Barbara; Mitjans, Marina] Univ Barcelona, CIBERSAM, Inst Biomed IBUB, Barcelona, Catalonia, Spain. [Backlund, Lena; Frisen, Louise; Lavebratt, Catharina; Leckband, Susan G.; Schalling, Martin] Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden. [Frisen, Louise] Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden. [Oesby, Urban] Karolinska Inst, Dept Neurobiol Care Sci & Soc, Stockholm, Sweden. Karolinska Univ Hosp, Ctr Mol Med, Stockholm, Sweden. [Frisen, Louise] Child & Adolescent Psychiat Res Ctr, Stockholm, Sweden. [Banzato, Claudio E. M.; Dantas, Clarissa R.] Univ Campinas Unicamp, Dept Psychiat, Campinas, SP, Brazil. [Benabarre, Antoni; Colom, Francesc; Jimenez, Esther; Vieta, Eduard] Univ Barcelona, IDIBAPS, CIBERSAM, Bipolar Disorder Program,Inst Neurosci,Hosp Clin, Barcelona, Catalonia, Spain. [Bengesser, Susanne; Birner, Armin; Lackner, Nina; Reininghaus, Eva Z.] Med Univ Graz, Dept Psychiat, Neurobiol Background & Anthropometr Bipolar Affec, Graz, Austria. [Shekhtman, Tatyana; Kelsoe, John R.] San Diego Healthcare Syst, Vet Adm, San Diego, CA USA. [Bhattacharjee, Abesh Kumar; Nievergelt, Caroline M.; Shekhtman, Tatyana; Shilling, Paul D.; Kelsoe, John R.] Univ Calif San Diego, Dept Psychiat, San Diego, CA 92103 USA. [Biernacka, Joanna M.] Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA. [Biernacka, Joanna M.; Frye, Mark A.] Mayo Clin, Dept Psychiat & Psychol, Rochester, MN USA. [Brichant-Petitjean, Clara; Bellivier, Frank] Univ Paris Diderot Pole Psychiat, INSERM, UMR S 1144, Grp Hosp Lariboisiere F Widal,AP HP, Paris, France. [Cervantes, Pablo] McGill Univ, Ctr Hlth, Neuromodulat Unit, Montreal, PQ, Canada. [Chen, Guo-Bo; Wray, Naomi R.] Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia. [Chen, Hsi-Chung] Natl Taiwan Univ Hosp, Dept Psychiat, Taipei, Taiwan. [Chen, Hsi-Chung] Natl Taiwan Univ Hosp, Ctr Sleep Disorders, Taipei, Taiwan. [Kuo, Po-Hsiu] Natl Taiwan Univ, Inst Epidemiol & Prevent Med, Taipei 10764, Taiwan. [Cichon, Sven; Herms, Stefan; Hoffmann, Per] Univ Basel Hosp, Human Genom Res Grp, Dept Biomed, CH-4031 Basel, Switzerland. [Clark, Scott R.; Schubert, K. Oliver; Baune, Bernhard T.] Univ Adelaide, Discipline Psychiat, Adelaide, SA, Australia. [Cousins, David A.] Newcastle Univ, Campus Ageing & Vital, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. [Cruceanu, Cristiana; Turecki, Gustavo] McGill Univ, Douglas Mental Hlth Univ Inst, Montreal, PQ, Canada. [Czerski, Piotr M.; Hauser, Joanna] Poznan Univ Med Sci, Psychiat Genet Unit, Poznan, Poland. [Dayer, Alexandre; Aubry, Jean-Michel] Univ Hosp Geneva, Dept Mental Hlth & Psychiat, Mood Disorders Unit, Geneva, Switzerland. [Etain, Bruno; Jamain, Stephane] Hop Henri Mondor, INSERM, U955, Psychiat Translat, F-94010 Creteil, France. [Fullerton, Janice M.; Schofield, Peter R.] Neurosci Res Australia, Mental Illness Res Theme, Sydney, NSW, Australia. [Fullerton, Janice M.; Schofield, Peter R.] Univ New S Wales, Sch Med Sci, Sydney, NSW, Australia. [Gard, Sebastien] Ctr Hosp Charles Perrens, Pole Psychiat Gen Univ, Bordeaux, France. [Garnham, Julie S.; Slaney, Claire M.; Alda, Martin] Dalhousie Univ, Dept Psychiat, Halifax, NS, Canada. [Goes, Fernando S.; Mondimore, Francis M.; Schweizer, Barbara W.; DePaulo, J. Raymond; Schulze, Thomas G.] Johns Hopkins Univ, Dept Psychiat & Behav Sci, Baltimore, MD USA. [Grof, Paul] Mood Disorders Ctr Ottawa, Ottawa, ON, Canada. [Hashimoto, Ryota] Osaka Univ, Mol Res Ctr Childrens Mental Dev, United Grad Sch Child Dev, Osaka, Japan. [Kahn, Jean-Pierre] Univ Lorraine, Ctr Psychotherap Nancy Laxou, Serv Psychiat & Psychol Clin, Nancy, France. [Kittel-Schneider, Sarah; Volkert, Julia; Reif, Andreas] Univ Hosp Frankfurt, Dept Psychiat Psychosomat Med & Psychotherapy, Frankfurt, Germany. [Kliwicki, Sebastian; Rybakowski, Janusz K.] Poznan Univ Med Sci, Dept Adult Psychiat, Poznan, Poland. [Koenig, Barbara] Landesklinikum Neunkirchen, Dept Psychiat & Psychotherapeut Med, Neunkirchen, Austria. [Kusumi, Ichiro] Hokkaido Univ, Grad Sch Med, Dept Psychiat, Sapporo, Hokkaido, Japan. [Landen, Mikael] Gothenburg Univ, Inst Neurosci & Physiol, Sahlgrenska Acad, Gothenburg, Sweden. [Landen, Mikael] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Martinsson, Lina] Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden. [Leboyer, Marion] Hop Albert Chenevier Henri Mondor, Assistance Publ Hop Paris, Pole Psychiat, Creteil, France. [Leckband, Susan G.] San Diego Healthcare Syst, Dept Pharm, San Diego, CA USA. [McCarthy, Michael J.] San Diego Healthcare Syst, Dept Psychiat, San Diego, CA USA. [Lopez Jaramillo, Carlos A.] Univ Antioquia, Dept Psychiat, Medellin, Colombia. [MacQueen, Glenda] Univ Calgary, Dept Psychiat, Calgary, AB, Canada. [Manchia, Mirko; Severino, Giovanni; Squassina, Alessio; Del Zompo, Maria] Univ Cagliari, Dept Biomed Sci, Cagliari, Italy. [Manchia, Mirko] Dalhousie Univ, Dept Pharmacol, Halifax, NS B3H 4H7, Canada. [Mattheisen, Manuel] Aarhus Univ, Dept Biomed, Aarhus, Denmark. [McElroy, Susan L.] Univ Cincinnati, Lindner Ctr Hope, Dept Psychiat, Mason, OH USA. [Monteleone, Palmiero] Univ Salerno, Dept Med & Surg, Neurosci Sect, I-84100 Salerno, Italy. [Monteleone, Palmiero; Tortorella, Alfonso; Maj, Mario] Univ Naples SUN, Dept Psychiat, Naples, Italy. [Ozaki, Norio] Nagoya Univ, Grad Sch Med, Dept Psychiat, Nagoya, Aichi 4648601, Japan. [Perlis, Roy H.; Smoller, Jordan W.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Perlis, Roy H.; Smoller, Jordan W.] Harvard Univ, Sch Med, Boston, MA USA. [Pfennig, Andrea; Bauer, Michael] Tech Univ Dresden, Univ Hosp Carl Gustav Carus, Dept Psychiat & Psychotherapy, Fac Med, D-01062 Dresden, Germany. [Rouleau, Guy A.] McGill Univ, Montreal Neurol Inst & Hosp, Montreal, PQ, Canada. [Shimoda, Kazutaka] Dokkyo Med Univ, Sch Med, Dept Psychiat, Mibu, Tochigi, Japan. [Simhandl, Christian] Bipolar Ctr Wiener Neustadt, Wiener Neustadt, Austria. [Stopkova, Pavla; Novak, Tomas; Alda, Martin] Natl Inst Mental Hlth, Klecany, Czech Republic. [Tighe, Sarah K.; Potash, James B.] Univ Iowa, Dept Psychiat, Iowa City, IA 52242 USA. [Tighe, Sarah K.] Univ Iowa, Carver Coll Med, Iowa City, IA USA. [Tighe, Sarah K.] Univ Iowa, Coll Publ Hlth, VA Qual Scholars Program, Iowa City VA Hosp, Iowa City, IA USA. [Witt, Stephanie; Rietschel, Marcella; Schulze, Thomas G.] Heidelberg Univ, Med Fac Mannheim, Cent Inst Mental Hlth, Dept Genet Epidemiol Psychiat, Mannheim, Germany. [Wright, Adam; Mitchell, Philip B.] Univ New S Wales, Sch Psychiat, Sydney, NSW, Australia. [Wright, Adam; Mitchell, Philip B.] Black Dog Inst, Sydney, NSW, Australia. [Young, L. Trevor] Univ Toronto, Dept Psychiat, Toronto, ON, Canada. [Zandi, Peter P.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Mental Hlth, Baltimore, MD USA. [Kato, Tadafumi] RIKEN, Brain Sci Inst, Lab Mol Dynam Mental Disorders, Saitama, Japan. [Grigoroiu-Serbanescu, Maria] Alexandru Obregia Psychiat Hosp, Biometr Psychiat Genet Res Unit, Bucharest, Romania. RP Schulze, TG (reprint author), Univ Munich, Med Ctr, IPPG, Munich, Germany.; McMahon, FJ (reprint author), NIMH, Human Genet Branch, Intramural Res Program, Bethesda, MD 20892 USA.; McMahon, FJ (reprint author), NIMH, Genet Basis Mood & Anxiety Disorders Sect, Intramural Res Program, Bethesda, MD 20892 USA. EM mcmahonf@mail.nih.gov; thomas.schulze@med.uni-muenchen.de RI Banzato, Claudio/B-2517-2008; Hou, Liping/G-1648-2011; BELLIVIER, FRANK/H-5197-2012; Novak, Tomas/B-8008-2017; Chen, Hsi-Chung/E-9949-2017; OI Mitjans, Marina/0000-0001-5543-7320; Colom, Francesc/0000-0002-9516-9030; Kato, Tadafumi/0000-0001-7856-3952; Squassina, Alessio/0000-0001-7415-7607; Etain, Bruno/0000-0002-5377-1488; Dayer, Alexandre/0000-0002-4490-9780; Grigoroiu-Serbanescu, Maria/0000-0002-1304-6687; Chen, Guo-Bo/0000-0001-5475-8237; Mitchell, Philip/0000-0002-7954-5235; Banzato, Claudio/0000-0002-8556-3982; Manchia, Mirko/0000-0003-4175-6413; Kittel-Schneider, Sarah/0000-0003-3057-6150; Hou, Liping/0000-0003-3972-245X; Novak, Tomas/0000-0001-9156-9654; Chen, Hsi-Chung/0000-0003-3191-0093; Nievergelt, Caroline/0000-0001-5766-8923; Reininghaus, Eva/0000-0001-5964-4087; McMahon, Francis/0000-0002-9469-305X; Nothen, Markus/0000-0002-8770-2464 FU Deutsche Forschungsgemeinschaft; National Institute of Mental Health Intramural Research Program; Deutsche Forschungsgemeinschaft (DFG) [RI 908/7-1, FOR2107, RI 908/11-1, NO 246/10-1]; National Institute of Mental Health [ZIA-MH00284311, NCT00001174]; German Federal Ministry of Education and Research (BMBF) through the Integrated Network IntegraMent (Integrated Understanding of Causes and Mechanisms in Mental Disorders) under e:Med Programme; German Federal Ministry of Education and Research (BMBF); Alfried Krupp von Bohlen und Halbach-Stiftung; BONFOR Programme of the University of Bonn, Germany; Land Steiermark; Swedish Research Council; Swedish Brain Foundation; Karolinska Institutet; Karolinska University Hospital; NIH from National Cancer Institute [P50CA89392]; NIH from National Institute of Drug Abuse [5K02DA021237]; Canadian Institutes of Health Research [64410]; Australian NHMRC Program Grant [1037196]; Centro de Investigacion en Red de Salud Mental (CIBERSAM) IDIBAPS [PI080247, PI1200906, PI12/00018]; Secretaria d'Universitats i Recerca del Departament d'Economia i Coneixement [2014SGR1636, 2014SGR398]; Swiss National Science Foundation [32003B_125469]; Swiss National Science Foundation (NCCR Synapsy); Medical Research Council Clinician Scientist Fellowship Award [MR/L006642/1]; Swedish Research Council [523-2011-3807]; UEFISCDI, Romania [89/2012]; Taiwan Ministry of Science and Technology [MST 99-2314-B-002-140-MY3, 102-2314-B-002-117-MY3]; University of Antioquia; Ministry of Health of the Czech Republic [IGA NT13891]; Reuben Stoltzfus Bipolar Research Fund; James Wah Fund; Project MATCH; Dr-Lisa-Oehler-Foundation (Kassel, Germany); Sardinia Regional Government POR Sardegna FSE Operational Program of the Autonomous Region of Sardinia, European Social Fund; Australian NHMRC Fellowships [613602, 1078901]; Stanley Center for Psychiatric Research at the Broad Institute FX Deutsche Forschungsgemeinschaft, National Institute of Mental Health Intramural Research Program.; We are greatly indebted to all the study participants without whom this research would not have been possible. We thank the members of our Scientific Advisory Board for critical input over the course of the project. This work was in part funded by the Deutsche Forschungsgemeinschaft (DFG; grant no RI 908/7-1; grant FOR2107, RI 908/11-1 to Marcella Rietschel, Michael Bauer, and Thomas G Schulze, NO 246/10-1 to MMN) and the Intramural Research Program of the National Institute of Mental Health (ZIA-MH00284311; NCT00001174). The genotyping was in part funded by the German Federal Ministry of Education and Research (BMBF) through the Integrated Network IntegraMent (Integrated Understanding of Causes and Mechanisms in Mental Disorders), under the auspices of the e:Med Programme (grants awarded to TGS, MR, and MMN). OG, AP, TSt, MB, AR, and TGS received support from the German Federal Ministry of Education and Research (BMBF) within the framework of the BipolLife network. MMN received support from the Alfried Krupp von Bohlen und Halbach-Stiftung. Franziska Degenhardt received support from the BONFOR Programme of the University of Bonn, Germany. EZR received funding from the Land Steiermark as principal investigator. MS received funds from the Swedish Research Council, Swedish Brain Foundation and funds from Karolinska Institutet and Karolinska University Hospital. Some data and biomaterials were collected as part of eleven projects (Study 40) that participated in the National Institute of Mental Health (NIMH) Bipolar Disorder Genetics Initiative. From 2003-07, the principal investigators and co-investigators were: Indiana University, Indianapolis, IN, R01 MH59545 (John Nurnberger, Marvin J Miller, Elizabeth S Bowman, N Leela Rau, P Ryan Moe, Nalini Samavedy, Rif El-Mallakh [University of Louisville], Husseini Manji [Johnson and Johnson], Debra A Glitz [Wayne State University], Eric T Meyer [Oxford University, UK], Carrie Smiley, Tatiana Foroud, Leah Flury, Danielle M Dick [Virginia Commonwealth University], Howard Edenberg); Washington University, St Louis, MO, R01 MH059534 (John Rice, Theodore Reich, Allison Goate, Laura Bierut [K02 DA21237]); Johns Hopkins University, Baltimore, R01 MH59533 (Melvin McInnis, J Raymond DePaulo Jr, Dean F MacKinnon, Francis M Mondimore, James B Potash, Peter P Zandi, Dimitrios Avramopoulos, Jennifer Payne); University of Pennsylvania, PA, R01 MH59553 (Wade Berrettini); University of California at San Francisco, CA, R01 MH60068 (William Byerley, Sophia Vinogradov); University of Iowa, IA, R01 MH059548 (William Coryell, Raymond Crowe); University of Chicago, IL, R01 MH59535 (Elliot Gershon, Judith Badner, Francis McMahon, Chunyu Liu, Alan Sanders, Maria Caserta, Steven Dinwiddie, Tu Nguyen, Donna Harakal); University of California at San Diego, CA, R01 MH59567 (John Kelsoe, Rebecca McKinney); Rush University, IL, R01 MH059556 (William Scheftner, Howard M Kravitz, Diana Marta, Annette Vaughn-Brown, Laurie Bederow); and NIMH Intramural Research Program, Bethesda, 1Z01MH002810-01 (Francis J McMahon, Layla Kassem, PsyD, Sevilla Detera-Wadleigh, Lisa Austin, Dennis L Murphy [Howard University], William B Lawson, Evarista Nwulia, Maria Hipolito). This work was supported by the NIH grants P50CA89392 from the National Cancer Institute and 5K02DA021237 from the National Institute of Drug Abuse. The Canadian part of the study was supported by a grant #64410 from the Canadian Institutes of Health Research to MAl. We wish to thank Joanne Petite and Giselle Kraus for assistance with data collection.; Collection and phenotyping of the Australian UNSW sample, by PBM, PRS, JMF, and AW, was funded by an Australian NHMRC Program Grant (No. 1037196). The collection of the Barcelona sample was supported by the Centro de Investigacion en Red de Salud Mental (CIBERSAM) IDIBAPS (grant numbers PI080247, PI1200906, PI12/00018), and Secretaria d'Universitats i Recerca del Departament d'Economia i Coneixement (2014SGR1636 and 2014SGR398). J-MA and AD were supported by the Swiss National Science Foundation (grant number 32003B_125469 and NCCR Synapsy). DC was supported by a Medical Research Council Clinician Scientist Fellowship Award (MR/L006642/1). LF was supported by the Swedish Research Council (grant no 523-2011-3807). MG-S was supported by UEFISCDI, Romania, grant no 89/2012. P-HK was funded by the Taiwan Ministry of Science and Technology (grant no MST 99-2314-B-002-140-MY3 and 102-2314-B-002-117-MY3). CALJ was funded by the "Estrategia de Sostenibilidad 2014-2015" program of the University of Antioquia. TN was supported by the Ministry of Health of the Czech Republic (grant no IGA NT13891). JBP was supported by the Reuben Stoltzfus Bipolar Research Fund and with SKT received funding from the James Wah Fund and Project MATCH. TGS and UH received support from the Dr-Lisa-Oehler-Foundation (Kassel, Germany). AS has a postdoctoral fellowship funded by the Sardinia Regional Government POR Sardegna FSE Operational Program of the Autonomous Region of Sardinia, European Social Fund 2007-2013-Axis IV Human Resources, Objective l.3, Line of Activity l.3.1. NRW was funded by Australian NHMRC Fellowships 613602 and 1078901. MMan is now a resident in the psychiatry training program at the Section of Psychiatry, Department of Public Health, Clinical and Molecular Medicine, University of Cagliari, Cagliari, Italy. This study used the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health, Bethesda, MD. Genotyping for part of the Swedish sample was funded by the Stanley Center for Psychiatric Research at the Broad Institute. NR 33 TC 23 Z9 25 U1 13 U2 32 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 MAR 12 PY 2016 VL 387 IS 10023 BP 1085 EP 1093 DI 10.1016/S0140-6736(16)00143-4 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA DG0SD UT WOS:000371775000028 PM 26806518 ER PT J AU Acharya, M Sokolovska, A Tam, JM Conway, KL Stefani, C Raso, F Mukhopadhyay, S Feliu, M Paul, E Savill, J Hynes, RO Xavier, RJ Vyas, JM Stuart, LM Lacy-Hulbert, A AF Acharya, Mridu Sokolovska, Anna Tam, Jenny M. Conway, Kara L. Stefani, Caroline Raso, Fiona Mukhopadhyay, Subhankar Feliu, Marianela Paul, Elahna Savill, John Hynes, Richard O. Xavier, Ramnik J. Vyas, Jatin M. Stuart, Lynda M. Lacy-Hulbert, Adam TI alpha v Integrins combine with LC3 and atg5 to regulate Toll-like receptor signalling in B cells SO NATURE COMMUNICATIONS LA English DT Article ID EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; MICE LACKING; ACTIVATION; AUTOPHAGY; RESPONSES; ANTIGENS; IMMUNITY; BETA; DNA; DIFFERENTIATION AB Integrin signalling triggers cytoskeletal rearrangements, including endocytosis and exocytosis of integrins and other membrane proteins. In addition to recycling integrins, this trafficking can also regulate intracellular signalling pathways. Here we describe a role for alpha v integrins in regulating Toll-like receptor (TLR) signalling by modulating intracellular trafficking. We show that deletion of alpha v or beta 3 causes increased B-cell responses to TLR stimulation in vitro, and alpha v-conditional knockout mice have elevated antibody responses to TLR-ligand-associated antigens. av regulates TLR signalling by promoting recruitment of the autophagy component LC3 (microtubule-associated proteins 1 light chain 3) to TLR-containing endosomes, which is essential for progression from NF-kappa B to IRF signalling, and ultimately for traffic to lysosomes where signalling is terminated. Disruption of LC3 recruitment leads to prolonged NF-kappa B signalling and increased B-cell proliferation and antibody production. This work identifies a previously unrecognized role for av and the autophagy components LC3 and atg5 in regulating TLR signalling and B-cell immunity. C1 [Acharya, Mridu; Stefani, Caroline; Raso, Fiona; Stuart, Lynda M.; Lacy-Hulbert, Adam] Benaroya Res Inst, Program Immunol, 1201 Ninth Ave, Seattle, WA 98101 USA. [Sokolovska, Anna; Feliu, Marianela; Paul, Elahna] Harvard Med Sch, Massachusetts Gen Hosp, Dept Pediat, Lab Dev Immunol, 55 Fruit St, Boston, MA 02114 USA. [Tam, Jenny M.; Xavier, Ramnik J.; Vyas, Jatin M.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Med, Div Infect Dis, 55 Fruit St, Boston, MA 02114 USA. [Conway, Kara L.] Harvard Med Sch, Gastrointestinal Unit, 55 Fruit St, Boston, MA 02114 USA. [Conway, Kara L.] Harvard Med Sch, Massachusetts Gen Hosp, Ctr Study Inflammatory Bowel Dis, 55 Fruit St, Boston, MA 02114 USA. [Mukhopadhyay, Subhankar] Wellcome Trust Sanger Inst, Microbial Pathogenesis Grp, Cambridge CB10 1SA, England. [Savill, John] Univ Edinburgh, MRC, Ctr Inflammat Res, 47 Little France Crescent, Edinburgh EH16 4TJ, Midlothian, Scotland. [Hynes, Richard O.] MIT, Koch Inst Integrated Canc Biol, Howard Hughes Med Inst, 500 Main St, Cambridge, MA 02139 USA. [Stuart, Lynda M.] Bill & Melinda Gates Fdn, 500 Fifth Ave N, Seattle, WA 98109 USA. RP Lacy-Hulbert, A (reprint author), Benaroya Res Inst, Program Immunol, 1201 Ninth Ave, Seattle, WA 98101 USA. EM alacyhulbert@benaroyaresearch.org FU Wellcome Trust Grant [34561]; MRC Grant [G0802069]; Leukemia Research Foundation New Investigator Award; Howard Hughes Medical Institute; NIH grants [AI079198, DK093695]; Massachusetts General Hospital FX We thank all members of the Lacy-Hulbert and Stuart labs for assistance and advice on this project. This work was supported by Wellcome Trust Grant 34561 and MRC Grant G0802069 (to J.S.), a Leukemia Research Foundation New Investigator Award (A. L.-H.), Howard Hughes Medical Institute (R.O.H.) and NIH grants AI079198 (L.M.S.) and DK093695 (A. L.-H.). M.A. was supported in part by a Fund for Medical Discovery Fellowship from Massachusetts General Hospital. We also thank Charles Felts (Research Precision Instruments), Arthur McLelland (Harvard University), Wendy Salmon (Keck Imaging Institute, Whitehead Institute), and Ed Rader (Molecular Devices) for help with dSTORM imaging, and David Rawlings, Shaun Jackson and other members of the Rawlings lab (Seattle Children's Research Institute) for reagents and helpful discussion. NR 70 TC 3 Z9 3 U1 2 U2 2 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 MAR 11 PY 2016 VL 7 AR 10917 DI 10.1038/ncomms10917 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EH6BD UT WOS:000391856400001 PM 26965188 ER PT J AU Zanoni, P Khetarpal, SA Larach, DB Hancock-Cerutti, WF Millar, JS Cuchel, M DerOhannessian, S Kontush, A Surendran, P Saleheen, D Trompet, S Jukema, JW De Craen, A Deloukas, P Sattar, N Ford, I Packard, C Majumder, AA Alam, DS Di Angelantonio, E Abecasis, G Chowdhury, R Erdmann, J Nordestgaard, BG Nielsen, SF Tybjaerg-Hansen, A Schmidt, RF Kuulasmaa, K Liu, DJ Perola, M Blankenberg, S Salomaa, V Mannisto, S Amouyel, P Arveiler, D Ferrieres, J Muller-Nurasyid, M Ferrario, M Kee, F Willer, CJ Samani, N Schunkert, H Butterworth, AS Howson, JMM Peloso, GM Stitziel, NO Danesh, J Kathiresan, S Rader, DJ AF Zanoni, Paolo Khetarpal, Sumeet A. Larach, Daniel B. Hancock-Cerutti, William F. Millar, John S. Cuchel, Marina DerOhannessian, Stephanie Kontush, Anatol Surendran, Praveen Saleheen, Danish Trompet, Stella Jukema, J. Wouter De Craen, Anton Deloukas, Panos Sattar, Naveed Ford, Ian Packard, Chris Majumder, Abdullah al Shafi Alam, Dewan S. Di Angelantonio, Emanuele Abecasis, Goncalo Chowdhury, Rajiv Erdmann, Jeanette Nordestgaard, Borge G. Nielsen, Sune F. Tybjaerg-Hansen, Anne Schmidt, Ruth Frikke Kuulasmaa, Kari Liu, Dajiang J. Perola, Markus Blankenberg, Stefan Salomaa, Veikko Mannisto, Satu Amouyel, Philippe Arveiler, Dominique Ferrieres, Jean Muller-Nurasyid, Martina Ferrario, Marco Kee, Frank Willer, Cristen J. Samani, Nilesh Schunkert, Heribert Butterworth, Adam S. Howson, Joanna M. M. Peloso, Gina M. Stitziel, Nathan O. Danesh, John Kathiresan, Sekar Rader, Daniel J. CA Consortium, CE CARDIoGRAM Exome Consortium Global Lipids Genetics Consortium TI Rare variant in scavenger receptor BI raises HDL cholesterol and increases risk of coronary heart disease SO SCIENCE LA English DT Article ID HIGH-DENSITY-LIPOPROTEIN; SELECTIVE LIPID UPTAKE; I SR-BI; DEFICIENT MICE; TARGETED MUTATION; TRANSGENIC MICE; METABOLISM; EXPRESSION; ESTER; ATHEROSCLEROSIS AB Scavenger receptor BI (SR-BI) is the major receptor for high-density lipoprotein (HDL) cholesterol (HDL-C). In humans, high amounts of HDL-C in plasma are associated with a lower risk of coronary heart disease (CHD). Mice that have depleted Scarb1 (SR-BI knockout mice) have markedly elevated HDL-C levels but, paradoxically, increased atherosclerosis. The impact of SR-BI on HDL metabolism and CHD risk in humans remains unclear. Through targeted sequencing of coding regions of lipid-modifying genes in 328 individuals with extremely high plasma HDL-C levels, we identified a homozygote for a loss-of-function variant, in which leucine replaces proline 376 (P376L), in SCARB1, the gene encoding SR-BI. The P376L variant impairs posttranslational processing of SR-BI and abrogates selective HDL cholesterol uptake in transfected cells, in hepatocyte-like cells derived from induced pluripotent stem cells from the homozygous subject, and in mice. Large population-based studies revealed that subjects who are heterozygous carriers of the P376L variant have significantly increased levels of plasma HDL-C. P376L carriers have a profound HDL-related phenotype and an increased risk of CHD (odds ratio = 1.79, which is statistically significant). C1 [Zanoni, Paolo; Khetarpal, Sumeet A.; Larach, Daniel B.; Hancock-Cerutti, William F.; Millar, John S.; Cuchel, Marina; DerOhannessian, Stephanie; Rader, Daniel J.] Univ Penn, Perelman Sch Med, Div Translat Med & Human Genet, Dept Genet, Philadelphia, PA 19104 USA. [Zanoni, Paolo; Khetarpal, Sumeet A.; Larach, Daniel B.; Hancock-Cerutti, William F.; Millar, John S.; Cuchel, Marina; DerOhannessian, Stephanie; Rader, Daniel J.] Univ Penn, Perelman Sch Med, Div Translat Med & Human Genet, Dept Med, Philadelphia, PA 19104 USA. [Hancock-Cerutti, William F.; Kontush, Anatol] Univ Paris 06, Hop Pitie, INSERM UMR ICAN 1166, Paris, France. [Surendran, Praveen; Saleheen, Danish; Di Angelantonio, Emanuele; Chowdhury, Rajiv; Butterworth, Adam S.; Howson, Joanna M. M.; Danesh, John] Univ Cambridge, Dept Publ Hlth & Primary Care, Cardiovasc Epidemiol Unit, Cambridge, England. [Saleheen, Danish] Univ Penn, Perelman Sch Med, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Saleheen, Danish] Ctr Noncommunicable Dis, Karachi, Pakistan. [Trompet, Stella; De Craen, Anton] Leiden Univ, Med Ctr, Dept Gerontol & Geriatr, Leiden, Netherlands. [Trompet, Stella; Jukema, J. Wouter] Leiden Univ, Med Ctr, Dept Cardiol, Leiden, Netherlands. [Jukema, J. Wouter] Interuniv Cardiol Inst Netherlands, Utrecht, Netherlands. [Deloukas, Panos; Danesh, John] Wellcome Trust Sanger Inst, Genome Campus, Hinxton, England. [Sattar, Naveed] Univ Glasgow, Glasgow Cardiovasc Res Ctr, British Heart Fdn, Inst Cardiovasc & Med Sci, Glasgow, Lanark, Scotland. [Ford, Ian] Univ Glasgow, Robertson Ctr Biostat, Glasgow, Lanark, Scotland. [Packard, Chris] Western Infirm & Associated Hosp, Glasgow Clin Res Facil, Glasgow, Lanark, Scotland. [Majumder, Abdullah al Shafi] Natl Inst Cardiovasc Dis, Dhaka, Bangladesh. [Alam, Dewan S.] Int Ctr Diarrhoeal Dis Res, Dhaka, Bangladesh. [Abecasis, Goncalo] Univ Michigan, Sch Publ Hlth, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 USA. [Erdmann, Jeanette] Univ Lubeck, Inst Integrat & Expt Genom, D-23562 Lubeck, Germany. [Nordestgaard, Borge G.; Nielsen, Sune F.] Copenhagen Univ Hosp, Herlev Hosp, Dept Clin Biochem, Herlev, Denmark. [Tybjaerg-Hansen, Anne] Univ Copenhagen, Copenhagen Univ Hosp, Copenhagen, Denmark. [Schmidt, Ruth Frikke] Copenhagen Univ Hosp, Dept Clin Biochem, Rigshosp, Copenhagen, Denmark. [Kuulasmaa, Kari; Perola, Markus; Salomaa, Veikko; Mannisto, Satu] Natl Inst Hlth & Welf, Dept Hlth, Helsinki, Finland. [Liu, Dajiang J.] Penn State Univ, Coll Med, Dept Publ Hlth Sci, Hershey, PA 17033 USA. [Perola, Markus] Univ Helsinki, Inst Mol Med FIMM, Helsinki, Finland. [Blankenberg, Stefan] Univ Heart Ctr Hamburg, Dept Gen & Intervent Cardiol, Hamburg, Germany. [Blankenberg, Stefan] Univ Med Ctr Hamburg Eppendorf, Hamburg, Germany. [Amouyel, Philippe] Inst Pasteur, Dept Epidemiol & Publ Hlth, Lille, France. [Arveiler, Dominique] Univ Strasbourg, Dept Epidemiol & Publ Hlth, Strasbourg, France. [Ferrieres, Jean] Toulouse Univ, Dept Epidemiol, CHU Toulouse, Toulouse, France. [Muller-Nurasyid, Martina] Helmholtz Zentrum Munchen, Inst Genet Epidemiol, German Res Ctr Environm Hlth, Neuherberg, Germany. [Muller-Nurasyid, Martina] Univ Munich, Dept Med 1, Munich, Germany. [Ferrario, Marco] Univ Insubria, Dept Clin & Expt Med, Res Ctr Epidemiol & Prevent Med, Varese, Italy. [Kee, Frank] Queens Univ, UKCRC Ctr Excellence Publ Hlth, Belfast, Antrim, North Ireland. [Willer, Cristen J.] Univ Michigan, Dept Computat Med & Bioinformat, Dept Human Genet, Ann Arbor, MI 48109 USA. [Willer, Cristen J.] Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA. [Samani, Nilesh] Univ Leicester, Dept Cardiovasc Sci, Leicester, Leics, England. [Samani, Nilesh] Glenfield Hotel, Natl Inst Hlth Res NIHR, Leicester Cardiovasc Biomed Res Unit, Leicester, Leics, England. [Schunkert, Heribert] Tech Univ Munich, Deutsch Herzzentrum Munchen, Munich, Germany. [Peloso, Gina M.; Kathiresan, Sekar] Massachusetts Gen Hosp, Broad Inst, Boston, MA 02114 USA. [Peloso, Gina M.; Kathiresan, Sekar] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Stitziel, Nathan O.] Washington Univ, Sch Med, Dept Genet, Dept Med,Div Cardiol, St Louis, MO 63110 USA. [Stitziel, Nathan O.] Washington Univ, Sch Med, McDonnell Genome Inst, St Louis, MO 63110 USA. RP Rader, DJ (reprint author), Univ Penn, Perelman Sch Med, Div Translat Med & Human Genet, Dept Genet, Philadelphia, PA 19104 USA.; Rader, DJ (reprint author), Univ Penn, Perelman Sch Med, Div Translat Med & Human Genet, Dept Med, Philadelphia, PA 19104 USA. EM rader@mail.med.upenn.edu RI Bovet, Pascal/F-4477-2011; Kontush, Anatol/J-2198-2016; Bochud, Murielle/A-3981-2010; Wijmenga, Cisca/D-2173-2009; Deloukas, Panos/B-2922-2013; Colaus, PsyColaus/K-6607-2013; Feitosa, Mary/K-8044-2012; Erdmann, Jeanette/P-7513-2014; OI Gigante, Bruna/0000-0003-4508-7990; Kumari, Meena/0000-0001-9716-1035; Kuulasmaa, Kari/0000-0003-2165-1411; Kleber, Marcus/0000-0003-0663-7275; Hypponen, Elina/0000-0003-3670-9399; Ganna, Andrea/0000-0002-8147-240X; Mannisto, Satu/0000-0002-8668-3046; Bovet, Pascal/0000-0002-0242-4259; Bochud, Murielle/0000-0002-5727-0218; Deloukas, Panos/0000-0001-9251-070X; Feitosa, Mary/0000-0002-0933-2410; Erdmann, Jeanette/0000-0002-4486-6231; Stitziel, Nathan/0000-0002-4963-8211; Lakka, Timo/0000-0002-9199-2871; Ferrario, Marco M/0000-0003-2741-7124 FU National Center for Research Resources [TL1RR024133]; National Center for Advancing Translational Sciences of the NIH [TL1R000138]; Doris Duke Charitable Foundation FX We appreciate the participation and support of participants of the deep clinical phenotyping studies. We thank E. Mohler for assistance in interpretation of cIMT results and J. Billheimer and E. Pashos for helpful discussions. We also acknowledge J. Tabita-Martinez for expert assistance with clinical phenotyping studies. This work was supported in part by an award from the National Center for Research Resources (grant TL1RR024133) and National Center for Advancing Translational Sciences of the NIH (grant TL1R000138) to support patient recruitment. D.B.L. was supported by a fellowship from the Doris Duke Charitable Foundation. S.K. has financial relationships with Novartis, Aegerion, Bristol-Myers Squibb, Sanofi, AstraZeneca, Alnylam, Eli Lilly, Leerink Partners, Merck, Catabasis, Regeneron Genetic Center, San Therapeutics, and Celera. H.S. has financial relationships with MSD Sharp and Dohme, Sanofi-Aventis, and Amgen. S.B. has financial relationships with Boehringer Ingelheim, Bayer, Novartis, Roche, and Thermo Fisher. N.S has financial relationships with Amgen, Sanofi, Astrazeneca, and MSD Sharp and Dohme. A.K. has a financial relationship with Amgen. J.D. has a financial relationship with Novartis. A.T.-H. has financial relationships with Eli Lilly and LGC Genomics. Sequencing data have been deposited in GenBank (SRX1458096). Genotyping data have been deposited in the Gene Expression Omnibus (GSE76065). NR 39 TC 50 Z9 51 U1 11 U2 19 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 MAR 11 PY 2016 VL 351 IS 6278 BP 1166 EP 1171 DI 10.1126/science.aad3517 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DZ8YI UT WOS:000386158400038 PM 26965621 ER PT J AU Kryukov, GV Wilson, FH Ruth, JR Paulk, J Tsherniak, A Marlow, SE Vazquez, F Weir, BA Fitzgerald, ME Tanaka, M Bielski, CM Scott, JM Dennis, C Cowley, GS Boehm, JS Root, DE Golub, TR Clish, CB Bradner, JE Hahn, WC Garraway, LA AF Kryukov, Gregory V. Wilson, Frederick H. Ruth, Jason R. Paulk, Joshiawa Tsherniak, Aviad Marlow, Sara E. Vazquez, Francisca Weir, Barbara A. Fitzgerald, Mark E. Tanaka, Minoru Bielski, Craig M. Scott, Justin M. Dennis, Courtney Cowley, Glenn S. Boehm, Jesse S. Root, David E. Golub, Todd R. Clish, Clary B. Bradner, James E. Hahn, William C. Garraway, Levi A. TI MTAP deletion confers enhanced dependency on the PRMT5 arginine methyltransferase in cancer cells SO SCIENCE LA English DT Article ID METHYLTHIOADENOSINE PHOSPHORYLASE; HOMOZYGOUS DELETION; TUMOR-SUPPRESSOR; SM PROTEINS; GENE; METHYLATION; METHYLOSOME; CODELETION; INHIBITOR; DEFICIENT AB The discovery of cancer dependencies has the potential to inform therapeutic strategies and to identify putative drug targets. Integrating data from comprehensive genomic profiling of cancer cell lines and from functional characterization of cancer cell dependencies, we discovered that loss of the enzyme methylthioadenosine phosphorylase (MTAP) confers a selective dependence on protein arginine methyltransferase 5 (PRMT5) and its binding partner WDR77. MTAP is frequently lost due to its proximity to the commonly deleted tumor suppressor gene, CDKN2A. We observed increased intracellular concentrations of methylthioadenosine (MTA, the metabolite cleaved by MTAP) in cells harboring MTAP deletions. Furthermore, MTA specifically inhibited PRMT5 enzymatic activity. Administration of either MTA or a small-molecule PRMT5 inhibitor showed a modest preferential impairment of cell viability for MTAP-null cancer cell lines compared with isogenic MTAP-expressing counterparts. Together, our findings reveal PRMT5 as a potential vulnerability across multiple cancer lineages augmented by a common "passenger" genomic alteration. C1 [Kryukov, Gregory V.; Wilson, Frederick H.; Ruth, Jason R.; Paulk, Joshiawa; Marlow, Sara E.; Vazquez, Francisca; Weir, Barbara A.; Tanaka, Minoru; Bielski, Craig M.; Bradner, James E.; Hahn, William C.; Garraway, Levi A.] Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Kryukov, Gregory V.; Wilson, Frederick H.; Ruth, Jason R.; Paulk, Joshiawa; Tsherniak, Aviad; Marlow, Sara E.; Vazquez, Francisca; Weir, Barbara A.; Fitzgerald, Mark E.; Tanaka, Minoru; Bielski, Craig M.; Scott, Justin M.; Dennis, Courtney; Cowley, Glenn S.; Boehm, Jesse S.; Root, David E.; Golub, Todd R.; Clish, Clary B.; Bradner, James E.; Hahn, William C.; Garraway, Levi A.] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. RP Garraway, LA (reprint author), Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA.; Garraway, LA (reprint author), Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. EM levi_garraway@dfci.harvard.edu FU Slim Initiative in Genomic Medicine for the Americas project; Novartis Institutes for BioMedical Research; Dr. Miriam and Sheldon G. Adelson Medical Research Foundation; Melanoma Research Alliance; NIH; Integrative Cancer Biology Program [U54 CA112962]; NIH [U01 CA176058]; Conquer Cancer Foundation of the American Society of Clinical Oncology; AACR-Bristol-Myers Squibb [14-40-15-WILS]; Karin Grunebaum Cancer Research Foundation; Harvard Catalyst/The Harvard Clinical and Translational Science Center (National Center for Research Resources); Harvard Catalyst/The Harvard Clinical and Translational Science Center (National Center for Advancing Translational Sciences, NIH) [KL2 TR001100]; Novartis; Boehringer Ingelheim; Foundation Medicine FX Data from Project Achilles and the Cancer Cell Line Encyclopedia can be accessed at www.broadinstitute.org/achilles and www.broadinstitute.org/ccle/home, respectively. We thank members of the Garraway laboratory for helpful discussion. We thank D. Hernandez for assistance with seeding cell lines for metabolomics studies. We gratefully acknowledge the Carlos Slim Foundation for providing access to shRNA screening data (funded in part by the Slim Initiative in Genomic Medicine for the Americas project) for validation studies. Funding for this work was provided by the Novartis Institutes for BioMedical Research, the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, the Melanoma Research Alliance, a NIH PO1 Research Program Project grant (each to L.A.G.), an Integrative Cancer Biology Program grant (U54 CA112962 to T.R.G.), and an NIH U01 CA176058 (to W.C.H.). F.H.W. is supported by a Conquer Cancer Foundation of the American Society of Clinical Oncology Young Investigator Award, the 2014 AACR-Bristol-Myers Squibb Oncology Fellowship in Clinical Cancer Research (grant 14-40-15-WILS), a grant from the Karin Grunebaum Cancer Research Foundation, and a KL2/Catalyst Medical Research Investigator Training award (an appointed KL2 award) from Harvard Catalyst/The Harvard Clinical and Translational Science Center (National Center for Research Resources and the National Center for Advancing Translational Sciences, NIH Award KL2 TR001100). G.V.K., A.T., F.V., B.A.W., and C.M.B. performed computational analysis of data sets generated from Project Achilles and CCLE under the supervision of J.S.B., T.R.G., W.C.H., and L.A.G. G.S.C., D.E.R., and W.C.H. supervised the generation of Project Achilles screening data. F.H.W. and S.E.M. performed experiments to validate the computational shRNA screening findings. G.V.K., F.H.W., S.E.M., J.M.S., C.D., and C.B.C. performed metabolomic studies and analyzed data. Isogenic cell line pairs were generated and characterized by F.H.W. and J.R.R. J.R.R. conducted cell viability IC50 experiments and the MTA methyltransferase selectivity assay. J.P. performed the MTA mechanism of action study under the supervision of J.E.B. M.E.F. and M.T. synthesized EPZ015666 under the supervision of J.E.B. F.H.W., G.V.K., J.R.R., and L.A.G. wrote the manuscript. L.A.G. is a paid consultant for Novartis and Boehringer Ingelheim; he holds equity in, and is a paid consultant for, Foundation Medicine; and he is a recipient of a grant from Novartis. W.C.H. is a paid consultant for Novartis and recipient of a grant from Novartis. M.T. is a visiting scientist from Mitsubishi Tanabe Pharma Corporation (MTPC) and a recipient of nonresearch support from MTPC. The Broad Institute and the authors (L.A.G., F.H.W., G.V.K., and J.R.R.) have filed a patent application (BI2015/040 46783.00.2109 US PRO Pending 62/131,825) relating to the use of PRMT5 inhibitors to treat MTAP-deficient tumors. NR 33 TC 24 Z9 24 U1 6 U2 13 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 EI 1095-9203 J9 SCIENCE JI Science PD MAR 11 PY 2016 VL 351 IS 6278 BP 1214 EP 1218 DI 10.1126/science.aad5214 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DZ8YI UT WOS:000386158400049 PM 26912360 ER PT J AU Pal, SK Agarwal, N Grivas, P Choueiri, T AF Pal, Sumanta K. Agarwal, Neeraj Grivas, Petros Choueiri, Toni TI Adjuvant Chemotherapy for Bladder Cancer: Using Population-Based Data to Fill a Void of Prospective Evidence SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Editorial Material ID PHASE-III TRIAL; NEOADJUVANT CHEMOTHERAPY; UROTHELIAL CARCINOMA; RADICAL CYSTECTOMY; METAANALYSIS; CISPLATIN C1 [Pal, Sumanta K.] City Hope Comprehens Canc Ctr, Duarte, CA USA. [Agarwal, Neeraj] Univ Utah, Huntsman Canc Inst, Salt Lake City, UT USA. [Grivas, Petros] Cleveland Clin, Taussig Canc Inst, Cleveland, OH 44106 USA. [Choueiri, Toni] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Pal, SK (reprint author), City Hope Comprehens Canc Ctr, Duarte, CA USA. NR 15 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 MAR 10 PY 2016 VL 34 IS 8 BP 777 EP + DI 10.1200/JCO.2015.65.4368 PG 4 WC Oncology SC Oncology GA DJ6OV UT WOS:000374333700007 PM 26786913 ER PT J AU Demetri, GD von Mehren, M Jones, RL Hensley, ML Schuetze, SM Staddon, A Milhem, M Elias, A Ganjoo, K Tawbi, H Van Tine, BA Spira, A Dean, A Khokhar, NZ Park, YC Knoblauch, RE Parekh, TV Maki, RG Patel, SR AF Demetri, George D. von Mehren, Margaret Jones, Robin L. Hensley, Martee L. Schuetze, Scott M. Staddon, Arthur Milhem, Mohammed Elias, Anthony Ganjoo, Kristen Tawbi, Hussein Van Tine, Brian A. Spira, Alexander Dean, Andrew Khokhar, Nushmia Z. Park, Youn Choi Knoblauch, Roland E. Parekh, Trilok V. Maki, Robert G. Patel, Shreyaskumar R. TI Efficacy and Safety of Trabectedin or Dacarbazine for Metastatic Liposarcoma or Leiomyosarcoma After Failure of Conventional Chemotherapy: Results of a Phase III Randomized Multicenter Clinical Trial SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID SOFT-TISSUE SARCOMAS; DOXORUBICIN PLUS IFOSFAMIDE; EUROPEAN-ORGANIZATION; 1ST-LINE TREATMENT; ECTEINASCIDIN-743; GEMCITABINE; ANTITUMOR; EORTC; PAZOPANIB; PLACEBO AB Purpose This multicenter study, to our knowledge, is the first phase III trial to compare trabectedin versus dacarbazine in patients with advanced liposarcoma or leiomyosarcoma after prior therapy with an anthracycline and at least one additional systemic regimen. Patients and Methods Patients were randomly assigned in a 2:1 ratio to receive trabectedin or dacarbazine intravenously every 3 weeks. The primary end point was overall survival (OS), secondary end points were disease control-progression-free survival (PFS), time to progression, objective response rate, and duration of response-as well as safety and patient-reported symptom scoring. Results A total of 518 patients were enrolled and randomly assigned to either trabectedin (n = 345) or dacarbazine (n - 173). In the final analysis of PFS, trabectedin administration resulted in a 45% reduction in the risk of disease progression or death compared with dacarbazine (median PFS for trabectedin v dacarbazine, 4.2 v 1.5 months; hazard ratio, 0.55; P < . 001); benefits were observed across all preplanned subgroup analyses. The interim analysis of OS (64% censored) demonstrated a 13% reduction in risk of death in the trabectedin arm compared with dacarbazine (median OS for trabectedin v dacarbazine, 12.4 v 12.9 months; hazard ratio, 0.87; P = .37). The safety profiles were consistent with the well-characterized toxicities of both agents, and the most common grade 3 to 4 adverse effects were myelosuppression and transient elevation of transaminases in the trabectedin arm. Conclusion Trabectedin demonstrates superior disease control versus conventional dacarbazine in patients who have advanced liposarcoma and leiomyosarcoma after they experience failure of prior chemotherapy. Because disease control in advanced sarcomas is a clinically relevant end point, this study supports the activity of trabectedin for patients with these malignancies. (C) 2015 by American Society of Clinical Oncology C1 [Demetri, George D.] Dana Farber Canc Inst, Boston, MA USA. [Demetri, George D.] Ludwig Ctr Harvard, Boston, MA USA. [von Mehren, Margaret] Fox Chase Canc Ctr, Philadelphia, PA USA. [Staddon, Arthur] Univ Penn, Philadelphia, PA 19104 USA. [Tawbi, Hussein] Univ Pittsburgh, Inst Canc, Philadelphia, PA USA. [Jones, Robin L.] Seattle Canc Care Alliance, Seattle, WA USA. [Hensley, Martee L.] Mem Sloan Kettering Canc Ctr, New York, NY USA. [Maki, Robert G.] Mt Sinai Med Ctr, New York, NY 10029 USA. [Schuetze, Scott M.] Univ Michigan, Ann Arbor, MI 48109 USA. [Milhem, Mohammed] Univ Iowa Hosp & Clin, Iowa City, IA 52242 USA. [Elias, Anthony] Univ Colorado, Ctr Canc, Aurora, CO USA. [Ganjoo, Kristen] Stanford Hosp & Clin, Stanford, CA USA. [Van Tine, Brian A.] Washington Univ, St Louis, MO USA. [Spira, Alexander] Virginia Canc Specialists, Fairfax, VA USA. [Dean, Andrew] St John God Hosp, Bendat Canc Ctr, Subiaco, WA, Australia. [Khokhar, Nushmia Z.; Park, Youn Choi; Knoblauch, Roland E.; Parekh, Trilok V.] Janssen Res & Dev, Raritan, NJ USA. [Patel, Shreyaskumar R.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. RP Demetri, GD (reprint author), Harvard Univ, Sch Med, Ludwig Ctr Harvard, 450 Brookline Ave, Boston, MA 02215 USA.; Demetri, GD (reprint author), Dana Farber Canc Inst, Ctr Sarcoma & Bone Oncol, 450 Brookline Ave, Boston, MA 02215 USA. EM george_demetri@dfci.harvard.edu FU Janssen Pharmaceuticals; Adelson Medical Research Foundation FX Supported by Janssen Pharmaceuticals, and supported in part by the Adelson Medical Research Foundation (G.D.D.). NR 39 TC 58 Z9 60 U1 4 U2 7 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 MAR 10 PY 2016 VL 34 IS 8 BP 786 EP + DI 10.1200/JCO.2015.62.4734 PG 10 WC Oncology SC Oncology GA DJ6OV UT WOS:000374333700009 PM 26371143 ER PT J AU Long, GV Weber, JS Infante, JR Kim, KB Daud, A Gonzalez, R Sosman, JA Hamid, O Schuchter, L Cebon, J Kefford, RF Lawrence, D Kudchadkar, R Burris, HA Falchook, GS Algazi, A Lewis, K Puzanov, I Ibrahim, N Sun, P Cunningham, E Kline, AS Buono, H OpattMcDowell, D Patel, K Flaherty, KT AF Long, Georgina V. Weber, Jeffrey S. Infante, Jeffrey R. Kim, Kevin B. Daud, Adil Gonzalez, Rene Sosman, Jeffrey A. Hamid, Omid Schuchter, Lynn Cebon, Jonathan Kefford, Richard F. Lawrence, Donald Kudchadkar, Ragini Burris, Howard A., III Falchook, Gerald S. Algazi, Alain Lewis, Karl Puzanov, Igor Ibrahim, Nageatte Sun, Peng Cunningham, Elizabeth Kline, Amy S. Buono, HeatherDel OpattMcDowell, Diane Patel, Kiran Flaherty, Keith T. TI Overall Survival and Durable Responses in Patients With BRAF V600-Mutant Metastatic Melanoma Receiving Dabrafenib Combined With Trametinib SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID ACQUIRED-RESISTANCE; MEK INHIBITION; UNTREATED MELANOMA; MUTATED MELANOMA; OPEN-LABEL; IPILIMUMAB; NIVOLUMAB; EFFICACY; SAFETY; VEMURAFENIB AB Purpose To report the overall survival (OS) and clinical characteristics of BRAF inhibitor-naive long-term responders and survivors treated with dabrafenib plus trametinib in a phase I and II study of patients with BRAF V600 mutation-positive metastatic melanoma. Methods BRAF inhibitor-naive patients treated with dabrafenib 150 mg twice daily plus trametinib 2 mg daily (the 150/2 group) from the non-randomly assigned (part B) and randomly assigned (part C) cohorts of the study were analyzed for progression-free and OS separately. Baseline characteristics and factors on treatment were analyzed for associations with durable responses and OS. Results For BRAF inhibitor-naive patients in the 150/2 groups (n = 78), the progression-free survival at 1, 2, and 3 years was 44%, 22%, and 18%, respectively, for part B (n = 24) and 41%, 25%, and 21%, respectively, for part C (n = 54). Median OS was 27.4 months in part B and 25 months in part C. OS at 1, 2, and 3 years was 72%, 60%, and 47%, respectively, for part B and 80%, 51%, and 38%, respectively, for part C. Prolonged survival was associated with metastases in fewer than three organ sites and lower baseline lactate dehydrogenase. OS at 3 years was 62% in patients with normal baseline lactate dehydrogenase and 63% in patients with a complete response. Conclusion Dabrafenib plus trametinib results in a median OS of more than 2 years in BRAF inhibitor-naive patients with BRAF V600 mutation-positive metastatic melanoma, and approximately 20% were progression free at 3 years. Durable responses occurred in patients with good prognostic features at baseline, which may be predictive. (C) 2016 by American Society of Clinical Oncology C1 [Long, Georgina V.; Kefford, Richard F.] Melanoma Inst Australia, 40 Rocklands Rd, Sydney, NSW 2060, Australia. [Long, Georgina V.; Kefford, Richard F.] Univ Sydney, 40 Rocklands Rd, Sydney, NSW 2060, Australia. [Kefford, Richard F.] Macquarie Univ, Sydney, NSW 2109, Australia. [Kefford, Richard F.] Westmead Hosp, Westmead, NSW 2145, Australia. [Cebon, Jonathan] Austin Hlth, Melbourne, Vic, Australia. [Weber, Jeffrey S.; Kudchadkar, Ragini] Univ S Florida, H Lee Moffitt Canc Ctr, Tampa, FL 33682 USA. [Infante, Jeffrey R.; Burris, Howard A., III] Sarah Cannon Res Inst Tennessee Oncol, Nashville, TN USA. [Kim, Kevin B.] Calif Pacific Med Ctr, San Francisco, CA USA. [Daud, Adil; Algazi, Alain] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Hamid, Omid] Angeles Clin & Res Inst, Los Angeles, CA USA. [Gonzalez, Rene; Lewis, Karl] Univ Colorado, Boulder, CO 80309 USA. [Falchook, Gerald S.] HealthONE, Sarah Cannon Res Inst, Denver, CO USA. [Sosman, Jeffrey A.; Puzanov, Igor] Vanderbilt Univ, Med Ctr, Nashville, TN USA. [Schuchter, Lynn] Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA. [Ibrahim, Nageatte; Cunningham, Elizabeth] Merck, Kenilworth, NJ USA. [Sun, Peng; Kline, Amy S.; Buono, HeatherDel; OpattMcDowell, Diane] GlaxoSmithKline, Philadelphia, PA USA. [Lawrence, Donald; Patel, Kiran] Incyte Corp, Wilmington, DE USA. [Flaherty, Keith T.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. RP Long, GV (reprint author), Melanoma Inst Australia, 40 Rocklands Rd, Sydney, NSW 2060, Australia.; Long, GV (reprint author), Univ Sydney, 40 Rocklands Rd, Sydney, NSW 2060, Australia. EM georgina.long@sydney.edu.au FU GlaxoSmithKline FX Supported, administered, and sponsored by GlaxoSmithKline. Editorial assistance was provided by SciMentum and funded by GlaxoSmithKline. NR 27 TC 40 Z9 40 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 MAR 10 PY 2016 VL 34 IS 8 BP 871 EP + DI 10.1200/JCO.2015.62.9345 PG 10 WC Oncology SC Oncology GA DJ6OV UT WOS:000374333700019 PM 26811525 ER PT J AU Fathi, AT Lin, WM Durazzo, T Piris, A Sadrzadeh, H Bernardo, L Borger, DR McAfee, SL Kroshinsky, D Chen, YB AF Fathi, Amir T. Lin, William M. Durazzo, Tyler Piris, Adriano Sadrzadeh, Hossein Bernardo, Lindsay Borger, Darrel R. McAfee, Steven L. Kroshinsky, Daniela Chen, Yi-Bin TI Extensive Squamous Cell Carcinoma of the Skin Related to Use of Sorafenib for Treatment of FLT3-Mutant Acute Myeloid Leukemia SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID RAF INHIBITORS; THERAPY; INFLAMMATION; MUTATIONS; PATIENT C1 [Fathi, Amir T.; Lin, William M.; Durazzo, Tyler; Piris, Adriano; Sadrzadeh, Hossein; Bernardo, Lindsay; Borger, Darrel R.; McAfee, Steven L.; Kroshinsky, Daniela; Chen, Yi-Bin] Harvard Univ, Massachusetts Gen Hosp, Ctr Canc, Sch Med, Boston, MA 02114 USA. RP Fathi, AT (reprint author), Harvard Univ, Massachusetts Gen Hosp, Ctr Canc, Sch Med, Boston, MA 02114 USA. FU Seattle Genetics; Millennium Pharmaceuticals; Exelixis; Bayer; Onyx Pharmaceuticals FX Amir T. Fathi, Seattle Genetics, Millennium Pharmaceuticals, Exelixis; Yi-Bin Chen, Bayer, Onyx Pharmaceuticals NR 17 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 MAR 10 PY 2016 VL 34 IS 8 BP E70 EP E72 DI 10.1200/JCO.2013.50.7582 PG 3 WC Oncology SC Oncology GA DJ6OV UT WOS:000374333700003 PM 25024084 ER PT J AU Schrader, KA Stratton, KL Murali, R Laitman, Y Cavallone, L Offit, L Wen, YH Thomas, T Shah, S Rau-Murthy, R Manschreck, C Salo-Mullen, E Otegbeye, E Corines, M Zhang, LY Norton, L Hudis, C Klein, RJ Kauff, ND Robson, M Stadler, ZK Haber, DA Lipkin, SM Friedman, E Foulkes, WD Altshuler, D Vijai, J Offit, K AF Schrader, Kasmintan A. Stratton, Kelly L. Murali, Rajmohan Laitman, Yael Cavallone, Luca Offit, Lily Wen, Yong Hannah Thomas, Tinu Shah, Sohela Rau-Murthy, Rohini Manschreck, Christopher Salo-Mullen, Erin Otegbeye, Ebun Corines, Marina Zhang, Liying Norton, Larry Hudis, Clifford Klein, Robert J. Kauff, Noah D. Robson, Mark Stadler, Zsofia K. Haber, Daniel A. Lipkin, Steven M. Friedman, Eitan Foulkes, William D. Altshuler, David Vijai, Joseph Offit, Kenneth TI Genome Sequencing of Multiple Primary Tumors Reveals a Novel PALB2 Variant SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID CANCER SUSCEPTIBILITY MUTATION; FANCONI-ANEMIA; BREAST-CANCER; BRCA2-INTERACTING PROTEIN; PANCREATIC-CANCER; GENE; OVARIAN C1 [Schrader, Kasmintan A.; Stratton, Kelly L.; Murali, Rajmohan; Offit, Lily; Wen, Yong Hannah; Thomas, Tinu; Shah, Sohela; Rau-Murthy, Rohini; Manschreck, Christopher; Salo-Mullen, Erin; Otegbeye, Ebun; Corines, Marina; Zhang, Liying; Norton, Larry; Hudis, Clifford; Klein, Robert J.; Kauff, Noah D.; Robson, Mark; Stadler, Zsofia K.; Vijai, Joseph; Offit, Kenneth] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. [Laitman, Yael; Friedman, Eitan] Chaim Sheba Med Ctr, IL-52621 Tel Hashomer, Israel. [Laitman, Yael; Friedman, Eitan] Tel Aviv Univ, IL-69978 Tel Aviv, Israel. [Cavallone, Luca] McGill Univ, Jewish Gen Hosp, Lady Davis Inst, Montreal, PQ H3T 1E2, Canada. [Haber, Daniel A.] Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA USA. [Haber, Daniel A.] Harvard Univ, Sch Med, Charlestown, MA USA. [Haber, Daniel A.] Howard Hughes Med Inst, Chevy Chase, MD USA. [Lipkin, Steven M.] Weill Cornell Coll Med, New York, NY USA. [Foulkes, William D.] McGill Univ, Jewish Gen Hosp, Lady Davis Inst, Montreal, PQ H3T 1E2, Canada. [Altshuler, David] Broad Inst Harvard & Massachusetts Inst Technol, Cambridge, MA USA. RP Schrader, KA (reprint author), Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. OI Kauff, Noah/0000-0001-7242-6156; foulkes, william/0000-0001-7427-4651 FU Breast Cancer Research Foundation; Starr Foundation; Susan G. Komen Foundation; Josephine Rothman Truettner Memorial Fund; Weekend to End Breast Cancer-Jewish General Hospital Foundation; Matthew Bell Foundation; Weill-Cornell Medical College Clinical and Translational Sciences Center FX Research support was received from the Breast Cancer Research Foundation, Starr Foundation, Susan G. Komen Foundation, Josephine Rothman Truettner Memorial Fund, Weekend to End Breast Cancer-Jewish General Hospital Foundation, Matthew Bell Foundation, and Weill-Cornell Medical College Clinical and Translational Sciences Center. NR 24 TC 0 Z9 0 U1 2 U2 6 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 MAR 10 PY 2016 VL 34 IS 8 BP E61 EP E67 DI 10.1200/JCO.2013.50.0272 PG 7 WC Oncology SC Oncology GA DJ6OV UT WOS:000374333700001 PM 24982446 ER PT J AU Norton, DJ Nguyen, VA Lewis, MF Reynolds, GO Somers, DC Cronin-Golomb, A AF Norton, Daniel J. Nguyen, Victoria A. Lewis, Michaela F. Reynolds, Gretchen O. Somers, David C. Cronin-Golomb, Alice TI Visuospatial Attention to Single and Multiple Objects Is Independently Impaired in Parkinson's Disease SO PLOS ONE LA English DT Article ID LEFT HEMIPARKINSONS-DISEASE; SUPERIOR-COLLICULUS; PARIETAL CORTEX; TRACKING; NEGLECT; RESOURCES AB Parkinson's disease (PD) is associated with deficits in visuospatial attention. It is as yet unknown whether these attentional deficits begin at a perceptual level or instead reflect disruptions in oculomotor or higher-order processes. In the present study, non-demented individuals with PD and matched normal control adults (NC) participated in two tasks requiring sustained visuospatial attention, both based on a multiple object tracking paradigm. Eye tracking was used to ensure central fixation. In Experiment 1 (26 PD, 21 NC), a pair of identical red dots (one target, one distractor) rotated randomly for three seconds at varied speeds. The task was to maintain the identity of the sole target, which was labeled prior to each trial. PD were less accurate than NC overall (p = .049). When considering only trials where fixation was maintained, however, there was no significant group difference, suggesting that the deficit's origin is closely related to oculomotor processing. To determine whether PD had additional impairment in multifocal attention, in Experiment 2 (25 PD, 15 NC), two targets were presented along with distractors at a moderate speed, along with a control condition in which dots remained stationary. PD were less accurate than NC for moving (p = 0.02) but not stationary targets. This group difference remained significant when considering only trials where fixation was maintained, suggesting the source of the PD deficit was independent from oculomotor processing. Taken together, the results implicate separate mechanisms for single vs. multiple object tracking deficits in PD. C1 [Norton, Daniel J.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Norton, Daniel J.] Harvard Univ, Sch Med, Boston, MA USA. [Nguyen, Victoria A.; Reynolds, Gretchen O.; Somers, David C.; Cronin-Golomb, Alice] Boston Univ, Dept Psychol & Brain Sci, Boston, MA 02215 USA. [Lewis, Michaela F.] Brown Univ, Dept Neurosci, Providence, RI 02912 USA. RP Norton, DJ (reprint author), Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA.; Norton, DJ (reprint author), Harvard Univ, Sch Med, Boston, MA USA. EM danieljnorton@gmail.com FU NINDS [F31 NS07682, RO1NS067128]; NEI [R01EY022229] FX This research was supported by NINDS (F31 NS07682 to DJN; RO1NS067128 to ACG) and NEI (R01EY022229 to DCS). NR 42 TC 0 Z9 0 U1 4 U2 9 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 10 PY 2016 VL 11 IS 3 AR e0150013 DI 10.1371/journal.pone.0150013 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DG3TL UT WOS:000371993000023 PM 26963388 ER PT J AU Fedorenko, IV Abel, EV Koomen, JM Fang, B Wood, ER Chen, YA Fisher, KJ Iyengar, S Dahlman, KB Wargo, JA Flaherty, KT Sosman, JA Sondak, VK Messina, JL Gibney, GT Smalley, KSM AF Fedorenko, I. V. Abel, E. V. Koomen, J. M. Fang, B. Wood, E. R. Chen, Y. A. Fisher, K. J. Iyengar, S. Dahlman, K. B. Wargo, J. A. Flaherty, K. T. Sosman, J. A. Sondak, V. K. Messina, J. L. Gibney, G. T. Smalley, K. S. M. TI Fibronectin induction abrogates the BRAF inhibitor response of BRAF V600E/PTEN-null melanoma cells SO ONCOGENE LA English DT Article ID EPITHELIAL-MESENCHYMAL TRANSITION; CANCER-CELLS; E-CADHERIN; EXTRACELLULAR-MATRIX; METASTATIC MELANOMA; ADAPTIVE RESISTANCE; DRUG-RESISTANCE; RAF INHIBITORS; UP-REGULATION; LUNG-CANCER AB The mechanisms by which some melanoma cells adapt to Serine/threonine-protein kinase B-Raf (BRAF) inhibitor therapy are incompletely understood. In the present study, we used mass spectrometry-based phosphoproteomics to determine how BRAF inhibition remodeled the signaling network of melanoma cell lines that were BRAF mutant and PTEN null. Short-term BRAF inhibition was associated with marked changes in fibronectin-based adhesion signaling that were PTEN dependent. These effects were recapitulated through BRAF siRNA knockdown and following treatment with chemotherapeutic drugs. Increased fibronectin expression was also observed in mouse xenograft models as well as specimens from melanoma patients undergoing BRAF inhibitor treatment. Analysis of a melanoma tissue microarray showed loss of PTEN expression to predict for a lower overall survival, with a trend for even lower survival being seen when loss of fibronectin was included in the analysis. Mechanistically, the induction of fibronectin limited the responses of these PTEN-null melanoma cell lines to vemurafenib, with enhanced cytotoxicity observed following the knockdown of either fibronectin or its receptor alpha(5)beta(1) integrin. This in turn abrogated the cytotoxic response to BRAF inhibition via increased AKT signaling, which prevented the induction of cell death by maintaining the expression of the pro-survival protein Mcl-1. The protection conveyed by the induction of FN expression could be overcome through combined treatment with a BRAF and PI3K inhibitor. C1 [Fedorenko, I. V.; Koomen, J. M.; Wood, E. R.; Smalley, K. S. M.] Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Dept Mol Oncol, 12902 Magnolia Dr, Tampa, FL 33612 USA. [Abel, E. V.] Thomas Jefferson Univ, Dept Canc Biol, Philadelphia, PA 19107 USA. [Fang, B.; Wood, E. R.] Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Dept Prote, Tampa, FL 33612 USA. [Chen, Y. A.; Fisher, K. J.] Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Dept Biostat & Bioinformat, Tampa, FL 33612 USA. [Iyengar, S.; Sondak, V. K.; Messina, J. L.; Gibney, G. T.; Smalley, K. S. M.] Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Dept Cutaneous Oncol, Tampa, FL 33612 USA. [Dahlman, K. B.; Sosman, J. A.] Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Nashville, TN 37212 USA. [Wargo, J. A.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Flaherty, K. T.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. RP Smalley, KSM (reprint author), Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Dept Mol Oncol, 12902 Magnolia Dr, Tampa, FL 33612 USA. EM keiran.smalley@moffitt.org FU National Institutes of Health [R01 CA161107] FX We thank Gideon Bollag (Plexxikon) for providing vemurafenib and the PLX4720 chow; Noel Clark, Ashley Troutman, Kelli Noyd, Jayme O'Neal and Holly Crandell for assistance with IHC staining; Marta Perez and Monica Torres for assistance with xenograft studies; Agnieszka Kasprazak and Joseph Johnson for assistance with microscopy; and Laura Hall for assistance with qRT-PCR. The work in the Smalley laboratory is supported by R01 CA161107 from the National Institutes of Health. NR 50 TC 11 Z9 11 U1 2 U2 8 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 EI 1476-5594 J9 ONCOGENE JI Oncogene PD MAR 10 PY 2016 VL 35 IS 10 BP 1225 EP 1235 DI 10.1038/onc.2015.188 PG 11 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA DG0NY UT WOS:000371763100003 PM 26073081 ER PT J AU Kellnberger, S Rosenthal, A Myklatun, A Westmeyer, GG Sergiadis, G Ntziachristos, V AF Kellnberger, Stephan Rosenthal, Amir Myklatun, Ahne Westmeyer, Gil G. Sergiadis, George Ntziachristos, Vasilis TI Magnetoacoustic Sensing of Magnetic Nanoparticles SO PHYSICAL REVIEW LETTERS LA English DT Article ID IRON-OXIDE NANOPARTICLES; THERMOACOUSTIC TOMOGRAPHY; FLUID HYPERTHERMIA; REMOTE-CONTROL; FIELD; ULTRASOUND; DELIVERY; CELLS; WAVES; WATER AB The interaction of magnetic nanoparticles and electromagnetic fields can be determined through electrical signal induction in coils due to magnetization. However, the direct measurement of instant electromagnetic energy absorption by magnetic nanoparticles, as it relates to particle characterization or magnetic hyperthermia studies, has not been possible so far. We introduce the theory of magnetoacoustics, predicting the existence of second harmonic pressure waves from magnetic nanoparticles due to energy absorption from continuously modulated alternating magnetic fields. We then describe the first magnetoacoustic system reported, based on a fiber-interferometer pressure detector, necessary for avoiding electric interference. The magnetoacoustic system confirmed the existence of previously unobserved second harmonic magnetoacoustic responses from solids, magnetic nanoparticles, and nanoparticle-loaded cells, exposed to continuous wave magnetic fields at different frequencies. We discuss how magnetoacoustic signals can be employed as a nanoparticle or magnetic field sensor for biomedical and environmental applications. C1 [Kellnberger, Stephan] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiovasc Res Ctr,Cardiol Div, 185 Cambridge St, Boston, MA 02114 USA. [Kellnberger, Stephan; Rosenthal, Amir; Ntziachristos, Vasilis] Tech Univ Munich, Chair Biol Imaging, Trogerstr 9, D-81675 Munich, Germany. [Kellnberger, Stephan; Rosenthal, Amir; Myklatun, Ahne; Westmeyer, Gil G.; Ntziachristos, Vasilis] Helmholtz Zentrum Munchen, Inst Biol & Med Imaging, Ingolstodter Landstr 1, D-85764 Munich, Germany. [Rosenthal, Amir] Technion Israel Inst Technol, Andrew & Erna Viterbi Fac Elect Engn, IL-32000 Haifa, Israel. [Myklatun, Ahne; Westmeyer, Gil G.] Helmholtz Zentrum Munchen, IDG, Ingolstodter Landstr 1, D-85764 Munich, Germany. [Westmeyer, Gil G.] Tech Univ Munich, Dept Nucl Med, Ismaninger Str 22, D-81675 Munich, Germany. [Sergiadis, George] Aristotle Univ Thessaloniki, Dept Elect & Comp Engn, Thessaloniki 54124, Greece. RP Kellnberger, S (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiovasc Res Ctr,Cardiol Div, 185 Cambridge St, Boston, MA 02114 USA.; Kellnberger, S; Ntziachristos, V (reprint author), Tech Univ Munich, Chair Biol Imaging, Trogerstr 9, D-81675 Munich, Germany.; Kellnberger, S; Ntziachristos, V (reprint author), Helmholtz Zentrum Munchen, Inst Biol & Med Imaging, Ingolstodter Landstr 1, D-85764 Munich, Germany. EM stephan.kellnberger@tum.de; v.ntziachristos@tum.de FU Alexander von Humboldt-Stiftung through a Feodor Lynen Research Fellowship; German Research Foundation (DFG) Research [RO 4268/4-1]; DFG Reinhart Koselleck [NT 3/9-1] FX We acknowledge financial support from the Alexander von Humboldt-Stiftung through a Feodor Lynen Research Fellowship, from the German Research Foundation (DFG) Research Grant No. RO 4268/4-1, and support from the DFG Reinhart Koselleck award "High resolution near-field thermoacoustic sensing and imaging" Research Grant No. NT 3/9-1. NR 46 TC 2 Z9 2 U1 12 U2 23 PU AMER PHYSICAL SOC PI COLLEGE PK PA ONE PHYSICS ELLIPSE, COLLEGE PK, MD 20740-3844 USA SN 0031-9007 EI 1079-7114 J9 PHYS REV LETT JI Phys. Rev. Lett. PD MAR 10 PY 2016 VL 116 IS 10 AR 108103 DI 10.1103/PhysRevLett.116.108103 PG 6 WC Physics, Multidisciplinary SC Physics GA DF9ZX UT WOS:000371722500011 PM 27015511 ER PT J AU Mendonca, ME Simis, M Grecco, LC Battistella, LR Baptista, AF Fregni, F AF Mendonca, Mariana E. Simis, Marcel Grecco, Luanda C. Battistella, Linamara R. Baptista, Abrahao F. Fregni, Felipe TI Transcranial Direct Current Stimulation Combined with Aerobic Exercise to Optimize Analgesic Responses in Fibromyalgia: A Randomized Placebo-Controlled Clinical Trial SO FRONTIERS IN HUMAN NEUROSCIENCE LA English DT Article DE transcranial direct current stimulation (tDCS); fibromyalgia; aerobic exercise; combined therapy; motor cortex ID MAGNETIC STIMULATION; MOTOR CORTEX; CHRONIC PAIN; INTRACORTICAL INHIBITION; NEUROPATHIC PAIN; DC STIMULATION; PLASTICITY; BRAIN; TDCS; COGNITION AB Fibromyalgia is a chronic pain syndrome that is associated with maladaptive plasticity in neural central circuits. One of the neural circuits that are involved in pain in fibromyalgia is the primary motor cortex. We tested a combination intervention that aimed to modulate the motor system: transcranial direct current stimulation (tDCS) of the primary motor cortex (M1) and aerobic exercise (AE). In this phase II, sham-controlled randomized clinical trial, 45 subjects were assigned to 1 of 3 groups: tDCS + AE, AE only, and tDCS only. The following outcomes were assessed: intensity of pain, level of anxiety, quality of life, mood, pressure pain threshold, and cortical plasticity, as indexed by transcranial magnetic stimulation. There was a significant effect for the group-time interaction for intensity of pain, demonstrating that tDCS/AE was superior to AE [F-(13,F- 364) = 2.25, p = 0.007] and tDCS [F-(13,F- 364) = 2.33, p = 0.0056] alone. Post-hoc adjusted analysis showed a difference between tDCS/AE and tDCS group after the first week of stimulation and after 1 month intervention period (p = 0.02 and p = 0.03, respectively). Further, after treatment there was a significant difference between groups in anxiety and mood levels. The combination treatment effected the greatest response. The three groups had no differences regarding responses in motor cortex plasticity, as assessed by TMS. The combination of tDCS with aerobic exercise is superior compared with each individual intervention (cohen's d effect sizes > 0.55). The combination intervention had a significant effect on pain, anxiety and mood. Based on the similar effects on cortical plasticity outcomes, the combination intervention might have affected other neural circuits, such as those that control the affective-emotional aspects of pain. C1 [Mendonca, Mariana E.; Fregni, Felipe] Univ Sao Paulo, Inst Psychol, Dept Neurosci & Behav, Sao Paulo, Brazil. [Simis, Marcel; Battistella, Linamara R.] Univ Sao Paulo, Sch Med, Gen Hosp, Phys & Rehabil Med Inst, Sao Paulo, Brazil. [Grecco, Luanda C.] Pediat Neurosurg Ctr Rehabil CENEPE, Sao Paulo, Brazil. [Grecco, Luanda C.; Fregni, Felipe] Harvard Univ, Sch Med, Dept Phys Med & Rehabil, Spaulding Rehabil Hosp,Lab Neuromodulat, Boston, MA USA. [Grecco, Luanda C.; Fregni, Felipe] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Baptista, Abrahao F.] Univ Fed Bahia, Dept Biomorphol, Lab Funct Electrostimulat, BR-41170290 Salvador, BA, Brazil. RP Fregni, F (reprint author), Univ Sao Paulo, Inst Psychol, Dept Neurosci & Behav, Sao Paulo, Brazil.; Fregni, F (reprint author), Harvard Univ, Sch Med, Dept Phys Med & Rehabil, Spaulding Rehabil Hosp,Lab Neuromodulat, Boston, MA USA.; Fregni, F (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. EM felipe.fregni@ppcr.hms.harvard.edu RI Grecco , Luanda/N-5075-2015 FU Brazilian funding agency Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES); Brazilian funding agency Fundacao de Amparo a Pesquisa do Estado de Sao Paulo [FAPESP 2012/06519-5] FX This study was supported by the Brazilian funding agencies Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES) and Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP 2012/06519-5). The authors are grateful to Angela Valle for help in the recruitment and to Fernanda Rezende and Mariana Vita for their help in the data collection. The authors are also grateful to Fernanda Oliveira for the graphical art of the article. NR 42 TC 4 Z9 4 U1 3 U2 11 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1662-5161 J9 FRONT HUM NEUROSCI JI Front. Hum. Neurosci. PD MAR 10 PY 2016 VL 10 AR 68 DI 10.3389/fnhum.2016.00068 PG 12 WC Neurosciences; Psychology SC Neurosciences & Neurology; Psychology GA DF8WN UT WOS:000371641400001 PM 27014012 ER PT J AU Yajnik, V McDermott, S Khalili, H Everett, JM AF Yajnik, Vijay McDermott, Shaunagh Khalili, Hamed Everett, Jamie M. TI Case 7-2016: An 80-Year-Old Man with Weight Loss, Abdominal Pain, Diarrhea, and an Ileocecal Mass SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID INTESTINAL TUBERCULOSIS; CROHNS-DISEASE C1 [Yajnik, Vijay; Khalili, Hamed] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [McDermott, Shaunagh] Massachusetts Gen Hosp, Dept Radiol, Boston, MA USA. [Everett, Jamie M.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Yajnik, Vijay; Khalili, Hamed] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [McDermott, Shaunagh] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Everett, Jamie M.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Yajnik, V (reprint author), Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA.; Yajnik, V (reprint author), Harvard Univ, Sch Med, Dept Med, Boston, MA USA. FU AbbVie FX Dr. Khalili reports receiving consulting fees from AbbVie. No other potential conflict of interest relevant to this article was reported. NR 8 TC 1 Z9 1 U1 1 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 MAR 10 PY 2016 VL 374 IS 10 BP 970 EP 979 DI 10.1056/NEJMcpc1509455 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA DF9DH UT WOS:000371660000012 PM 26962732 ER PT J AU Rubin, EJ Greene, MF Baden, LR AF Rubin, Eric J. Greene, Michael F. Baden, Lindsey R. TI Zika Virus and Microcephaly SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID INFECTION C1 [Rubin, Eric J.] Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, 665 Huntington Ave, Boston, MA 02115 USA. [Greene, Michael F.] Massachusetts Gen Hosp, Dept Obstet & Gynecol, Boston, MA 02114 USA. RP Rubin, EJ (reprint author), Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, 665 Huntington Ave, Boston, MA 02115 USA. NR 7 TC 35 Z9 40 U1 7 U2 44 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 MAR 10 PY 2016 VL 374 IS 10 BP 984 EP 985 DI 10.1056/NEJMe1601862 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA DF9DH UT WOS:000371660000015 PM 26862812 ER PT J AU Haynes, BF Shaw, GM Korber, B Kelsoe, G Sodroski, J Hahn, BH Borrow, P McMichael, AJ AF Haynes, Barton F. Shaw, George M. Korber, Bette Kelsoe, Garnett Sodroski, Joseph Hahn, Beatrice H. Borrow, Persephone McMichael, Andrew J. TI HIV-Host Interactions: Implications for Vaccine Design SO CELL HOST & MICROBE LA English DT Review ID BROADLY NEUTRALIZING ANTIBODIES; HIGHLY PATHOGENIC SIV; T-CELL RESPONSES; TEST-OF-CONCEPT; GERMINAL-CENTER; RHESUS-MONKEYS; B-CELLS; IMMUNE-RESPONSES; TRANSMITTED-FOUNDER; PROTECTIVE EFFICACY AB Development of an effective AIDS vaccine is a global priority. However, the extreme diversity of HIV type 1 (HIV-1), which is a consequence of its propensity to mutate to escape immune responses, along with host factors that prevent the elicitation of protective immune responses, continue to hinder vaccine development. Breakthroughs in understanding of the biology of the transmitted virus, the structure and nature of its envelope trimer, vaccine-induced CD8 T cell control in primates, and host control of broadly neutralizing antibody elicitation have given rise to new vaccine strategies. Despite this promise, emerging data from preclinical trials reinforce the need for additional insight into virus-host biology in order to facilitate the development of a successful vaccine. C1 [Haynes, Barton F.] Duke Univ, Dept Med, Durham, NC 27710 USA. [Haynes, Barton F.; Kelsoe, Garnett] Duke Univ, Dept Immunol, Durham, NC 27710 USA. [Haynes, Barton F.; Kelsoe, Garnett] Duke Univ, Human Vaccine Inst, Durham, NC 27710 USA. [Shaw, George M.; Hahn, Beatrice H.] Univ Penn, Dept Med, Perelman Sch Med, Philadelphia, PA 19104 USA. [Shaw, George M.] Univ Penn, Dept Microbiol, Perelman Sch Med, Philadelphia, PA 19104 USA. [Korber, Bette] Los Alamos Natl Lab, POB 1663, Los Alamos, NM 87544 USA. [Sodroski, Joseph] Harvard Univ, Dana Farber Canc Inst, Harvard Med Sch, Boston, MA 02215 USA. [Borrow, Persephone; McMichael, Andrew J.] Univ Oxford, Nuffield Dept Clin Med, Oxford OX3 7FZ, England. RP Haynes, BF (reprint author), Duke Univ, Dept Med, Durham, NC 27710 USA.; Haynes, BF (reprint author), Duke Univ, Dept Immunol, Durham, NC 27710 USA.; Haynes, BF (reprint author), Duke Univ, Human Vaccine Inst, Durham, NC 27710 USA. EM barton.haynes@duke.edu OI Korber, Bette/0000-0002-2026-5757 FU Division of AIDS, NIH, NIAID [UM1-AI10064]; Bill and Melinda Gates Foundation FX This work was supported by the Division of AIDS, NIH, NIAID grant UM1-AI10064 for the Duke Center for HIV/AIDS Vaccine Immunology-Immunogen Discovery and Collaboration for AIDS Vaccine Discovery grants from the Bill and Melinda Gates Foundation to B.F.H. We thank Todd Bradley and Kevin Wiehe for Figure 3. The authors thank Kelly Soderberg, Thomas Denny, Cherie Lahti, and Stuart Shapiro for administrative leadership and all of our collaborators in the Duke CHAVI and CHAVI-ID for their invaluable work over the past 10 years. We apologize that due to space limitations we could not fully reference all the fine work of our colleagues in the field. We thank Stephanie Risbon for expert secretarial assistance. NR 115 TC 22 Z9 22 U1 9 U2 11 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 MAR 9 PY 2016 VL 19 IS 3 BP 292 EP 303 DI 10.1016/j.chom.2016.02.002 PG 12 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA DH0FI UT WOS:000372457500007 PM 26922989 ER PT J AU Monaco, CL Gootenberg, DB Zhao, GY Handley, SA Ghebremichael, MS Lim, ES Lankowski, A Baldridge, MT Wilen, CB Flagg, M Norman, JM Keller, BC Luevano, JM Wang, D Boum, Y Martin, JN Hunt, PW Bangsberg, DR Siedner, MJ Kwon, DS Virgin, HW AF Monaco, Cynthia L. Gootenberg, David B. Zhao, Guoyan Handley, Scott A. Ghebremichael, Musie S. Lim, Efrem S. Lankowski, Alex Baldridge, Megan T. Wilen, Craig B. Flagg, Meaghan Norman, Jason M. Keller, Brian C. Luevano, Jesus Mario Wang, David Boum, Yap Martin, Jeffrey N. Hunt, Peter W. Bangsberg, David R. Siedner, Mark J. Kwon, Douglas S. Virgin, Herbert W. TI Altered Virome and Bacterial Microbiome in Human Immunodeficiency Virus-Associated Acquired Immunodeficiency Syndrome SO CELL HOST & MICROBE LA English DT Article ID SYSTEMIC IMMUNE ACTIVATION; CHRONIC HIV-INFECTION; ENTERIC VIROME; TT VIRUS; TRANSLOCATION; MUCOSAL; DISEASE; PATHOGENESIS; COMMUNITIES; PREVALENCE AB Human immunodeficiency virus (HIV) infection is associated with increased intestinal translocation of microbial products and enteropathy as well as alterations in gut bacterial communities. However, whether the enteric virome contributes to this infection and resulting immunodeficiency remains unknown. We characterized the enteric virome and bacterial microbiome in a cohort of Ugandan patients, including HIV-uninfected or HIV-infected subjects and those either treated with anti-retroviral therapy (ART) or untreated. Low peripheral CD4 T cell counts were associated with an expansion of enteric adenovirus sequences and this increase was independent of ART treatment. Additionally, the enteric bacterial microbiome of patients with lower CD4 T counts exhibited reduced phylogenetic diversity and richness with specific bacteria showing differential abundance, including increases in Enterobacteriaceae, which have been associated with inflammation. Thus, immunodeficiency in progressive HIV infection is associated with alterations in the enteric virome and bacterial microbiome, which may contribute to AIDS-associated enteropathy and disease progression. C1 [Monaco, Cynthia L.; Keller, Brian C.] Washington Univ, Sch Med, Dept Med, St Louis, MO 63110 USA. [Gootenberg, David B.; Ghebremichael, Musie S.; Flagg, Meaghan; Luevano, Jesus Mario; Kwon, Douglas S.] Ragon Inst MGH MIT & Harvard, Cambridge, MA 02139 USA. [Zhao, Guoyan; Handley, Scott A.; Lim, Efrem S.; Baldridge, Megan T.; Wilen, Craig B.; Wang, David; Virgin, Herbert W.] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO 63110 USA. [Norman, Jason M.] Vedanta Biosci, Cambridge, MA 02139 USA. [Lim, Efrem S.; Wang, David] Washington Univ, Sch Med, Dept Mol Microbiol, St Louis, MO 63110 USA. [Lankowski, Alex; Bangsberg, David R.; Siedner, Mark J.; Kwon, Douglas S.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Lankowski, Alex; Bangsberg, David R.; Siedner, Mark J.; Kwon, Douglas S.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Boum, Yap] Med Sans Frontieres Epictr, Mbarara 1956, Uganda. [Martin, Jeffrey N.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Hunt, Peter W.] Univ Calif San Francisco, Dept Med, San Francisco, CA 94110 USA. [Bangsberg, David R.] Harvard Univ, Sch Publ Hlth, Boston, MA 02114 USA. [Keller, Brian C.] Ohio State Univ Hosp, Div Pulm Allergy Crit Care & Sleep Med, Columbus, OH 43210 USA. RP Kwon, DS (reprint author), Ragon Inst MGH MIT & Harvard, Cambridge, MA 02139 USA.; Virgin, HW (reprint author), Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO 63110 USA.; Kwon, DS (reprint author), Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA.; Kwon, DS (reprint author), Harvard Univ, Sch Med, Boston, MA 02114 USA. EM dkwon@mgh.harvard.edu; virgin@wustl.edu RI Keller, Brian/E-2996-2016; OI Keller, Brian/0000-0003-2997-6712; Wilen, Craig/0000-0003-2495-9403; Baldridge, Megan/0000-0002-7030-6131 FU NIH [5T32AI007172-34, 5T32CA009547, 5T32AI007163-35, T32 HL007317-36, P30 AI027763, R01 MH054907, UM1 CA181255]; Harvard CFAR [2P30 AI060354]; Harvard Center for AIDS Research; NCI Cancer Center Support Grant [P30 CA91842]; ICTS/CTSA Grant from the National Center for Research Resources (NCRR) [UL1TR000448]; [R01 MH54907]; [R21 HL124712-01]; [T32DK007191]; [R24 ODO19793]; [R01 OD011170]; [R01 AI111918]; [R01 DK101354]; [K23 MH099916] FX UARTO was funded by R01 MH54907 and R21 HL124712-01 (Bangsberg). The following were supported by NIH training grants: C.L.M. (5T32AI007172-34), M.T.B. (5T32CA009547), J.M.N. (5T32AI007163-35), and B.C.K. (T32 HL007317-36). D.B.G. is supported by a medical student research supplement to training grant T32DK007191. H.W.V., C.L.M., S.A.H., and J.M.N. were supported by R24 ODO19793, R01 OD011170, R01 AI111918, and R01 DK101354. M.J.S. was supported by K23 MH099916, M.G. is supported by Harvard CFAR 2P30 AI060354, and the Harvard Center for AIDS Research. J.N.M. was supported by NIH grants P30 AI027763, R01 MH054907, and UM1 CA181255. We would like to thank the Genome Technology Access Center (GTAC) in the Department of Genetics and Jessica Hoisington-Lopez from the Center for Genome Sciences at Washington University School of Medicine for use of their instruments and sequencing. GTAC is partially supported by NCI Cancer Center Support Grant #P30 CA91842 to the Siteman Cancer Center and by ICTS/CTSA Grant# UL1TR000448 from the National Center for Research Resources (NCRR). This publication is solely the responsibility of the authors and does not necessarily represent the official view of NCRR or NIH. We would like to thank study participants and research nurses for sample collection. NR 55 TC 16 Z9 16 U1 11 U2 21 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 MAR 9 PY 2016 VL 19 IS 3 BP 311 EP 322 DI 10.1016/j.chom.2016.02.011 PG 12 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA DH0FI UT WOS:000372457500009 PM 26962942 ER PT J AU Kasar, S Underbayev, C Hassan, M Ilev, I Degheidy, H Bauer, S Marti, G Lutz, C Raveche, E Batish, M AF Kasar, Siddha Underbayev, Chingiz Hassan, Moinuddin Ilev, Ilko Degheidy, Heba Bauer, Steven Marti, Gerald Lutz, Carol Raveche, Elizabeth Batish, Mona TI Alterations in the mir-15a/16-1 Loci Impairs Its Processing and Augments B-1 Expansion in De Novo Mouse Model of Chronic Lymphocytic Leukemia (CLL) SO PLOS ONE LA English DT Article ID B-CELL LYMPHOCYTOSIS; ZEALAND BLACK MOUSE; SIDE POPULATION; INFRARED-SPECTROSCOPY; DROSHA-DGCR8 COMPLEX; PRIMARY MICRORNA; MATURE MICRORNA; PROGRESSION; EXPRESSION; IDENTIFICATION AB New Zealand Black (NZB) mice, a de novo model of CLL, share multiple characteristics with CLL patients, including decreased expression of miR-15a/16-1. We previously discovered a point mutation and deletion in the 3' flanking region of mir-16-1 of NZB and a similar mutation has been found in a small number of CLL patients. However, it was unknown whether the mutation is the cause for the reduced miR-15a/16-1 expression and CLL development. Using PCR and in vitro microRNA processing assays, we found that the NZB sequence alterations in the mir-15a/16-1 loci result in deficient processing of the precursor forms of miR-15a/16-1, in particular, we observe impaired conversion of pri-miR-15a/16-1 to pre-miR-15a/16-1. The in vitro data was further supported by derivation of congenic strains with replaced mir-15a/16-1 loci at one or both alleles: NZB congenic mice (NmiR+/-) and DBA congenic mice (DmiR-/-). The level of miR-15a/16-1 reflected the configuration of the mir-15a/16-1 loci with DBA congenic mice (DmiR-/-) showing reduced miR-15a levels compared to homozygous wild-type allele, while the NZB congenic mice (NmiR+/-) showed an increase in miR-15a levels relative to homozygous mutant allele. Similar to Monoclonal B-cell Lymphocytosis (MBL), the precursor stage of the human disease, an overall expansion of the B-1 population was observed in DBA congenic mice (DmiR-/-) relative to wild-type (DmiR+/+). These studies support our hypothesis that the mutations in the mir-15a/16-1 loci are responsible for decreased expression of this regulatory microRNA leading to B-1 expansion and CLL development. C1 [Kasar, Siddha; Underbayev, Chingiz; Lutz, Carol; Raveche, Elizabeth; Batish, Mona] Rutgers State Univ, New Jersey Med Sch, Newark, NJ 07103 USA. [Hassan, Moinuddin; Ilev, Ilko; Marti, Gerald] US FDA, OSEL, CDRH, White Oak, MD USA. [Degheidy, Heba; Bauer, Steven] US FDA, CBER, White Oak, MD USA. [Kasar, Siddha] Dana Faber Canc Inst, Boston, MA USA. RP Batish, M (reprint author), Rutgers State Univ, New Jersey Med Sch, Newark, NJ 07103 USA. EM batishmo@njms.rutgers.edu FU NIH [R01CA12926]; NIH Director's Early Independence Award [DP5OD012160-01]; UMDNJ-NJMS Flow Cytometry Core, Molecular Resource Facility; Transgenic Core FX This work was supported by NIH R01CA12926 (ESR) and NIH Director's Early Independence Award DP5OD012160-01 (MB). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.; This work was supported by NIH R01CA12926 (ESR) and NIH Director's Early Independence Award DP5OD012160-01 (MB). We thank the UMDNJ-NJMS Flow Cytometry Core, Molecular Resource Facility and the Transgenic Core for their support. NR 50 TC 1 Z9 1 U1 1 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 9 PY 2016 VL 11 IS 3 AR e0149331 DI 10.1371/journal.pone.0149331 PG 17 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DG3TF UT WOS:000371992300009 PM 26959643 ER PT J AU Wang, SM Blois, A El Rayes, T Liu, JF Hirsch, MS Gravdal, K Palakurthi, S Bielenberg, DR Akslen, LA Drapkin, R Mittal, V Watnick, RS AF Wang, Suming Blois, Anna El Rayes, Tina Liu, Joyce F. Hirsch, Michelle S. Gravdal, Karsten Palakurthi, Sangeetha Bielenberg, Diane R. Akslen, Lars A. Drapkin, Ronny Mittal, Vivek Watnick, Randolph S. TI Development of a prosaposin-derived therapeutic cyclic peptide that targets ovarian cancer via the tumor microenvironment SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID CHAIN FATTY-ACIDS; D-AMINO ACIDS; EPITHELIAL OVARIAN; IN-VITRO; MOUSE MODEL; THROMBOSPONDIN-1; STABILITY; SURVIVAL; CELLS; CD36 AB The vast majority of ovarian cancer-related deaths are caused by metastatic dissemination of tumor cells, resulting in subsequent organ failure. However, despite our increased understanding of the physiological processes involved in tumor metastasis, there are no clinically approved drugs that have made a major impact in increasing the overall survival of patients with advanced, metastatic ovarian cancer. We identified prosaposin (psap) as a potent inhibitor of tumor metastasis, which acts via stimulation of p53 and the antitumorigenic protein thrombospondin-1 (TSP-1) in bone marrow-derived cells that are recruited to metastatic sites. We report that more than 97% of human serous ovarian tumors tested express CD36, the receptor that mediates the proapoptotic activity of TSP-1. Accordingly, we sought to determine whether a peptide derived from psap would be effective in treating this form of ovarian cancer. To that end, we developed a cyclic peptide with drug-like properties derived from the active sequence in psap. The cyclic psap peptide promoted tumor regression in a patient-derived tumor xenograft model of metastatic ovarian cancer. Thus, we hypothesize that a therapeutic agent based on this psap peptide would have efficacy in treating patients with metastatic ovarian cancer. C1 [Wang, Suming; Blois, Anna; Bielenberg, Diane R.; Watnick, Randolph S.] Boston Childrens Hosp, Vasc Biol Program, Boston, MA 02115 USA. [Wang, Suming; Blois, Anna; Bielenberg, Diane R.; Watnick, Randolph S.] Harvard Univ, Sch Med, Dept Surg, Boston, MA 02115 USA. [Blois, Anna; Gravdal, Karsten; Akslen, Lars A.] Univ Bergen, Dept Clin Med, Ctr Canc Biomarkers CCBIO, NO-5020 Bergen, Norway. [El Rayes, Tina; Mittal, Vivek] Weill Cornell Med Coll, Dept Cardiothorac Surg, New York, NY 10065 USA. [El Rayes, Tina; Mittal, Vivek] Weill Cornell Med Coll, Dept Cell & Dev Biol, New York, NY 10065 USA. [El Rayes, Tina; Mittal, Vivek] Weill Cornell Med Coll, Neuberger Berman Lung Canc Ctr, New York, NY 10065 USA. [Liu, Joyce F.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Liu, Joyce F.; Drapkin, Ronny] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Hirsch, Michelle S.; Drapkin, Ronny] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Gravdal, Karsten; Akslen, Lars A.] Haukeland Hosp, Dept Pathol, N-5021 Bergen, Norway. [Palakurthi, Sangeetha] Dana Farber Canc Inst, Belfer Ctr Appl Canc Sci, Boston, MA 02115 USA. [Drapkin, Ronny] Univ Penn, Dept Obstet & Gynecol, Ovarian Canc Res Ctr, Philadelphia, PA 19104 USA. RP Watnick, RS (reprint author), Boston Childrens Hosp, Vasc Biol Program, Boston, MA 02115 USA.; Watnick, RS (reprint author), Harvard Univ, Sch Med, Dept Surg, Boston, MA 02115 USA. EM randy.watnick@childrens.harvard.edu RI Akslen, Lars /C-1202-2017; OI Akslen, Lars /0000-0003-2710-9543; Drapkin, Ronny/0000-0002-6912-6977 FU NIH [CA135417]; Norwegian Cancer Society; Norwegian Research Council; Dr. Miriam and Sheldon G. Adelson Medical Research Foundation; Honorable Tina Brozman Foundation; Cornell Center on the Microenvironment and Metastasis through award from the National Cancer Institute [U54CA143876]; Robert I. Goldman Foundation; Elsa U. Pardee Foundation; Boston Children's Hospital Technology Development Fund; Vascular Biology Program at Boston Children's Hospital; Ovarian Cancer Research Fund; Pallotta Investigator Award; [NIH P50-CA083636]; [NIH U01-CA152990]; [NIH R21-CA156021] FX This study was supported by NIH grant CA135417 to V.M. and R.S.W. and by grants from the Norwegian Cancer Society and the Norwegian Research Council to L.A.A. R.D. was supported by NIH P50-CA083636, NIH U01-CA152990, NIH R21-CA156021, the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, and the Honorable Tina Brozman Foundation. This study was also partially supported by the Cornell Center on the Microenvironment and Metastasis through award no. U54CA143876 from the National Cancer Institute and Robert I. Goldman Foundation to V.M. and by the Elsa U. Pardee Foundation and Boston Children's Hospital Technology Development Fund to R.S.W. D.R.B. and R.S.W. were supported by the Vascular Biology Program at Boston Children's Hospital. J.F.L. received funding from the Ovarian Cancer Research Fund and Pallotta Investigator Award. NR 39 TC 1 Z9 1 U1 1 U2 10 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 MAR 9 PY 2016 VL 8 IS 329 AR 329ra34 DI 10.1126/scitranslmed.aad5653 PG 11 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA DG4YP UT WOS:000372079400006 PM 26962158 ER PT J AU Ito, T Yamada, A Batal, I Yeung, MY McGrath, MM Sayegh, MH Chandraker, A Ueno, T AF Ito, Toshiro Yamada, Akira Batal, Ibrahim Yeung, Melissa Y. McGrath, Martina M. Sayegh, Mohamed H. Chandraker, Anil Ueno, Takuya TI The Limits of Linked Suppression for Regulatory T Cells SO FRONTIERS IN IMMUNOLOGY LA English DT Article DE costimulation; indirect pathway; MHC class II; tolerance; regulatory T cells ID TRANSPLANTATION TOLERANCE; INDIRECT RECOGNITION; GRAFT-REJECTION; CARDIAC ALLOGRAFTS; CUTTING EDGE; SURVIVAL AB Background: We have previously found that CD4+CD25+ regulatory T cells (Tregs) can adoptively transfer tolerance after its induction with costimulatory blockade in a mouse model of murine cardiac allograft transplantation. In these experiments, we tested an hypothesis with three components: (1) the Tregs that transfer tolerance have the capacity for linked suppression, (2) the determinants that stimulate the Tregs are expressed by the indirect pathway, and (3) the donor peptides contributing to these indirect determinants are derived from donor major histocompatibility complex (MHC) antigens (Ags). Methods: First heart transplants were performed from the indicated donor strain to B10. D2 recipients along with costimulatory blockade treatment (250 mu g i.p. injection of MR1 on day 0 and 250 mu g i.p. injection of CTLA-4 Ig on day 2). At least 8 weeks later, a second heart transplant was performed to a new B10.D2 recipient who had been irradiated with 450 cGy. This recipient was given 40 x 106 naive B10.D2 spleen cells + 40 x 106 B10.D2 spleen cells from the first (tolerant) recipient. We performed three different types of heart transplants using various donors. Results: (1) Tregs suppress the graft rejection in an Ag-specific manner. (2) Tregs generated in the face of MHC disparities suppress the rejection of grafts expressing third party MHC along with tolerant MHC. Conclusion: The limits of linkage appear to be quantitative and not universally determined by either the indirect pathway or by peptides of donor MHC Ags. C1 [Ito, Toshiro; Yamada, Akira; Ueno, Takuya] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Transplantat Unit,Surg Serv, Boston, MA USA. [Batal, Ibrahim; Yeung, Melissa Y.; McGrath, Martina M.; Sayegh, Mohamed H.; Chandraker, Anil; Ueno, Takuya] Harvard Univ, Brigham & Womens Hosp, Sch Med, Transplantat Res Ctr, Boston, MA 02115 USA. [Batal, Ibrahim; Yeung, Melissa Y.; McGrath, Martina M.; Sayegh, Mohamed H.; Chandraker, Anil; Ueno, Takuya] Harvard Univ, Childrens Hosp, Sch Med, Boston, MA 02115 USA. RP Ueno, T (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Transplantat Unit,Surg Serv, Boston, MA USA.; Ueno, T (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med, Transplantat Res Ctr, Boston, MA 02115 USA.; Ueno, T (reprint author), Harvard Univ, Childrens Hosp, Sch Med, Boston, MA 02115 USA. EM ueno.takuya@mgh.harvard.edu FU American Heart Association; JSPS KAKENHI; American Heart Association Scientist Development Grant [11SDG5150000]; [15K15179] FX This work was supported by American Heart Association and JSPS KAKENHI. TU is a recipient of the American Heart Association Scientist Development Grant (11SDG5150000) and Grant in Aid for Challenging Exploratory Research (15K15179). NR 17 TC 2 Z9 2 U1 0 U2 1 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1664-3224 J9 FRONT IMMUNOL JI Front. Immunol. PD MAR 9 PY 2016 VL 7 AR 82 DI 10.3389/fimmu.2016.00082 PG 4 WC Immunology SC Immunology GA DF8VN UT WOS:000371638500001 PM 27014262 ER PT J AU Koss, B Ryan, J Budhraja, A Szarama, K Yang, X Bathina, M Cardone, MH Nikolovska-Coleska, Z Letai, A Opferman, JT AF Koss, Brian Ryan, Jeremy Budhraja, Amit Szarama, Katherine Yang, Xue Bathina, Madhavi Cardone, Michael H. Nikolovska-Coleska, Zaneta Letai, Anthony Opferman, Joseph T. TI Defining specificity and on-target activity of BH3-mimetics using engineered B-ALL cell lines SO ONCOTARGET LA English DT Article DE BH3 mimetics; apoptosis; BCL-2; cancer model; drug development ID ACUTE LYMPHOBLASTIC-LEUKEMIA; BCL-2 FAMILY-MEMBERS; STRUCTURE-GUIDED DESIGN; ACUTE MYELOID-LEUKEMIA; X-L INHIBITOR; MCL-1 INHIBITORS; LYMPHOID MALIGNANCIES; ANTIAPOPTOTIC MCL-1; ANTITUMOR-ACTIVITY; HIGH-AFFINITY AB One of the hallmarks of cancer is a resistance to the induction of programmed cell death that is mediated by selection of cells with elevated expression of anti-apoptotic members of the BCL-2 family. To counter this resistance, new therapeutic agents known as BH3-mimetic small molecules are in development with the goal of antagonizing the function of anti-apoptotic molecules and promoting the induction of apoptosis. To facilitate the testing and modeling of BH3-mimetic agents, we have developed a powerful system for evaluation and screening of agents both in culture and in immune competent animal models by engineering mouse leukemic cells and re-programming them to be dependent on exogenously expressed human anti-apoptotic BCL-2 family members. Here we demonstrate that this panel of cell lines can determine the specificity of BH3-mimetics to individual anti-apoptotic BCL-2 family members (BCL-2, BCL-X L, BCL-W, BFL-1, and MCL-1), demonstrate whether cell death is due to the induction of apoptosis (BAX and BAK-dependent), and faithfully assess the efficacy of BH3-mimetic small molecules in pre-clinical mouse models. These cells represent a robust and valuable pre-clinical screening tool for validating the efficacy, selectivity, and on-target action of BH3-mimetic agents. C1 [Koss, Brian; Budhraja, Amit; Szarama, Katherine; Yang, Xue; Bathina, Madhavi; Opferman, Joseph T.] St Jude Childrens Res Hosp, Dept Cell & Mol Biol, 332 N Lauderdale St, Memphis, TN 38105 USA. [Ryan, Jeremy; Letai, Anthony] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Adult Oncol, 44 Binney St, Boston, MA 02115 USA. [Yang, Xue] Univ Tennessee, Ctr Hlth Sci, Integrated Program Biomed Sci, Memphis, TN 38163 USA. [Cardone, Michael H.] Eutropics Inc, Cambridge, MA USA. [Nikolovska-Coleska, Zaneta] Univ Michigan, Sch Med, Dept Pathol, Ann Arbor, MI USA. RP Opferman, JT (reprint author), St Jude Childrens Res Hosp, Dept Cell & Mol Biol, 332 N Lauderdale St, Memphis, TN 38105 USA. EM Joseph.Opferman@stjude.org FU National Institute of Health [R01HL102175, R01CA149442]; American Cancer Society [119130-RSG-10-255-01-LIB]; Cancer Center Support Grant [P30CA021765]; American Lebanese Syrian Associated Charities (ALSAC) of St. Jude FX We thank the members of the Opferman laboratory, Drs. S. Baker and R. K. Guy for helpful discussions. The BH3-mimetic small molecules: navitoclax, venetoclax, A-1210477, and A-1155463 were kindly provided by AbbVie. The project was supported by the National Institute of Health R01HL102175 (J.T.O) and R01CA149442 (Z.N.C.); the American Cancer Society 119130-RSG-10-255-01-LIB (J.T.O); a Cancer Center Support Grant P30CA021765; and the American Lebanese Syrian Associated Charities (ALSAC) of St. Jude. NR 45 TC 4 Z9 4 U1 0 U2 0 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD MAR 8 PY 2016 VL 7 IS 10 BP 11500 EP 11511 PG 12 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DL5LK UT WOS:000375678300059 PM 26862853 ER PT J AU Teo, AKK Lau, HH Valdez, IA Dirice, E Tjora, E Raeder, H Kulkarni, RN AF Teo, Adrian Kee Keong Lau, Hwee Hui Valdez, Ivan Achel Dirice, Ercument Tjora, Erling Raeder, Helge Kulkarni, Rohit N. TI Early Developmental Per turbations in a Human Stem Cell Model of MODY5/HNF1B Pancreatic Hypoplasia SO STEM CELL REPORTS LA English DT Article ID TRANSCRIPTION FACTORS; DEFINITIVE ENDODERM; BETA-CELLS; GENE; AGENESIS; EXPRESSION; MUTATIONS; ONSET; YOUNG; PAX6 AB Patients with an HNF1B (S148L/+) mutation (MODY5) typically exhibit pancreatic hypoplasia. However, the molecular mechanisms are unknown due to inaccessibility of patient material and because mouse models do not fully recapitulate MODY5. Here, we differentiated MODY5 human-induced pluripotent stem cells (hiPSCs) into pancreatic progenitors, and show that the HNF1B S148L/+ mutation causes a compensatory increase in several pancreatic transcription factors, and surprisingly, a decrease in PAX6 pancreatic gene expression. The lack of suppression of PDX1, PTF1A, GATA4, and GATA6 indicates that MODY5-mediated pancreatic hypoplasia is mechanistically independent. Overexpression studies demonstrate that a compensatory increase in PDX1 gene expression is due to mutant HNF1B(S148L/+) but not wild-type HNF1B or HNF1A. Furthermore, HNF1B does not appear to directly regulate PAX6 gene expression necessary for glucose tolerance. Our results demonstrate compensatory mechanisms in the pancreatic transcription factor network due to mutant HNF1B(S148L/+) protein. Thus, patients typically develop MODY5 but not neonatal diabetes despite exhibiting pancreatic hypoplasia. C1 [Teo, Adrian Kee Keong; Valdez, Ivan Achel; Dirice, Ercument; Kulkarni, Rohit N.] Harvard Univ, Brigham & Womens Hosp, Sect Islet Cell & Regenerat Biol,Med Sch, Joslin Diabet Ctr,Dept Med,Harvard Stem Cell Inst, 1 Joslin Pl, Boston, MA 02215 USA. [Teo, Adrian Kee Keong; Lau, Hwee Hui] Inst Mol & Cell Biol, Discovery Res Div, 61 Biopolis Dr,Proteos 06-07, Singapore 138673, Singapore. [Teo, Adrian Kee Keong] Nanyang Technol Univ, Sch Biol Sci, Singapore 637551, Singapore. [Teo, Adrian Kee Keong] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Biochem, Singapore 117596, Singapore. [Teo, Adrian Kee Keong] Nanyang Technol Univ, Lee Kong Chian Sch Med, Singapore 308232, Singapore. [Tjora, Erling; Raeder, Helge] Haukeland Hosp, Dept Pediat, N-5021 Bergen, Norway. [Tjora, Erling; Raeder, Helge] Univ Bergen, KG Jebsen Ctr Diabet Res, Dept Clin Sci, N-5021 Bergen, Norway. RP Teo, AKK; Kulkarni, RN (reprint author), Harvard Univ, Brigham & Womens Hosp, Sect Islet Cell & Regenerat Biol,Med Sch, Joslin Diabet Ctr,Dept Med,Harvard Stem Cell Inst, 1 Joslin Pl, Boston, MA 02215 USA.; Teo, AKK (reprint author), Inst Mol & Cell Biol, Discovery Res Div, 61 Biopolis Dr,Proteos 06-07, Singapore 138673, Singapore.; Teo, AKK (reprint author), Nanyang Technol Univ, Sch Biol Sci, Singapore 637551, Singapore.; Teo, AKK (reprint author), Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Biochem, Singapore 117596, Singapore.; Teo, AKK (reprint author), Nanyang Technol Univ, Lee Kong Chian Sch Med, Singapore 308232, Singapore. EM ateo@imcb.a-star.edu.sg; rohit.kulkarni@joslin.harvard.edu RI Dirice, Ercument/B-2825-2017; OI Teo, Adrian/0000-0001-5901-7075 FU Joslin DRC iPS Core Facility [NIH 5 P30 DK036836-27]; HSCI/DRC Flow Core [NIH P30DK036836]; Juvenile Diabetes Research Foundation (JDRF) Postdoctoral Fellowship; A*STAR [NHGKTPH SIG/14033]; NUHS-CG Metabolic In-Vitro Core Seed Funding; JCO Career Development Award (CDA) [15302FG148]; HSCI Sternlicht Director's Fund Award [NIH F31DK098931]; Advanced JDRF Postdoctoral Fellowship; Bergen Forskningsstiftelse (BFS); Western Norway Regional Health Authority; Novo Nordisk Foundation; HSCI; NIH [RO1 DK 67536, RO1 DK 055523, R01103215]; AstraZeneca; Institute of Molecular and Cell Biology (IMCB); [NIHP50-NS40828]; [NIH-P30-HD18655] FX The hiPSC lines used were derived with support from the Joslin DRC iPS Core Facility (NIH 5 P30 DK036836-27). FACS analysis was supported by the HSCI/DRC Flow Core (NIH P30DK036836). Microarray studies were performed by the Molecular Genetics Core Facility at Children's Hospital Boston, supported by NIHP50-NS40828 and NIH-P30-HD18655. We thank B. Wagner for assistance with microarray analyses; and K. Tomita, E.K. Tan, N.R. Dunn, Y.-H. Zhou, and Y.-I. Chi for providing plasmids. A.K.K.T. was supported by a Juvenile Diabetes Research Foundation (JDRF) Postdoctoral Fellowship and is currently supported by the Institute of Molecular and Cell Biology (IMCB), A*STAR, NHGKTPH SIG/14033, the NUHS-CG Metabolic In-Vitro Core Seed Funding, and the JCO Career Development Award (CDA) 15302FG148, A*STAR. I.A.V. is supported by an HSCI Sternlicht Director's Fund Award and a NIH F31DK098931 award. E.D. is supported by an Advanced JDRF Postdoctoral Fellowship. H.R. is supported by grants from Bergen Forskningsstiftelse (BFS), the Western Norway Regional Health Authority and the Novo Nordisk Foundation. R.N.K. is supported by the HSCI, NIH grants RO1 DK 67536, RO1 DK 055523, and R01103215, and a grant from AstraZeneca. NR 33 TC 2 Z9 2 U1 1 U2 2 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2213-6711 J9 STEM CELL REP JI Stem Cell Rep. PD MAR 8 PY 2016 VL 6 IS 3 BP 357 EP 367 DI 10.1016/j.stemcr.2016.01.007 PG 11 WC Cell & Tissue Engineering; Cell Biology SC Cell Biology GA DI8ZR UT WOS:000373791600009 PM 26876668 ER PT J AU Gao, X Wu, TY Johnson, KD Lahvic, JL Ranheim, EA Zon, LI Bresnick, EH AF Gao, Xin Wu, Tongyu Johnson, Kirby D. Lahvic, Jamie L. Ranheim, Erik A. Zon, Leonard I. Bresnick, Emery H. TI GATA Factor-G-Protein-Coupled Receptor Circuit Suppresses Hematopoiesis SO STEM CELL REPORTS LA English DT Article ID GENOME-WIDE ANALYSIS; ERYTHROID GENE-EXPRESSION; STEM-CELL HOMEOSTASIS; PROGENITOR CELLS; BONE-MARROW; TRANSCRIPTIONAL REPRESSION; CHROMATIN OCCUPANCY; AORTIC ENDOTHELIUM; INDUCED APOPTOSIS; HSC GENERATION AB Hematopoietic stem cells (HSCs) originate from hemogenic endothelium within the aorta-gonad-mesonephros (AGM) region of the mammalian embryo. The relationship between genetic circuits controlling stem cell genesis and multi-potency is not understood. A Gata2 cis element (+9.5) enhances Gata2 expression in the AGM and induces the endothelial to HSC transition. We demonstrated that GATA-2 rescued hematopoiesis in +9.5(-/-) AGMs. As G-protein-coupled receptors (GPCRs) are the mostcommontargets for FDA-approved drugs, we analyzed the GPCR gene ensemble to identify GATA-2-regulated GPCRs. Of the 20 GATA-2-activated GPCR genes, four were GATA-1-activated, and only Gpr65 expression resembled Gata2. Contrasting with the paradigm in which GATA-2-activated genes promote hematopoietic stem and progenitor cell genesis/function, our mouse and zebrafish studies indicated that GPR65 suppressed hematopoiesis. GPR65 established repressive chromatin at the +9.5 site, restricted occupancy by the activator Scl/TAL1, and repressed Gata2 transcription. Thus, a Gata2 cis element creates a GATA-2-GPCR circuit that limits positive regulators that promote hematopoiesis. C1 [Gao, Xin; Wu, Tongyu; Johnson, Kirby D.; Bresnick, Emery H.] Univ Wisconsin, Sch Med & Publ Hlth, Dept Cell & Regenerat Biol, UW Madison Blood Res Program,Carbone Canc Ctr, Madison, WI 53705 USA. [Lahvic, Jamie L.; Zon, Leonard I.] Harvard Univ, Childrens Hosp, Stem Cell Program, Boston, MA 02114 USA. [Lahvic, Jamie L.; Zon, Leonard I.] Harvard Univ, Childrens Hosp, Div Hematol Oncol, Boston, MA 02114 USA. [Lahvic, Jamie L.; Zon, Leonard I.] Harvard Univ, Howard Hughes Med Inst, Dana Farber Canc Inst,Med Sch, Harvard Stem Cell Inst,Stem Cell & Regenerat Biol, Boston, MA 02114 USA. [Ranheim, Erik A.] Univ Wisconsin, Sch Med & Publ Hlth, Dept Pathol, Madison, WI 53705 USA. RP Bresnick, EH (reprint author), Univ Wisconsin, Sch Med & Publ Hlth, Dept Cell & Regenerat Biol, UW Madison Blood Res Program,Carbone Canc Ctr, Madison, WI 53705 USA. EM ehbresni@wisc.edu FU NIH [DK68634, DK50107, HL04880, HL032262, HL10001-05, DK092760]; [P30CA014520] FX The work was supported by NIH DK68634 and DK50107 (to E.H.B.), Cancer Center Support Grant P30CA014520, and NIH HL04880, HL032262, HL10001-05, and DK092760 (to L.I.Z). We thank Michelle Ammerman and Prathibha Sanalkumar for assistance with zebrafish experiments and Western blotting, respectively. NR 69 TC 1 Z9 1 U1 2 U2 2 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2213-6711 J9 STEM CELL REP JI Stem Cell Rep. PD MAR 8 PY 2016 VL 6 IS 3 BP 368 EP 382 DI 10.1016/j.stemcr.2016.01.008 PG 15 WC Cell & Tissue Engineering; Cell Biology SC Cell Biology GA DI8ZR UT WOS:000373791600010 PM 26905203 ER PT J AU Svensson, KJ Long, JZ Jedrychowski, MP Cohen, P Lo, JC Serag, S Kir, S Shinoda, K Tartaglia, JA Rao, RR Chedotal, A Kajimura, S Gygi, SP Spiegelman, BM AF Svensson, Katrin J. Long, Jonathan Z. Jedrychowski, Mark P. Cohen, Paul Lo, James C. Serag, Sara Kir, Serkan Shinoda, Kosaku Tartaglia, Julia A. Rao, Rajesh R. Chedotal, Alain Kajimura, Shingo Gygi, Steven P. Spiegelman, Bruce M. TI A Secreted Slit2 Fragment Regulates Adipose Tissue Thermogenesis and Metabolic Function SO CELL METABOLISM LA English DT Article ID ADAPTIVE THERMOGENESIS; ENERGY-EXPENDITURE; BROWN ADIPOCYTES; BEIGE ADIPOCYTES; AXON GUIDANCE; ADULT HUMANS; FAT; PROTEINS; ABLATION; PRDM16 AB Activation of brown and beige fat can reduce obesity and improve glucose homeostasis through nonshivering thermogenesis. Whether brown or beige fat also secretes paracrine or endocrine factors to promote and amplify adaptive thermogenesis is not fully explored. Here we identify Slit2, a 180 kDa member of the Slit extracellular protein family, as a PRDM16-regulated secreted factor from beige fat cells. In isolated cells and in mice, full-length Slit2 is cleaved to generate several smaller fragments, and we identify an active thermogenic moiety as the C-terminal fragment. This Slit2-C fragment of 50 kDa promotes adipose thermogenesis, augments energy expenditure, and improves glucose homeostasis in vivo. Mechanistically, Slit2 induces a robust activation of PKA signaling, which is required for its prothermogenic activity. Our findings establish a previously unknown peripheral role for Slit2 as a beige fat secreted factor that has therapeutic potential for the treatment of obesity and related metabolic disorders. C1 [Svensson, Katrin J.; Long, Jonathan Z.; Serag, Sara; Kir, Serkan; Tartaglia, Julia A.; Rao, Rajesh R.; Spiegelman, Bruce M.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Jedrychowski, Mark P.; Gygi, Steven P.] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. [Cohen, Paul] Rockefeller Univ, Lab Mol Metab, New York, NY 10065 USA. [Lo, James C.] Weill Cornell Med Coll, Metabol Hlth Ctr, Dept Med, New York, NY 10021 USA. [Chedotal, Alain] Univ Paris 06, Sorbonne Univ, CNRS, INSERM,Inst Vis, 17 Rue Moreau, F-75012 Paris, France. [Shinoda, Kosaku; Kajimura, Shingo] Univ Calif San Francisco, Ctr Diabet, San Francisco, CA 94143 USA. RP Spiegelman, BM (reprint author), Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. EM bruce_spiegelman@dfci.harvard.edu OI Svensson, Katrin J/0000-0001-5376-5128 FU NIH [DK031405]; JPB Foundation; Swedish Research Council [PE 2013/613]; American and Canadian Diabetes Association [PF-3-12-3927-JL] FX We thank the Rodent Histopathology Core at Harvard Medical School for histology processing, the Nikon Imaging Center at Harvard Medical School for use of microscopy equipment, and the Joslin Diabetes Core for ELISA measurements. We thank Dr. Pere Puigserver and members of the B.M.S. lab for helpful discussions. This work was supported by NIH grants DK031405 and the JPB Foundation (B.M.S.). K.J.S. is supported by a postdoctoral fellowship from the Swedish Research Council (PE 2013/613). J.Z.L. is supported by a joint postdoctoral fellowship from the American and Canadian Diabetes Association (PF-3-12-3927-JL). B.M.S. is a consultant to Calico, Inc. NR 33 TC 9 Z9 10 U1 2 U2 10 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1550-4131 EI 1932-7420 J9 CELL METAB JI Cell Metab. PD MAR 8 PY 2016 VL 23 IS 3 BP 454 EP 466 DI 10.1016/j.cmet.2016.01.008 PG 13 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA DI6MU UT WOS:000373614100013 PM 26876562 ER PT J AU Davidson, SM Papagiannakopoulos, T Olenchock, BA Heyman, JE Keibler, MA Luengo, A Bauer, MR Jha, AK O'Brien, JP Pierce, KA Gui, DY Sullivan, LB Wasylenko, TM Subbaraj, L Chin, CR Stephanopolous, G Mott, BT Jacks, T Clish, CB Heiden, MGV AF Davidson, Shawn M. Papagiannakopoulos, Thales Olenchock, Benjamin A. Heyman, Julia E. Keibler, Mark A. Luengo, Alba Bauer, Matthew R. Jha, Abhishek K. O'Brien, James P. Pierce, Kerry A. Gui, Dan Y. Sullivan, Lucas B. Wasylenko, Thomas M. Subbaraj, Lakshmipriya Chin, Christopher R. Stephanopolous, Gregory Mott, Bryan T. Jacks, Tyler Clish, Clary B. Heiden, Matthew G. Vander TI Environment Impacts the Metabolic Dependencies of Ras-Driven Non-Small Cell Lung Cancer SO CELL METABOLISM LA English DT Article ID TUMOR-CELLS; IN-VIVO; MITOCHONDRIAL METABOLISM; PYRUVATE-CARBOXYLASE; BREAST-CANCER; K-RAS; GLUTAMINE; GROWTH; MICE; PROLIFERATION AB Cultured cells convert glucose to lactate, and glutamine is the major source of tricarboxylic acid (TCA)-cycle carbon, but whether the same metabolic phenotype is found in tumors is less studied. We infused mice with lung cancers with isotope-labeled glucose or glutamine and compared the fate of these nutrients in tumor and normal tissue. As expected, lung tumors exhibit increased lactate production from glucose. However, glutamine utilization by both lung tumors and normal lung was minimal, with lung tumors showing increased glucose contribution to the TCA cycle relative to normal lung tissue. Deletion of enzymes involved in glucose oxidation demonstrates that glucose carbon contribution to the TCA cycle is required for tumor formation. These data suggest that understanding nutrient utilization by tumors can predict metabolic dependencies of cancers in vivo. Furthermore, these data argue that the in vivo environment is an important determinant of the metabolic phenotype of cancer cells. C1 [Davidson, Shawn M.; Papagiannakopoulos, Thales; Olenchock, Benjamin A.; Heyman, Julia E.; Luengo, Alba; Bauer, Matthew R.; O'Brien, James P.; Gui, Dan Y.; Sullivan, Lucas B.; Subbaraj, Lakshmipriya; Chin, Christopher R.; Jacks, Tyler; Heiden, Matthew G. Vander] MIT, Koch Inst Integrat Canc Res, Cambridge, MA 02142 USA. [Davidson, Shawn M.; Olenchock, Benjamin A.; Luengo, Alba; Pierce, Kerry A.; Jacks, Tyler; Heiden, Matthew G. Vander] Broad Inst IT, Cambridge, MA 02142 USA. [Davidson, Shawn M.; Olenchock, Benjamin A.; Pierce, Kerry A.; Clish, Clary B.; Heiden, Matthew G. Vander] Harvard Univ, Cambridge, MA 02142 USA. [Olenchock, Benjamin A.] Brigham & Womens Hosp, Dept Med, Div Cardiovasc Med, 75 Francis St, Boston, MA 02115 USA. [Keibler, Mark A.; Stephanopolous, Gregory] MIT, Dept Chem Engn, Cambridge, MA 02139 USA. [Jha, Abhishek K.] Elucidata Corp, Dept Chem Engn, Cambridge, MA 02139 USA. [Mott, Bryan T.] Natl Ctr Adv Translat Sci, NIH, Bethesda, MD 20892 USA. [Heiden, Matthew G. Vander] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Heiden, MGV (reprint author), MIT, Koch Inst Integrat Canc Res, Cambridge, MA 02142 USA.; Heiden, MGV (reprint author), Broad Inst IT, Cambridge, MA 02142 USA.; Heiden, MGV (reprint author), Harvard Univ, Cambridge, MA 02142 USA.; Heiden, MGV (reprint author), Dana Farber Canc Inst, Boston, MA 02115 USA. EM mvh@mit.edu FU NSF; Hope Funds for Cancer Research Fellowship; Gilead Sciences Research Scholars Program; Broad Institute SPARC program; Ludwig Center at MIT; Burroughs Wellcome Fund; NIH [P30CA1405141, R01CA168653]; [T32GM007287]; [K08HL119355]; [T32GM007753] FX We thank Natalia Drosu for reagents and advice, the Swanson Biotechnology Center for mouse tissue processing, and the M.G.V.H. lab for thoughtful discussions. S.M.D. and A.L. were supported by an NSF Graduate Research Fellowship and T32GM007287. T.P. received support from Hope Funds for Cancer Research Fellowship. B.A.O. received support from K08HL119355 and Gilead Sciences Research Scholars Program. D.Y.G. received support from T32GM007753. M.G.V.H acknowledges support from the Broad Institute SPARC program, the Ludwig Center at MIT, the Burroughs Wellcome Fund, and the NIH (P30CA1405141, R01CA168653). M.G.V.H. is a consultant and scientific advisory board member, and A.K.J. is a consultant, for Agios Pharmaceuticals. NR 47 TC 47 Z9 47 U1 11 U2 22 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1550-4131 EI 1932-7420 J9 CELL METAB JI Cell Metab. PD MAR 8 PY 2016 VL 23 IS 3 BP 517 EP 528 DI 10.1016/j.cmet.2016.01.007 PG 12 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA DI6MU UT WOS:000373614100018 PM 26853747 ER PT J AU Bhattacharyya, S Darby, RR Raibagkar, P Castro, LNG Berkowitz, AL AF Bhattacharyya, Shamik Darby, R. Ryan Raibagkar, Pooja Castro, L. Nicolas Gonzalez Berkowitz, Aaron L. TI Antibiotic-associated encephalopathy SO NEUROLOGY LA English DT Review ID INTENSIVE-CARE-UNIT; MECHANICALLY VENTILATED PATIENTS; BETA-LACTAM ANTIBIOTICS; CENTRAL-NERVOUS-SYSTEM; INTRAVENOUS PROCAINE; DELIRIUM; PENICILLIN; NEUROTOXICITY; MECHANISMS; FLUOROQUINOLONES AB Delirium is a common and costly complication of hospitalization. Although medications are a known cause of delirium, antibiotics are an underrecognized class of medications associated with delirium. In this article, we comprehensively review the clinical, radiologic, and electrophysiologic features of antibiotic-associated encephalopathy (AAE). AAE can be divided into 3 unique clinical phenotypes: encephalopathy commonly accompanied by seizures or myoclonus arising within days after antibiotic administration (caused by cephalosporins and penicillin); encephalopathy characterized by psychosis arising within days of antibiotic administration (caused by quinolones, macrolides, and procaine penicillin); and encephalopathy accompanied by cerebellar signs and MRI abnormalities emerging weeks after initiation of antibiotics (caused by metronidazole). We correlate these 3 clinical phenotypes with underlying pathophysiologic mechanisms of antibiotic neurotoxicity. Familiarity with these types of antibiotic toxicity can improve timely diagnosis of AAE and prompt antibiotic discontinuation, reducing the time patients spend in the delirious state. C1 [Bhattacharyya, Shamik; Darby, R. Ryan; Raibagkar, Pooja; Castro, L. Nicolas Gonzalez; Berkowitz, Aaron L.] Brigham & Womens Hosp, Dept Neurol, 75 Francis St, Boston, MA 02115 USA. [Darby, R. Ryan; Raibagkar, Pooja; Castro, L. Nicolas Gonzalez] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Bhattacharyya, Shamik; Darby, R. Ryan; Raibagkar, Pooja; Castro, L. Nicolas Gonzalez; Berkowitz, Aaron L.] Harvard Univ, Sch Med, Boston, MA USA. RP Bhattacharyya, S (reprint author), Brigham & Womens Hosp, Dept Neurol, 75 Francis St, Boston, MA 02115 USA. EM sbhattacharyya3@partners.org OI Bhattacharyya, Shamik/0000-0001-8047-3622 NR 54 TC 12 Z9 12 U1 16 U2 20 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 MAR 8 PY 2016 VL 86 IS 10 BP 963 EP 971 DI 10.1212/WNL.0000000000002455 PG 9 WC Clinical Neurology SC Neurosciences & Neurology GA DG1NA UT WOS:000371833600013 PM 26888997 ER PT J AU Zaworski, P von Herrmann, KM Taylor, S Sunshine, SS McCarthy, K Risher, N Newcomb, T Weetall, M Prior, TW Swoboda, KJ Chen, KS Paushkin, S AF Zaworski, Phillip von Herrmann, Katharine M. Taylor, Shannon Sunshine, Sara S. McCarthy, Kathleen Risher, Nicole Newcomb, Tara Weetall, Marla Prior, Thomas W. Swoboda, Kathryn J. Chen, Karen S. Paushkin, Sergey TI SMN Protein Can Be Reliably Measured in Whole Blood with an Electrochemiluminescence (ECL) Immunoassay: Implications for Clinical Trials SO PLOS ONE LA English DT Article ID SPINAL MUSCULAR-ATROPHY; NATURAL-HISTORY; SURVIVAL; BIOMARKER; SEVERITY; MICE AB Spinal muscular atrophy (SMA) is caused by defects in the survival motor neuron 1 (SMN1) gene that encodes survival motor neuron (SMN) protein. The majority of therapeutic approaches currently in clinical development for SMA aim to increase SMN protein expression and there is a need for sensitive methods able to quantify increases in SMN protein levels in accessible tissues. We have developed a sensitive electrochemiluminescence (ECL)-based immunoassay for measuring SMN protein in whole blood with a minimum volume requirement of 5 mu L. The SMN-ECL immunoassay enables accurate measurement of SMN in whole blood and other tissues. Using the assay, we measured SMN protein in whole blood from SMA patients and healthy controls and found that SMN protein levels were associated with SMN2 copy number and were greater in SMA patients with 4 copies, relative to those with 2 and 3 copies. SMN protein levels did not vary significantly in healthy individuals over a four-week period and were not affected by circadian rhythms. Almost half of the SMN protein was found in platelets. We show that SMN protein levels in C/C-allele mice, which model a mild form of SMA, were high in neonatal stage, decreased in the first few weeks after birth, and then remained stable throughout the adult stage. Importantly, SMN protein levels in the CNS correlated with SMN levels measured in whole blood of the C/C-allele mice. These findings have implications for the measurement of SMN protein induction in whole blood in response to SMN-upregulating therapy. C1 [Zaworski, Phillip; Taylor, Shannon] PharmOptima, Portage, MI USA. [von Herrmann, Katharine M.; Sunshine, Sara S.; McCarthy, Kathleen; Chen, Karen S.; Paushkin, Sergey] Spinal Muscular Atrophy Fdn, New York, NY USA. [Risher, Nicole; Weetall, Marla] PTC Therapeut, South Plainfield, NJ USA. [Newcomb, Tara; Swoboda, Kathryn J.] Univ Utah, Sch Med, Dept Neurol, Salt Lake City, UT USA. [Prior, Thomas W.] Ohio State Univ, Wexner Med Ctr, Dept Mol Pathol, Columbus, OH 43210 USA. [von Herrmann, Katharine M.] Geisel Sch Med Dartmouth, Hanover, NH USA. [McCarthy, Kathleen] F Hoffmann La Roche Ltd, CH-4070 Basel, Switzerland. [Swoboda, Kathryn J.] Massachusetts Gen Hosp, Dept Neurol, Ctr Human Genet Res, Boston, MA 02114 USA. RP Paushkin, S (reprint author), Spinal Muscular Atrophy Fdn, New York, NY USA. EM spaushkin@smafoundation.org FU SMA Foundation; National Institutes of Health [R01-HD69045]; PTC Therapeutics; PharmOptima FX The study was funded by the SMA Foundation. Work at University of Utah was supported in part by National Institutes of Health grant R01-HD69045 to KJS. PTC Therapeutics provided support in the form of salaries to NR and MW and PharmOptima provided support in the form of salaries for PZ and ST, but neither PTC Therapeutics or PharmOptima had any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the 'author contributions' section. NR 33 TC 3 Z9 3 U1 2 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 8 PY 2016 VL 11 IS 3 AR e0150640 DI 10.1371/journal.pone.0150640 PG 18 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DG3SW UT WOS:000371991300038 PM 26953792 ER PT J AU Havenar-Daughton, C Lindqvist, M Heit, A Wu, JE Reiss, SM Kendric, K Belanger, S Kasturi, SP Landais, E Akondy, RS McGuire, HM Bothwell, M Vagefi, PA Scully, E Tomaras, GD Davis, MM Poignard, P Ahmed, R Walker, BD Pulendran, B McElrath, MJ Kaufmann, DE Crotty, S AF Havenar-Daughton, Colin Lindqvist, Madelene Heit, Antje Wu, Jennifer E. Reiss, Samantha M. Kendric, Kayla Belanger, Simon Kasturi, Sudhir Pai Landais, Elise Akondy, Rama S. McGuire, Helen M. Bothwell, Marcella Vagefi, Parsia A. Scully, Eileen Tomaras, Georgia D. Davis, Mark M. Poignard, Pascal Ahmed, Rafi Walker, Bruce D. Pulendran, Bali McElrath, M. Juliana Kaufmann, Daniel E. Crotty, Shane CA IAVI Protocol C Principal Investga TI CXCL13 is a plasma biomarker of germinal center activity SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE vaccines; CXCL13; HIV; antibodies; Tfh ID HELPER-CELL DIFFERENTIATION; IMMUNODEFICIENCY VIRUS-INFECTION; CD4 T-CELLS; ANTIBODY-RESPONSES; CHEMOKINE CXCL13; LYMPHOID FOLLICLES; NEUTRALIZING ANTIBODIES; VACCINE DEVELOPMENT; HIV-1 INFECTION; DENDRITIC CELLS AB Significantly higher levels of plasma CXCL13 [chemokine (C-X-Cmotif) ligand 13] were associated with the generation of broadly neutralizing antibodies (bnAbs) against HIV in a large longitudinal cohort of HIV-infected individuals. Germinal centers (GCs) perform the remarkable task of optimizing B-cell Ab responses. GCs are required for almost all B-cell receptor affinity maturation and will be a critical parameter to monitor if HIV bnAbs are to be induced by vaccination. However, lymphoid tissue is rarely available from immunized humans, making the monitoring of GC activity by direct assessment of GC B cells and germinal center CD4(+) T follicular helper (GC Tfh) cells problematic. The CXCL13-CXCR5 [chemokine (C-X-C motif) receptor 5] chemokine axis plays a central role in organizing both B-cell follicles and GCs. Because GC Tfh cells can produce CXCL13, we explored the potential use of CXCL13 as a blood biomarker to indicate GC activity. In a series of studies, we found that plasma CXCL13 levels correlated with GC activity in draining lymph nodes of immunized mice, immunized macaques, and HIV-infected humans. Furthermore, plasma CXCL13 levels in immunized humans correlated with the magnitude of Ab responses and the frequency of ICOS+ (inducible T-cell costimulator) Tfh-like cells in blood. Together, these findings support the potential use of CXCL13 as a plasma biomarker of GC activity in human vaccine trials and other clinical settings. C1 [Havenar-Daughton, Colin; Wu, Jennifer E.; Reiss, Samantha M.; Kendric, Kayla; Belanger, Simon; Crotty, Shane] La Jolla Inst Allergy & Immunol, Div Vaccine Discovery, La Jolla, CA 92037 USA. [Havenar-Daughton, Colin; Lindqvist, Madelene; Heit, Antje; Ahmed, Rafi; Walker, Bruce D.; Pulendran, Bali; McElrath, M. Juliana; Kaufmann, Daniel E.; Crotty, Shane] Ctr HIV AIDS Vaccine Immunol & Immunogen Discover, La Jolla, CA 92037 USA. [Lindqvist, Madelene; Scully, Eileen; Walker, Bruce D.; Kaufmann, Daniel E.] MIT, Massachusetts Gen Hosp, Ragon Inst, Boston, MA 02114 USA. [Lindqvist, Madelene; Scully, Eileen; Walker, Bruce D.; Kaufmann, Daniel E.] Harvard Univ, Boston, MA USA. [Heit, Antje; McElrath, M. Juliana] Fred Hutchinson Canc Res Ctr, Vaccine & Infect Dis Div, Seattle, WA 98109 USA. [Kasturi, Sudhir Pai; Pulendran, Bali] Emory Univ, Yerkes Natl Primate Res Ctr, Atlanta, GA 30322 USA. [Kasturi, Sudhir Pai; Akondy, Rama S.; Ahmed, Rafi; Pulendran, Bali] Emory Univ, Sch Med, Emory Vaccine Ctr, Atlanta, GA 30322 USA. [Poignard, Pascal] Int AIDS Vaccine Initiat, Neutralizing Antibody Ctr, La Jolla, CA 92037 USA. [McGuire, Helen M.; Davis, Mark M.] Stanford Univ, Sch Med, Dept Microbiol & Immunol, Stanford, CA 94304 USA. [Bothwell, Marcella] Univ Calif San Diego, Dept Surg, San Diego, CA 92123 USA. [Bothwell, Marcella] Rady Childrens Hosp San Diego, Pediat Otolaryngol, San Diego, CA 92123 USA. [Vagefi, Parsia A.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [IAVI Protocol C Principal Investga] Int AIDS Vaccine Initiat, New York, NY 10038 USA. [Tomaras, Georgia D.] Duke Univ, Sch Med, Duke Human Vaccine Inst, Durham, NC 27710 USA. [Davis, Mark M.] Stanford Univ, Sch Med, Howard Hughes Med Inst, Stanford, CA 94304 USA. [Poignard, Pascal] Scripps Res Inst, Dept Immunol & Microbial Sci, La Jolla, CA 92037 USA. [Walker, Bruce D.] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. [Kaufmann, Daniel E.] Univ Montreal, Dept Med, Montreal, PQ H2X 0A9, Canada. [Kaufmann, Daniel E.] CRCHUM, Montreal, PQ H2X 0A9, Canada. RP Crotty, S (reprint author), La Jolla Inst Allergy & Immunol, Div Vaccine Discovery, La Jolla, CA 92037 USA.; Crotty, S (reprint author), Ctr HIV AIDS Vaccine Immunol & Immunogen Discover, La Jolla, CA 92037 USA. EM shane@lji.org RI Tomaras, Georgia/J-5041-2016; poignard, pascal/N-6678-2013; OI Havenar-Daughton, Colin/0000-0002-2880-3927 FU National Institute of Allergy and Infectious Diseases; International AIDS Vaccine Initiative (IAVI); Scripps Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (Scripps CHAVI-ID) FX We thank all project study volunteers and clinical and study team members. This work was supported by grants from the National Institute of Allergy and Infectious Diseases, International AIDS Vaccine Initiative (IAVI), and the Scripps Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (Scripps CHAVI-ID). NR 50 TC 20 Z9 21 U1 1 U2 7 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAR 8 PY 2016 VL 113 IS 10 BP 2702 EP 2707 DI 10.1073/pnas.1520112113 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DG4AW UT WOS:000372013300044 PM 26908875 ER PT J AU Grant, CC Chen, MH Bandara, DK Marks, EJ Gilchrist, CA Lewycka, S Carr, PEA Robinson, EM Pryor, JE Camargo, CA Morton, SMB AF Grant, Cameron C. Chen, Mei-Hua Bandara, Dinusha K. Marks, Emma J. Gilchrist, Catherine A. Lewycka, Sonia Carr, Polly E. Atatoa Robinson, Elizabeth M. Pryor, Jan E. Camargo, Carlos A. Morton, Susan M. B. TI Antenatal immunisation intentions of expectant parents: Relationship to immunisation timeliness during infancy SO VACCINE LA English DT Article DE Decision making; Fathers; Immunisation; Mothers; Pregnancy ID IN-NEW-ZEALAND; GROWING-UP; DECISION AID; CHILDHOOD IMMUNIZATION; VACCINATION DECISIONS; DELAYED IMMUNIZATION; MMR VACCINATION; PERTUSSIS; PROVIDER; FATHERS AB Background: Most women decide about infant immunisation during pregnancy. However, we have limited knowledge of the immunisation intentions of their partners. We aimed to describe what pregnant women and their partners intended for their future child's immunisations, and to identify associations between parental intentions and the subsequent timeliness of infant immunisation. Methods: We recruited a cohort of pregnant New Zealand (NZ) women expecting to deliver between April 2009 and March 2010. The cohort included 11% of births in NZ during the recruitment period and was generalisable to the national birth cohort. We completed antenatal interviews independently with mothers and partners. We determined immunisation receipt from the National Immunisation Register and defined timely immunisation as receiving all vaccines (scheduled at 6-weeks, 3- and 5-months) within 30 days of their due date. We described independent associations of immunisation intentions with timeliness using adjusted odds ratios (OR) and 95% confidence intervals (CI). Results: Of 6172 women, 5014 (81%) intended full immunisation, 245 (4%) partial immunisation, 140 (2%) no immunisation and 773 (13%) were undecided. Of 4152 partners, 2942 (71%) intended full immunisation, 208 (5%) partial immunisation, 83 (2%) no immunisation and 921 (22%) were undecided. Agreement between mothers and partners was moderate (Kappa = 0.42). Timely immunisation occurred in 70% of infants. Independent of their partner's intentions, infants of pregnant women who decided upon full immunisation were more likely to be immunised on time (OR = 7.65, 95% CI: 4.87 - 12.18). Independent of the future mother's intentions, infants of partners who had decided upon full immunisations were more likely to be immunised on time (OR = 3.33, 95% CI: 2.29 - 4.84). Conclusions: During pregnancy, most future parents intend to fully immunise their child; however, more partners than mothers remain undecided about immunisation. Both future mothers' and future fathers' intentions are independently associated with the timeliness of their infant's immunisations. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Grant, Cameron C.; Lewycka, Sonia; Carr, Polly E. Atatoa; Morton, Susan M. B.] Univ Auckland, Ctr Longitudinal Res He Ara Ki Mua, Auckland 1, New Zealand. [Chen, Mei-Hua; Bandara, Dinusha K.; Marks, Emma J.; Carr, Polly E. Atatoa; Robinson, Elizabeth M.; Pryor, Jan E.; Morton, Susan M. B.] Univ Auckland, Growing New Zealand, Auckland 1, New Zealand. [Gilchrist, Catherine A.] Univ Auckland, Dept Paediat Child & Youth Hlth, Auckland 1, New Zealand. [Grant, Cameron C.] Auckland Dist Hlth Board, Starship Childrens Hosp, Auckland, New Zealand. [Carr, Polly E. Atatoa] Univ Auckland, Waikato Clin Sch, Hamilton, New Zealand. [Marks, Emma J.] Univ Auckland, Bioinformat Inst, Auckland 1, New Zealand. [Robinson, Elizabeth M.] Univ Auckland, Sch Populat Hlth, Dept Epidemiol & Biostat, Auckland 1, New Zealand. [Pryor, Jan E.] Victoria Univ, Roy McKenzie Ctr Study Families, Wellington, New Zealand. [Camargo, Carlos A.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Emergency Med, Cambridge, MA 02138 USA. RP Grant, CC (reprint author), Univ Auckland Tamaki Campus, Ctr Longitudinal Res He Ara Ki Mua, 261 Morrin Rd, Auckland 1743, New Zealand. EM cc.grant@auckland.ac.nz OI Grant, Cameron/0000-0002-4032-7230; Gilchrist, Catherine/0000-0002-7467-7933 FU Health Research Council; New Zealand Ministry of Social Development; Auckland UniServices; University of Auckland; Kaitiaki Group; national and international Expert Scientific Advisory Group FX Most importantly, we would like to acknowledge the children and the families who are part of the Growing Up in New Zealand study. We would also like to acknowledge the initial funders, in particular the New Zealand Ministry of Social Development, supported by the Health Research Council, as well as the ongoing support from Auckland UniServices and The University of Auckland. The funders play no role in the design and conduct of the study; collection, management, analysis and interpretation of the data; and preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. The authors of this paper are members of the current research team including the Study Director, Associate Directors and the domain and theme experts. We acknowledge all the members of the Growing Up in New Zealand team, including those members and managers of the operational (in-person and computer-assisted telephone interviewing), data, communications, community and quality aspects of the study. We acknowledge the ongoing support and advice provided by our Kaitiaki Group and our national and international Expert Scientific Advisory Group. We also acknowledge the members of the Morton Consortium responsible for planning and design of this study in the Development Phase. NR 41 TC 0 Z9 0 U1 3 U2 4 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X EI 1873-2518 J9 VACCINE JI Vaccine PD MAR 8 PY 2016 VL 34 IS 11 BP 1379 EP 1388 DI 10.1016/j.vaccine.2016.01.048 PG 10 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA DG3DP UT WOS:000371950000009 PM 26850758 ER PT J AU Bonaca, MP Gutierrez, JA Creager, MA Scirica, BM Olin, J Murphy, SA Braunwald, E Morrow, DA AF Bonaca, Marc P. Gutierrez, J. Antonio Creager, Mark A. Scirica, Benjamin M. Olin, Jeffrey Murphy, Sabina A. Braunwald, Eugene Morrow, David A. TI Acute Limb Ischemia and Outcomes With Vorapaxar in Patients With Peripheral Artery Disease Results From the Trial to Assess the Effects of Vorapaxar in Preventing Heart Attack and Stroke in Patients With Atherosclerosis-Thrombolysis in Myocardial Infarction 50 (TRA2 degrees P-TIMI 50) SO CIRCULATION LA English DT Article DE peripheral artery disease; thrombosis; peripheral vascular diseases; limb ischemia; limb ID ANKLE BRACHIAL INDEX; CARDIOVASCULAR EVENT RATES; SECONDARY PREVENTION; RISK; MORTALITY; ASPIRIN; MANAGEMENT; AMPUTATION; ATHEROTHROMBOSIS; OUTPATIENTS AB Background- Patients with peripheral artery disease (PAD) are at heightened risk of acute limb ischemia (ALI), a morbid event that may result in limb loss. We investigated the causes, sequelae, and predictors of ALI in a contemporary population with symptomatic PAD and whether protease-activated receptor 1 antagonism with vorapaxar reduced ALI overall and by type. Methods and Results- The Trial to Assess the Effects of Vorapaxar in Preventing Heart Attack and Stroke in Patients With Atherosclerosis-Thrombolysis in Myocardial Infarction 50 (TRA2 degrees P-TIMI 50) was a randomized, double-blind, placebo-controlled trial of vorapaxar in stable patients, including 3787 with symptomatic PAD. ALI was a prespecified adjudicated end point using a formal definition. A total of 150 ALI events occurred in 108 patients during follow-up (placebo 3-year rate, 3.9%; 1.3% annualized). For patients with symptomatic PAD, previous peripheral revascularization, smoking, and the ankle-brachial index were predictive of ALI. The majority of ALI events occurred as a result of surgical graft thrombosis (56%), followed by native vessel in situ thrombosis (27%). Stent thrombosis and thromboembolism caused ALI in 13% and 5%, respectively. Amputation occurred in 17.6% presenting with ALI. Vorapaxar reduced first ALI events by 41% (hazard ratio, 0.58; 95% confidence interval, 0.39-0.86; P=0.006) and total ALI events by 41% (94 versus 56 events; risk ratio, 0.59; 95% confidence interval, 0.38-0.93; P=0.022). The efficacy of vorapaxar was consistent across types of ALI. Conclusions- In selected patients with symptomatic PAD and without atrial fibrillation, ALI occurs at a rate of 1.3%/y, is most frequently caused by acute bypass graft thrombosis or in situ thrombosis of a diseased vessel, and often results in limb loss. Vorapaxar reduces ALI in patients with symptomatic PAD with consistency across type, including PAD resulting from surgical graft thrombosis and in-situ thrombosis. Clinical Trial Registration- URL: [GRAPHICS] . Unique identifier: NCT00526474. C1 [Bonaca, Marc P.; Gutierrez, J. Antonio; Scirica, Benjamin M.; Murphy, Sabina A.; Braunwald, Eugene; Morrow, David A.] Brigham & Womens Hosp, Dept Med, Div Cardiovasc, TIMI Study Grp, Boston, MA 02115 USA. [Creager, Mark A.] Geisel Sch Med Dartmouth, Dartmouth Hitchcock Heart & Vasc Ctr, Lebanon, NH USA. [Olin, Jeffrey] Mt Sinai Sch Med, Wiener Cardiovasc Inst, New York, NY USA. [Olin, Jeffrey] Mt Sinai Sch Med, Marie Jose & Henry R Kravis Ctr Cardiovasc Hlth, New York, NY USA. RP Bonaca, MP (reprint author), Brigham & Womens Hosp, Div Cardiovasc, TIMI Study Grp, 75 Francis St, Boston, MA 02115 USA. EM mbonaca@partners.org FU Merck and Co.; Research Career Development Award from the National Heart, Lung, and Blood Institute [K12 HL083786] FX This TRA2 degrees P-TIMI 50 trial was supported by a grant from Merck and Co. Dr Bonaca was supported by a Research Career Development Award (K12 HL083786) from the National Heart, Lung, and Blood Institute. NR 29 TC 11 Z9 12 U1 1 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 MAR 8 PY 2016 VL 133 IS 10 BP 997 EP 1005 DI 10.1161/CIRCULATIONAHA.115.019355 PG 9 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA DF6QV UT WOS:000371481600006 PM 26826179 ER PT J AU Rodosthenous, RS Coull, BA Lu, Q Vokonas, PS Schwartz, JD Baccarelli, AA AF Rodosthenous, Rodosthenis S. Coull, Brent A. Lu, Quan Vokonas, Pantel S. Schwartz, Joel D. Baccarelli, Andrea A. TI Ambient particulate matter and microRNAs in extracellular vesicles: a pilot study of older individuals SO PARTICLE AND FIBRE TOXICOLOGY LA English DT Article DE Air pollution; Particulate matter; Cardiovascular disease; Extracellular vesicles; MicroRNAs ID AMERICAN-HEART-ASSOCIATION; CELL-ADHESION MOLECULE-1; LONG-TERM EXPOSURE; AIR-POLLUTION; CIRCULATING MICRORNAS; OXIDATIVE STRESS; EXPRESSION; DISEASE; INFLAMMATION; RNA AB Background: Air pollution from particulate matter (PM) has been linked to cardiovascular morbidity and mortality; however the underlying biological mechanisms remain to be uncovered. Gene regulation by microRNAs (miRNAs) that are transferred between cells by extracellular vesicles (EVs) may play an important role in PM-induced cardiovascular risk. This study sought to determine if ambient PM2.5 levels are associated with expression of EV-encapsulated miRNAs (evmiRNAs), and to investigate the participation of such evmiRNAs in pathways related to cardiovascular disease (CVD). Methods: We estimated the short-(1-day), intermediate-(1-week and 1-month) and long-term (3-month, 6-month, and 1-year) moving averages of ambient PM2.5 levels at participants' addresses using a validated hybrid spatio-temporal land-use regression model. We collected 42 serum samples from 22 randomly selected participants in the Normative Aging Study cohort and screened for 800 miRNAs using the NanoString nCounter (R) platform. Mixed effects regression models, adjusted for potential confounders were used to assess the association between ambient PM2.5 levels and evmiRNAs. All p-values were adjusted for multiple comparisons. In-silico Ingenuity Pathway Analysis (IPA) was performed to identify biological pathways that are regulated by PM-associated evmiRNAs. Results: We found a significant association between long-term ambient PM2.5 exposures and levels of multiple evmiRNAs circulating in serum. In the 6-month window, ambient PM2.5 exposures were associated with increased levels of miR-126-3p (0.74 +/- 0.21; p = 0.02), miR-19b-3p (0.52 +/- 0.15; p = 0.02), miR-93-5p (0.78 +/- 0.22; p = 0.02), miR-223-3p (0.74 +/- 0.22; p = 0.02), and miR-142-3p (0.81 +/- 0.21; p = 0.03). Similarly, in the 1-year window, ambient PM2.5 levels were associated with increased levels of miR-23a-3p (0.83 +/- 0.23; p = 0.02), miR-150-5p (0.90 +/- 0.24; p = 0.02), miR-15a-5p (0.70 +/- 0.21; p = 0.02), miR-191-5p (1.20 +/- 0.35; p = 0.02), and let-7a-5p (1.42 +/- 0.39; p = 0.02). In silico pathway analysis on PM2.5-associated evmiRNAs identified several key CVD-related pathways including oxidative stress, inflammation, and atherosclerosis. Conclusions: We found an association between long-term ambient PM2.5 levels and increased levels of evmiRNAs circulating in serum. Further observational studies are warranted to confirm and extend these important findings in larger and more diverse populations, and experimental studies are needed to elucidate the exact roles of evmiRNAs in PM-induced CVD. C1 [Rodosthenous, Rodosthenis S.; Coull, Brent A.; Lu, Quan; Schwartz, Joel D.; Baccarelli, Andrea A.] Harvard Univ, Dept Environm Hlth, TH Chan Sch Publ Hlth, Boston, MA 02115 USA. [Vokonas, Pantel S.] VA Boston Healthcare Syst, Boston, MA USA. RP Rodosthenous, RS (reprint author), Harvard Univ, Dept Environm Hlth, TH Chan Sch Publ Hlth, Boston, MA 02115 USA. EM rrodosth@hsph.harvard.edu OI Rodosthenous, Rodosthenis/0000-0002-2312-5530 FU Harvard T. H. Chan School of Public Health-NIEHS Center for Environmental Health [ES000002]; National Institute of Environmental Health Science [ES015172, ES021733]; Cooperative Studies Program/ERIC, U.S. Department of Veterans Affairs; U.S. Department of Agriculture, Agricultural Research Service [53-K06-510] FX This work was supported by the Harvard T. H. Chan School of Public Health-NIEHS Center for Environmental Health (ES000002) and the National Institute of Environmental Health Science (ES015172 and ES021733). The U.S. Department of Veterans Affairs (VA) Normative Aging Study (NAS) is supported by the Cooperative Studies Program/ERIC, U.S. Department of Veterans Affairs, and is a research component of the Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC). Additional support to the VA Normative Aging Study was provided by the U.S. Department of Agriculture, Agricultural Research Service (contract 53-K06-510). The views expressed in this paper are those of the authors and do not necessarily represent the views of the U.S. Department of Veterans Affairs. This publication was made possible by USEPA (RD-834798-01). Its contents are solely the responsibility of the grantee and do not necessarily represent the official views of the USEPA. Further, USEPA does not endorse the purchase of any commercial products or services mentioned in the publication. NR 60 TC 3 Z9 3 U1 3 U2 11 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1743-8977 J9 PART FIBRE TOXICOL JI Part. Fibre Toxicol. PD MAR 8 PY 2016 VL 13 AR 13 DI 10.1186/s12989-016-0121-0 PG 13 WC Toxicology SC Toxicology GA DG0VR UT WOS:000371784400001 PM 26956024 ER PT J AU Jimenez, AM Lee, J Wynn, JK Cohen, MS Engel, SA Glahn, DC Nuechterlein, KH Reavis, EA Green, MF AF Jimenez, Amy M. Lee, Junghee Wynn, Jonathan K. Cohen, Mark S. Engel, Stephen A. Glahn, David C. Nuechterlein, Keith H. Reavis, Eric A. Green, Michael F. TI Abnormal Ventral and Dorsal Attention Network Activity during Single and Dual Target Detection in Schizophrenia SO FRONTIERS IN PSYCHOLOGY LA English DT Article DE schizophrenia; fMRI; visual attention; RSVP; attentional blink ID SERIAL VISUAL PRESENTATION; NEGATIVE SYMPTOMS; HUMAN BRAIN; BLINK; SALIENCE; MEMORY; TASK; FMRI; DEACTIVATION; ENVIRONMENT AB Early visual perception and attention are impaired in schizophrenia, and these deficits can be observed on target detection tasks. These tasks activate distinct ventral and dorsal brain networks which support stimulus-driven and goal-directed attention, respectively. We used single and dual target rapid serial visual presentation (RSVP) tasks during fMRI with an ROI approach to examine regions within these networks associated with target detection and the attentional blink (AB) in 21 schizophrenia outpatients and 25 healthy controls. In both tasks, letters were targets and numbers were distractors. For the dual target task, the second target (T2) was presented at three different lags after the first target (T1) (lag1 = 100 ms, lag3 = 300 ms, lag7 = 700ms). For both single and dual target tasks, patients identified fewer targets than controls. For the dual target task, both groups showed the expected AB effect with poorer performance at lag 3 than at lags 1 or 7, and there was no group by lag interaction. During the single target task, patients showed abnormally increased deactivation of the temporo-parietal junction (TPJ), a key region of the ventral network. When attention demands were increased during the dual target task, patients showed overactivation of the posterior intraparietal cortex, a key dorsal network region, along with failure to deactivate TPJ. Results suggest inefficient and faulty suppression of salience-oriented processing regions, resulting in increased sensitivity to stimuli in general, and difficulty distinguishing targets from non-targets. C1 [Jimenez, Amy M.; Lee, Junghee; Wynn, Jonathan K.; Reavis, Eric A.; Green, Michael F.] VA Greater Los Angeles Healthcare Syst, Desert Pacific MIRECC, Los Angeles, CA USA. [Jimenez, Amy M.; Lee, Junghee; Wynn, Jonathan K.; Cohen, Mark S.; Nuechterlein, Keith H.; Reavis, Eric A.; Green, Michael F.] Univ Calif Los Angeles, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90024 USA. [Engel, Stephen A.] Univ Minnesota, Dept Psychol, Minneapolis, MN USA. [Glahn, David C.] Yale Univ, Dept Psychiat, New Haven, CT 06520 USA. RP Jimenez, AM (reprint author), VA Greater Los Angeles Healthcare Syst, Desert Pacific MIRECC, Los Angeles, CA USA.; Jimenez, AM (reprint author), Univ Calif Los Angeles, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90024 USA. EM amjimenez@ucla.edu RI Wynn, Jonathan/H-3749-2014; Lee, Junghee/C-5226-2014 OI Wynn, Jonathan/0000-0002-1763-8540; Lee, Junghee/0000-0001-9567-8700 FU NIMH [MH043292]; Brain Mapping Medical Research Organization; Brain Mapping Support Foundation; Pierson-Lovelace Foundation; Ahmanson Foundation; William M. and Linda R. Dietel Philanthropic Fund at the Northern Piedmont Community Foundation; Tamkin Foundation; Jennifer Jones-Simon Foundation; Capital Group Companies Charitable Foundation; Robson Family; Northstar Fund FX This research was supported by NIMH Grant MH043292 (PI: MG). Writing of this manuscript was supported by the Office of Academic Affiliations, Advanced Fellowship Program in Mental Illness Research and Treatment, Department of Veterans Affairs. For generous support, we also thank the Brain Mapping Medical Research Organization, Brain Mapping Support Foundation, Pierson-Lovelace Foundation, The Ahmanson Foundation, William M. and Linda R. Dietel Philanthropic Fund at the Northern Piedmont Community Foundation, Tamkin Foundation, Jennifer Jones-Simon Foundation, Capital Group Companies Charitable Foundation, Robson Family, and Northstar Fund. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 53 TC 0 Z9 0 U1 5 U2 8 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1664-1078 J9 FRONT PSYCHOL JI Front. Psychol. PD MAR 8 PY 2016 VL 7 AR 323 DI 10.3389/fpsyg.7015.00323 PG 11 WC Psychology, Multidisciplinary SC Psychology GA DF5NF UT WOS:000371398100001 PM 27014135 ER PT J AU Lipska, KJ Krumholz, H Soones, T Lee, SJ AF Lipska, Kasia J. Krumholz, Harlan Soones, Tacara Lee, Sei J. TI Polypharmacy in the Aging Patient A Review of Glycemic Control in Older Adults With Type 2 Diabetes SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Review ID INTENSIVE GLUCOSE CONTROL; CLINICAL-PRACTICE GUIDELINES; DRUG-DRUG INTERACTIONS; CARDIOVASCULAR OUTCOMES; RISK-FACTORS; SEVERE HYPOGLYCEMIA; INSULIN-RESISTANCE; ACCORD TRIAL; FOLLOW-UP; HEMOGLOBIN A(1C) AB IMPORTANCE There is substantial uncertainty about optimal glycemic control in older adults with type 2 diabetes mellitus. OBSERVATIONS Four large randomized clinical trials (RCTs), ranging in size from 1791 to 11 440 patients, provide the majority of the evidence used to guide diabetes therapy. Most RCTs of intensive vs standard glycemic control excluded adults older than 80 years, used surrogate end points to evaluate microvascular outcomes and provided limited data on which subgroups are most likely to benefit or be harmed by specific therapies. Available data from randomized clinical trials suggest that intensive glycemic control does not reduce major macrovascular events in older adults for at least 10 years. Furthermore, intensive glycemic control does not lead to improved patient-centered microvascular outcomes for at least 8 years. Data from randomized clinical trials consistently suggest that intensive glycemic control immediately increases the risk of severe hypoglycemia 1.5-to 3-fold. Based on these data and observational studies, for the majority of adults older than 65 years, the harms associated with a hemoglobin A1c (HbA1c) target lower than 7.5% or higher than 9% are likely to outweigh the benefits. However, the optimal target depends on patient factors, medications used to reach the target, life expectancy, and patient preferences about treatment. If only medications with low treatment burden and hypoglycemia risk (such as metformin) are required, a lower HbA1c targetmay be appropriate. If patients strongly prefer to avoid injections or frequent fingerstick monitoring, a higher HbA1c target that obviates the need for insulin may be appropriate. CONCLUSIONS AND RELEVANCE High-quality evidence about glycemic treatment in older adults is lacking. Optimal decisions need to be made collaboratively with patients, incorporating the likelihood of benefits and harms and patient preferences about treatment and treatment burden. For the majority of older adults, an HbA1c target between 7.5% and 9% will maximize benefits and minimize harms. C1 [Lipska, Kasia J.] Yale Univ, Sch Med, Dept Internal Med, Endocrinol Sect, 333 Cedar St,POB 208020, New Haven, CT 06520 USA. [Krumholz, Harlan] Yale New Haven Med Ctr, Ctr Outcomes Res & Evaluat, 20 York St, New Haven, CT 06504 USA. [Krumholz, Harlan] Yale Univ, Sch Med, Sect Cardiovasc Med, New Haven, CT 06520 USA. [Krumholz, Harlan] Yale Univ, Sch Med, Robert Wood Johnson Fdn, Clin Scholars Program, New Haven, CT 06520 USA. [Krumholz, Harlan] Yale Univ, Sch Publ Hlth, Dept Hlth Policy & Management, New Haven, CT 06520 USA. [Soones, Tacara] Icahn Sch Med Mt Sinai, Dept Geriatr & Palliat Med, New York, NY 10029 USA. [Lee, Sei J.] Univ Calif San Francisco, Dept Med, Div Geriatr, San Francisco, CA USA. [Lee, Sei J.] San Francisco VA Med Ctr, San Francisco, CA USA. RP Lipska, KJ (reprint author), Yale Univ, Sch Med, Dept Internal Med, Endocrinol Sect, 333 Cedar St,POB 208020, New Haven, CT 06520 USA. EM kasia.lipska@yale.edu FU Beeson Career Development Award from the National Institute on Aging; American Federation of Aging Research [K23AG048359, K23AG040779]; Early Career Award from the S. D. Bechtel Jr Foundation FX Dr Lipska's effort on this project was supported through the Beeson Career Development Award from the National Institute on Aging and the American Federation of Aging Research (K23AG048359). Dr Lee's effort on this project was supported through the Beeson Career Development Award from the National Institute on Aging and the American Federation of Aging Research (K23AG040779) and an Early Career Award from the S. D. Bechtel Jr Foundation. NR 84 TC 16 Z9 16 U1 8 U2 12 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD MAR 8 PY 2016 VL 315 IS 10 BP 1034 EP 1045 DI 10.1001/jama.2016.0299 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA DF7LW UT WOS:000371540200016 PM 26954412 ER PT J AU Voog, JC Smith, MR Efstathiou, JA AF Voog, Justin C. Smith, Matthew R. Efstathiou, Jason A. TI Radiation With or Without Androgen Deprivation Therapy for Localized Prostate Cancer SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter C1 [Voog, Justin C.] Harvard Radiat Oncol Program, Boston, MA USA. [Smith, Matthew R.] Massachusetts Gen Hosp, Genitourinary Malignancies Program, Boston, MA 02114 USA. [Efstathiou, Jason A.] Massachusetts Gen Hosp, Dept Radiat Oncol, 100 Blossom St,Cox 3, Boston, MA 02114 USA. RP Efstathiou, JA (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, 100 Blossom St,Cox 3, Boston, MA 02114 USA. EM jefstathiou@partners.org NR 5 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 MAR 8 PY 2016 VL 315 IS 10 BP 1054 EP 1055 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA DF7LW UT WOS:000371540200023 PM 26954419 ER PT J AU D'Amico, AV Chen, MH Kantoff, PW AF D'Amico, Anthony V. Chen, Ming-Hui Kantoff, Philip W. TI Radiation With or Without Androgen Deprivation Therapy for Localized Prostate Cancer Reply SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter C1 [D'Amico, Anthony V.] Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA. [Chen, Ming-Hui] Univ Connecticut, Dept Stat, Storrs, CT 06269 USA. [Kantoff, Philip W.] Dana Farber Canc Inst, Dept Med, Boston, MA 02115 USA. RP D'Amico, AV (reprint author), Brigham & Womens Hosp, Dept Radiat Oncol, 75 Francis St, Boston, MA 02115 USA. EM adamico@partners.org NR 4 TC 1 Z9 1 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 MAR 8 PY 2016 VL 315 IS 10 BP 1055 EP 1056 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA DF7LW UT WOS:000371540200024 PM 26954420 ER PT J AU Libby, P Nahrendorf, M Swirski, FK AF Libby, Peter Nahrendorf, Matthias Swirski, Filip K. TI Leukocytes Link Local and Systemic Inflammation in Ischemic Cardiovascular Disease An Expanded "Cardiovascular Continuum" SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Review DE acute coronary syndromes; myocardial infarction; white blood cells ID COLONY-STIMULATING FACTOR; ACUTE MYOCARDIAL-INFARCTION; ACUTE CORONARY SYNDROMES; FACTOR GENE-EXPRESSION; MAST-CELLS; ATHEROSCLEROTIC LESIONS; HEMATOPOIETIC STEM; ADAPTIVE IMMUNITY; SPLENIC RESERVOIR; MONOCYTE SUBSETS AB Physicians have traditionally viewed ischemic heart disease in a cardiocentric manner: plaques grow in arteries until they block blood flow, causing acute coronary and other ischemic syndromes. Recent research provides new insight into the integrative biology of inflammation as it contributes to ischemic cardiovascular disease. These results have revealed hitherto unsuspected inflammatory signaling networks at work in these disorders that link the brain, autonomic nervous system, bone marrow, and spleen to the atherosclerotic plaque and to the infarcting myocardium. A burgeoning clinical published data indicates that such inflammatory networks-far from a mere laboratory curiosity-operate in our patients and can influence aspects of ischemic cardiovascular disease that determine decisively clinical outcomes. These new findings enlarge the circle of the traditional "cardiovascular continuum" beyond the heart and vessels to include the nervous system, the spleen, and the bone marrow. (C) 2016 by the American College of Cardiology Foundation. C1 [Libby, Peter] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Cardiovasc Med,Dept Med, 77 Ave Louis Pasteur, Boston, MA 02115 USA. [Nahrendorf, Matthias; Swirski, Filip K.] Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. RP Libby, P (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Cardiovasc Med,Dept Med, 77 Ave Louis Pasteur, Boston, MA 02115 USA. EM plibby@rics.bwh.harvard.edu FU National Heart, Lung, and Blood Institute [R01 HL080472]; GlaxoSmithKline; Kowa; Novartis; Sanofi-Regeneron; Takeda FX Dr. Libby is funded by the National Heart, Lung, and Blood Institute (R01 HL080472); is on the scientific advisory boards of Novartis and Interleukin Genetics; receives travel fees from GlaxoSmithKline, Kowa, Novartis, Sanofi-Regeneron, and Takeda; and consults for clinical trials for Novartis, Pfizer, Esperion, and Kowa. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. NR 76 TC 14 Z9 14 U1 3 U2 9 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 8 PY 2016 VL 67 IS 9 BP 1091 EP 1103 DI 10.1016/j.jacc.2015.12.048 PG 13 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DE9DV UT WOS:000370936800013 PM 26940931 ER PT J AU Poole, JE Singh, JP Birgersdotter-Green, U AF Poole, Jeanne E. Singh, Jagmeet P. Birgersdotter-Green, Ulrika TI QRS Duration or QRS Morphology What Really Matters in Cardiac Resynchronization Therapy? SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Review DE bundle branch block; implantable defibrillator; pacing ID BUNDLE-BRANCH-BLOCK; CHRONIC HEART-FAILURE; DEFIBRILLATOR IMPLANTATION TRIAL; RANDOMIZED-CONTROLLED-TRIALS; LEFT-VENTRICULAR DYSFUNCTION; CLINICAL EVENT REDUCTION; LEAD PLACEMENT; NARROW QRS; CARDIOVERTER-DEFIBRILLATOR; ELECTRICAL DELAY AB The beneficial effects of cardiac resynchronization therapy (CRT) have been well established in large, randomized trials. Despite the documented success of this treatment strategy, a significant proportion of patients with heart failure do not achieve the desired response. The aim of this review was to delineate factors contributing to a successful CRT response, emphasizing the interrelated roles of QRS morphology and QRS interval duration. More data are available on QRS duration, as this factor has been used as an enrollment criterion in clinical trials. Response to CRT seems to increase as the QRS duration becomes longer, with greatest benefit in QRS duration >= 150 ms. Recent data have placed more emphasis on QRS morphology, demonstrating variability in clinical response between patients with left bundle branch block, non-left bundle branch block, and right bundle branch block morphology. Notably, myocardial scarring and cardiac dimensions, among other variables, may alter heterogeneity in ventricular activation. Understanding the electrophysiological underpinnings of the QRS complex has become important not only to predict response but also to facilitate the patient-specific delivery of resynchronization therapy. (C) 2016 by the American College of Cardiology Foundation. C1 [Poole, Jeanne E.] Univ Washington, Dept Med, Seattle, WA USA. [Singh, Jagmeet P.] Harvard Univ, Sch Med, Dept Med, Massachusetts Gen Hosp, Boston, MA USA. [Birgersdotter-Green, Ulrika] Univ Calif San Diego, Dept Med, San Diego, CA 92103 USA. RP Poole, JE (reprint author), Univ Washington, 1959 NE Pacific St,Box 356422, Seattle, WA 98195 USA. EM jpoole@u.washington.edu FU Boston Scientific; St. Jude Medical; Medtronic FX Dr. Poole has received honoraria for speaking from Biotronik, Boston Scientific, Medtronic, St. Jude Medical, and Zoll; and has served on the advisory boards of Boston Scientific, and Physio Control. Dr. Singh has received honoraria from Biotronik, Boston Scientific, Medtronic, St. Jude Medical, Sorin, and Cardioinsight; and has received research grants from Boston Scientific, and St. Jude Medical. Dr. Birgersdotter-Green has received honoraria for speaking from Boston Scientific, Medtronic, and St. Jude Medical; and has received consulting fees and research grants from Medtronic, and St. Jude Medical. Arthur J. Moss, MD, served as Guest Editor for this paper. NR 61 TC 4 Z9 4 U1 0 U2 7 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 MAR 8 PY 2016 VL 67 IS 9 BP 1104 EP 1117 DI 10.1016/j.jacc.2015.12.039 PG 14 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DE9DV UT WOS:000370936800014 PM 26940932 ER PT J AU Nuvolone, M Hermann, M Sorce, S Russo, G Tiberi, C Schwarz, P Minikel, E Sanoudou, D Pelczar, P Aguzzi, A AF Nuvolone, Mario Hermann, Mario Sorce, Silvia Russo, Giancarlo Tiberi, Cinzia Schwarz, Petra Minikel, Eric Sanoudou, Despina Pelczar, Pawel Aguzzi, Adriano TI Strictly co-isogenic C57BL/6J-Prnp(-/-) mice: A rigorous resource for prion science SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID GENE-EXPRESSION; GENOTOXIC STRESS; MOUSE STRAINS; PROTEIN; BRAIN; PRP; CELLS; POLYMORPHISMS; PHAGOCYTOSIS; DATABASE AB Although its involvement in prion replication and neurotoxicity during transmissible spongiform encephalopathies is undisputed, the physiological role of the cellular prion protein (PrPC) remains enigmatic. A plethora of functions have been ascribed to PrPC based on phenotypes of Prnp(-/-) mice. However, all currently available Prnp(-/-) lines were generated in embryonic stem cells from the 129 strain of the laboratory mouse and mostly crossed to non-129 strains. Therefore, Prnp-linked loci polymorphic between 129 and the backcrossing strain resulted in systematic genetic confounders and led to erroneous conclusions. We used TAL EN-mediated genome editing in fertilized mouse oocytes to create the Zurich-3 (ZH3) Prnp-ablated allele on a pure C57BL/6J genetic background. Genomic, transcriptional, and phenotypic characterization of Prnp(ZH3/ZH3) mice failed to identify phenotypes previously described in non-co-isogenic Prnp(-/-) mice. However, aged Prnp(ZH3/ZH3) mice developed a chronic demyelinating peripheral neuropathy, confirming the crucial involvement of PrPC in peripheral myelin maintenance. This new line represents a rigorous genetic resource for studying the role of PrPC in physiology and disease. C1 [Nuvolone, Mario; Hermann, Mario; Sorce, Silvia; Tiberi, Cinzia; Schwarz, Petra; Aguzzi, Adriano] Univ Zurich Hosp, Inst Neuropathol, CH-8091 Zurich, Switzerland. [Hermann, Mario; Pelczar, Pawel] Univ Zurich, Inst Lab Anim Sci, CH-8091 Zurich, Switzerland. [Russo, Giancarlo] FGCZ, CH-8057 Zurich, Switzerland. [Minikel, Eric] Prion Alliance, Cambridge, MA 02139 USA. [Minikel, Eric] Broad Inst, Cambridge, MA 02142 USA. [Minikel, Eric] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA. [Sanoudou, Despina] Univ Athens, Sch Med, Attikon Hosp, Dept Internal Med 4, GR-11527 Athens, Greece. RP Aguzzi, A (reprint author), Univ Zurich Hosp, Inst Neuropathol, CH-8091 Zurich, Switzerland. EM adriano.aguzzi@usz.ch FU Collegio Ghislieri, Pavia, Italy; European Research Council [250356, 670958]; European Union (NEURINOX) [278611]; Swiss National Foundation [31003A_141193, CRSII3_147660, 316030_157745]; E-Rare JTC [31ER30_160672]; Novartis Research Foundation; University of Zurich; Swiss Initiative in System Biology SystemsX.ch [2014/260] FX This work was supported by grants from Collegio Ghislieri, Pavia, Italy (to M. Nuvolone). A. Aguzzi was supported by two Advanced Grants from the European Research Council (250356 and 670958); the European Union (NEURINOX, 278611); the Swiss National Foundation (31003A_141193, Sinergia grant, CRSII3_147660 and R'Equip, 316030_157745); the E-Rare JTC, 31ER30_160672; the Novartis Research Foundation; the Clinical Research Priority Programs "Small RNAs" and "Mechanisms and Models of Primary Human Hemato-Lymphatic Diseases" of the University of Zurich; and the Swiss Initiative in System Biology SystemsX.ch (2014/260, "Systems biology of prion diseases"). NR 50 TC 4 Z9 4 U1 2 U2 5 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 950 THIRD AVE, 2ND FLR, NEW YORK, NY 10022 USA SN 0022-1007 EI 1540-9538 J9 J EXP MED JI J. Exp. Med. PD MAR 7 PY 2016 VL 213 IS 3 BP 313 EP 327 DI 10.1084/jem.20151610 PG 15 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA DI3HS UT WOS:000373390300003 PM 26926995 ER PT J AU Rigoni, R Fontana, E Guglielmetti, S Fosso, B D'Erchia, AM Maina, V Taverniti, V Castiello, MC Mantero, S Pacchiana, G Musio, S Pedotti, R Selmi, C Mora, JR Pesole, G Vezzoni, P Poliani, PL Grassi, F Villa, A Cassani, B AF Rigoni, Rosita Fontana, Elena Guglielmetti, Simone Fosso, Bruno D'Erchia, Anna Maria Maina, Virginia Taverniti, Valentina Castiello, Maria Carmina Mantero, Stefano Pacchiana, Giovanni Musio, Silvia Pedotti, Rosetta Selmi, Carlo Mora, J. Rodrigo Pesole, Graziano Vezzoni, Paolo Poliani, Pietro Luigi Grassi, Fabio Villa, Anna Cassani, Barbara TI Intestinal microbiota sustains inflammation and autoimmunity induced by hypomorphic RAG defects SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID REGULATORY T-CELLS; OMENN-SYNDROME; BOWEL-DISEASE; DENDRITIC CELLS; ORAL TOLERANCE; GUT MICROBIOTA; TH17 CELLS; COMBINED IMMUNODEFICIENCY; HOMEOSTATIC EXPANSION; V(D)J RECOMBINATION AB Omenn syndrome (OS) is caused by hypomorphic Rag mutations and characterized by a profound immunodeficiency associated with autoimmune-like manifestations. Both in humans and mice, OS is mediated by oligoclonal activated T and B cells. The role of microbial signals in disease pathogenesis is debated. Here, we show that Rag2(R229Q) knock-in mice developed an inflammatory bowel disease affecting both the small bowel and colon. Lymphocytes were sufficient for disease induction, as intestinal CD4 T cells with a Th1/Th17 phenotype reproduced the pathological picture when transplanted into immunocompromised hosts. Moreover, oral tolerance was impaired in Rag2(R229Q) mice, and transfer of wild-type (WT) regulatory T cells ameliorated bowel inflammation. Mucosal immunoglobulin A (IgA) deficiency in the gut resulted in enhanced absorption of microbial products and altered composition of commensal communities. The Rag2(R229Q) microbiota further contributed to the immunopathology because its transplant into WT recipients promoted Th1/Th17 immune response. Consistently, long-term dosing of broad-spectrum antibiotics (ABXs) in Rag2(R229Q) mice ameliorated intestinal and systemic autoimmunity by diminishing the frequency of mucosal and circulating gut-tropic CCR9(+) Th1 and Th17 T cells. Remarkably, serum hyper-IgE, a hallmark of the disease, was also normalized by ABX treatment. These results indicate that intestinal microbes may play a critical role in the distinctive immune dysregulation of OS. C1 [Rigoni, Rosita; Pacchiana, Giovanni; Vezzoni, Paolo; Villa, Anna; Cassani, Barbara] CNR, Ist Ric Genet & Biomed, Milan Unit, I-20133 Milan, Italy. [Rigoni, Rosita; Pacchiana, Giovanni; Selmi, Carlo; Vezzoni, Paolo; Cassani, Barbara] Humanitas Clin & Res Ctr, I-20089 Milan, Italy. [Fontana, Elena; Poliani, Pietro Luigi] Univ Brescia, Sch Med, Pathol Unit, Dept Mol & Translat Med, I-25123 Brescia, Italy. [Guglielmetti, Simone; Taverniti, Valentina] Univ Milan, Dept Food Environm & Nutr Sci DeFENS, I-20122 Milan, Italy. [Grassi, Fabio] Univ Milan, Ist Nazl Genet Mol, Dept Med Biotechnol & Translat Med, I-20122 Milan, Italy. [Selmi, Carlo] Univ Milan, BIOMETRA Dept, I-20122 Milan, Italy. [D'Erchia, Anna Maria; Pesole, Graziano] Univ Bari, Dept Biosci Biotechnol & Pharmacol Sci, I-70121 Bari, Italy. [Fosso, Bruno; D'Erchia, Anna Maria; Pesole, Graziano] CNR, Inst Biomembranes & Bioenerget, I-70126 Bari, Italy. [Maina, Virginia; Castiello, Maria Carmina; Mantero, Stefano; Villa, Anna] Ist Sci San Raffaele, IRCCS, Div Regenerat Med Stem Cells & Gene Therapy, Telethon Inst Gene Therapy, I-20132 Milan, Italy. [Musio, Silvia; Pedotti, Rosetta] Fdn IRCCS Neurol Inst C Besta, Neuroimmunol & Neuromuscular Disorders Unit, I-20132 Milan, Italy. [Mora, J. Rodrigo] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Gastrointestinal Unit, Boston, MA 02115 USA. [Grassi, Fabio] Inst Res Biomed, CH-6500 Bellinzona, Switzerland. RP Villa, A; Cassani, B (reprint author), CNR, Ist Ric Genet & Biomed, Milan Unit, I-20133 Milan, Italy.; Cassani, B (reprint author), Humanitas Clin & Res Ctr, I-20089 Milan, Italy.; Villa, A (reprint author), Ist Sci San Raffaele, IRCCS, Div Regenerat Med Stem Cells & Gene Therapy, Telethon Inst Gene Therapy, I-20132 Milan, Italy. EM anna.villa@hsr.it; barbara.cassani@humanitasresearch.it RI Musio, Silvia/K-3072-2016; Cassani, Barbara/K-3871-2016; OI Musio, Silvia/0000-0002-8051-7389; Cassani, Barbara/0000-0002-4115-8109; Mantero, Stefano/0000-0003-0608-2724; Fosso, Bruno/0000-0003-2324-086X; D'ERCHIA, Anna Maria/0000-0002-4627-0626 FU Ministry of Education, University, and Research grant MIUR-FIR [RBFR12I3UB]; Ministry of Health Giovani Ricercatori grant [GR-2011-02349759, GR-2009-1607206]; Ministry of Education, University, and Research grant MIUR-FIRB [RBAP11H2R9-004]; Ministry of Education, University, and Research grant MIUR [PON01_02589]; Consiglio Nazionale delle Ricerche Medicina Personalizzata; San Raffaele Telethon Institute for Gene Therapy (TIGET) core grant A3 from the Italian Telethon Foundation; Fondazione Cariplo grant [N-2012-0519] FX This work was supported by Ministry of Education, University, and Research grant MIUR-FIR RBFR12I3UB and Ministry of Health Giovani Ricercatori grant GR-2011-02349759 to B. Cassani, Ministry of Education, University, and Research grant MIUR-FIRB RBAP11H2R9-004 to P. Vezzoni, Ministry of Education, University, and Research grant MIUR PON01_02589 and Consiglio Nazionale delle Ricerche Medicina Personalizzata to G. Pesole and A.M. D'Erchia, San Raffaele Telethon Institute for Gene Therapy (TIGET) core grant A3 from the Italian Telethon Foundation to A. Villa and Fondazione Cariplo grant N-2012-0519 to A. Villa, P.L. Poliani, and F. Grassi, and Ministry of Health Giovani Ricercatori grant GR-2009-1607206 to R. Pedotti. B. Cassani was the recipient of a Gerry Scotti fellowship, and R. Rigoni was the recipient of a short-term European Federation of Immunological Societies fellowship. NR 85 TC 3 Z9 3 U1 7 U2 11 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 950 THIRD AVE, 2ND FLR, NEW YORK, NY 10022 USA SN 0022-1007 EI 1540-9538 J9 J EXP MED JI J. Exp. Med. PD MAR 7 PY 2016 VL 213 IS 3 BP 355 EP 375 DI 10.1084/jem.20151116 PG 21 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA DI3HS UT WOS:000373390300006 PM 26926994 ER PT J AU Zhang, W Hartmann, R Tun, HM Elson, CO Khafipour, E Garvey, WT AF Zhang, Wei Hartmann, Riley Tun, Hein Min Elson, Charles O. Khafipour, Ehsan Garvey, W. Timothy TI Deletion of the Toll-Like Receptor 5 Gene Per Se Does Not Determine the Gut Microbiome Profile That Induces Metabolic Syndrome: Environment Trumps Genotype SO PLOS ONE LA English DT Article ID INTESTINAL MICROBIOTA; INNATE IMMUNITY; OBESITY; MICE; COMMUNITIES; DIET; SEQUENCE; SHAPES AB Over the past decade, emerging evidence has linked alterations in the gut microbial composition to a wide range of diseases including obesity, type 2 diabetes, and cardiovascular disease. Toll-like receptors (TLRs) are the major mediators for the interactions between gut microbiota and host innate immune system, which is involved in the localization and structuring of host gut microbiota. A previous study found that TLR5 deficient mice (TLR5KO1) had altered gut microbial composition which led to the development of metabolic syndrome including hyperlipidemia, hypertension, insulin resistance and increased adiposity. In the current study, a second TLR5-deficient mouse model was studied (TLR5KO2). TLR5 deficient mice did not manifest metabolic abnormalities related to the metabolic syndrome compared with littermate controls maintained on normal chow or after feeding a high fat diet. Analysis of the gut microbial composition of littermate TLR5KO2 and wild type mice revealed no significant difference in the overall microbiota structure between genotypes. However, the TLR5KO2 microbiota was distinctly different from that previously reported for TLR5KO1 mice with metabolic syndrome. We conclude that an altered composition of the microbiota in a given environment can result in metabolic syndrome, but it is not a consequence of TLR5 deficiency per se. C1 [Zhang, Wei; Garvey, W. Timothy] Univ Alabama Birmingham, Dept Nutr Sci, Sch Hlth Profess, Birmingham, AL 35294 USA. [Hartmann, Riley; Khafipour, Ehsan] Univ Manitoba, Dept Med Microbiol & Infect Dis, Winnipeg, MB, Canada. [Tun, Hein Min; Khafipour, Ehsan] Univ Manitoba, Dept Anim Sci, Winnipeg, MB R3T 2N2, Canada. [Elson, Charles O.] Univ Alabama Birmingham, Sch Med, Div Gastroenterol & Hepatol, Birmingham, AL USA. [Garvey, W. Timothy] Birmingham VA Med Ctr, Birmingham, AL USA. RP Garvey, WT (reprint author), Univ Alabama Birmingham, Dept Nutr Sci, Sch Hlth Profess, Birmingham, AL 35294 USA.; Khafipour, E (reprint author), Univ Manitoba, Dept Med Microbiol & Infect Dis, Winnipeg, MB, Canada.; Khafipour, E (reprint author), Univ Manitoba, Dept Anim Sci, Winnipeg, MB R3T 2N2, Canada.; Garvey, WT (reprint author), Birmingham VA Med Ctr, Birmingham, AL USA. EM Ehsan.Khafipour@umanitoba.ca; garveyt@uab.edu OI Khafipour, Ehsan/0000-0003-4673-7633 FU UAB Diabetes Research Center (NIDDK) [P60 DK-079626]; National Institutes of Health [RO1 DK083562, R01 DK-38765]; Merit Review Research Grant from the Department of Veterans Affairs FX The authors acknowledge support from UAB Diabetes Research Center (NIDDK, P60 DK-079626), individual research grants from the National Institutes of Health (RO1 DK083562; R01 DK-38765), and a Merit Review Research Grant from the Department of Veterans Affairs. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 47 TC 2 Z9 2 U1 2 U2 13 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 7 PY 2016 VL 11 IS 3 AR e0150943 DI 10.1371/journal.pone.0150943 PG 21 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DG3SL UT WOS:000371990100072 PM 26950299 ER PT J AU Hosios, AM Hecht, VC Danai, LV Johnson, MO Rathmell, JC Steinhauser, ML Manalis, SR Vander Heiden, MG AF Hosios, Aaron M. Hecht, Vivian C. Danai, Laura V. Johnson, Marc O. Rathmell, Jeffrey C. Steinhauser, Matthew L. Manalis, Scott R. Vander Heiden, Matthew G. TI Amino Acids Rather than Glucose Account for the Majority of Cell Mass in Proliferating Mammalian Cells SO DEVELOPMENTAL CELL LA English DT Article ID RAS-TRANSFORMED CELLS; AEROBIC GLYCOLYSIS; GLUTAMINE-METABOLISM; CANCER METABOLISM; ASPARTATE TRANSPORTER; ENDOTHELIAL-CELLS; EPITHELIAL-CELLS; LIPID-METABOLISM; PYRUVATE-KINASE; SUPPORTS GROWTH AB Cells must duplicate their mass in order to proliferate. Glucose and glutamine are the major nutrients consumed by proliferating mammalian cells, but the extent to which these and other nutrients contribute to cell mass is unknown. We quantified the fraction of cell mass derived from different nutrients and found that the majority of carbon mass in cells is derived from other amino acids, which are consumed at much lower rates than glucose and glutamine. While glucose carbon has diverse fates, glutamine contributes most to protein, suggesting that glutamine's ability to replenish tricarboxylic acid cycle intermediates (anaplerosis) is primarily used for amino acid biosynthesis. These findings demonstrate that rates of nutrient consumption are indirectly associated with mass accumulation and suggest that high rates of glucose and glutamine consumption support rapid cell proliferation beyond providing carbon for biosynthesis. C1 [Hosios, Aaron M.; Hecht, Vivian C.; Danai, Laura V.; Manalis, Scott R.; Vander Heiden, Matthew G.] MIT, Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA. [Hosios, Aaron M.; Danai, Laura V.; Vander Heiden, Matthew G.] MIT, Dept Biol, Cambridge, MA 02139 USA. [Hecht, Vivian C.; Manalis, Scott R.] MIT, Dept Biol Engn, Cambridge, MA 02139 USA. [Johnson, Marc O.; Rathmell, Jeffrey C.] Vanderbilt Univ, Med Ctr, Dept Pathol Microbiol & Immunol, Nashville, TN 37232 USA. [Steinhauser, Matthew L.] Brigham & Womens Hosp, Dept Med, Div Genet, Boston, MA 02115 USA. [Steinhauser, Matthew L.] Brigham & Womens Hosp, Dept Med, Div Cardiovasc Med, Boston, MA 02115 USA. [Steinhauser, Matthew L.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Vander Heiden, Matthew G.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. RP Vander Heiden, MG (reprint author), MIT, Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA.; Vander Heiden, MG (reprint author), MIT, Dept Biol, Cambridge, MA 02139 USA.; Vander Heiden, MG (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. EM mvh@mit.edu FU NIH [U54CA121852, R01CA168653, P30CA14051, R01HL108006, U54CA143874, K08DK090147]; Burroughs Wellcome Fund; Ludwig Center at MIT; Damon Runyon Cancer Research Foundation FX This work was supported by NIH grants U54CA121852, R01CA168653, P30CA14051, R01HL108006 (J.C.R.), U54CA143874 (S.R.M.), and K08DK090147 (M.L.S.); the Burroughs Wellcome Fund; the Ludwig Center at MIT; and the Damon Runyon Cancer Research Foundation. A.M.H. is a Howard Hughes Medical Institute International Student Research fellow and was a Vertex Scholar. NR 61 TC 14 Z9 14 U1 8 U2 19 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1534-5807 EI 1878-1551 J9 DEV CELL JI Dev. Cell PD MAR 7 PY 2016 VL 36 IS 5 BP 540 EP 549 DI 10.1016/j.devcel.2016.02.012 PG 10 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA DG1SZ UT WOS:000371849100010 PM 26954548 ER PT J AU Yin, BW Chu, KK Liang, CP Singh, K Reddy, R Tearney, G AF Yin, Biwei Chu, Kengyeh K. Liang, Chia-Pin Singh, Kanwarpal Reddy, Rohith Tearney, Guillermo TI mu OCT imaging using depth of focus extension by self-imaging wavefront division in a common-path fiber optic probe SO OPTICS EXPRESS LA English DT Article ID COHERENCE TOMOGRAPHY; SYNTHETIC-APERTURE; EXTENDED DEPTH; MICROSCOPY; BEAMS AB Optical coherence tomography (OCT) is an attractive medical modality due to its ability to acquire high-resolution, cross-sectional images inside the body using flexible, small-diameter, scanning fiber optic probes. Conventional, cross-sectional OCT imaging technologies have approximately 10-mu m axial resolution and 30-mu m lateral resolution, specifications that enable the visualization of microscopic architectural morphology. While this resolution is useful for many clinical applications, it is insufficient for resolving individual cells that characterize many diseases. To address this gap, a supercontinuum-laser-based, mu m-resolution OCT (mu OCT) system and a 500 mu m-diameter, extended depth of focus single fiber optic probe for endoscopic and intravascular imaging were designed and fabricated. At the distal tip of the fiber optic probe, a cylindrical waveguide was used to divide the wavefront to provide multiple circular propagation modes. Once transmitted through a relatively high NA lens (NA >0.1), these modes were projected as multiple coaxial foci (similar to 3 mu m full width at half maximum (FWHM)) over a greatly extended focal depth range. The distal tip of the probe also contained a common-path reference reflectance to minimize polarization and dispersion imbalances between sample and reference arm light. Measurements showed that the probe provides a 20-fold depth of focus extension, maintaining a 3-5 mu m lateral resolution (FWHM of PSF) and a 2 mu m axial resolution over a depth range of approximately 1 mm. These results suggest that this new optical configuration will be useful for achieving high-resolution, cross-sectional OCT imaging in catheter/endoscope-based medical imaging devices. (C) 2016 Optical Society of America C1 [Yin, Biwei; Chu, Kengyeh K.; Liang, Chia-Pin; Singh, Kanwarpal; Reddy, Rohith; Tearney, Guillermo] Harvard Univ, Sch Med, Wellman Ctr Photomed, 55 Fruit St, Boston, MA 02114 USA. [Yin, Biwei; Chu, Kengyeh K.; Liang, Chia-Pin; Singh, Kanwarpal; Reddy, Rohith; Tearney, Guillermo] Massachusetts Gen Hosp, 55 Fruit St, Boston, MA 02114 USA. [Tearney, Guillermo] MIT, Harvard Mit Div Hlth Sci & Technol, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Tearney, Guillermo] Harvard Univ, Sch Med, Dept Pathol, 55 Fruit St, Boston, MA 02114 USA. RP Tearney, G (reprint author), Harvard Univ, Sch Med, Wellman Ctr Photomed, 55 Fruit St, Boston, MA 02114 USA.; Tearney, G (reprint author), Massachusetts Gen Hosp, 55 Fruit St, Boston, MA 02114 USA.; Tearney, G (reprint author), MIT, Harvard Mit Div Hlth Sci & Technol, 77 Massachusetts Ave, Cambridge, MA 02139 USA.; Tearney, G (reprint author), Harvard Univ, Sch Med, Dept Pathol, 55 Fruit St, Boston, MA 02114 USA. EM gtearney@partners.org FU NIH [R01HL076398]; Ardea Biosciences; Canon Inc. FX The authors thank Dr. Joseph Gardecki for his help in OCT imaging and experimental sample preparation. This study is supported by NIH grant R01HL076398.; Dr. Tearney receives sponsored research funding from Ardea Biosciences and Canon Inc. Massachusetts General Hospital has a licensing arrangement with Terumo Corporation. Dr. Tearney has the rights to receive royalties from this licensing arrangement. Dr. Tearney also receives royalties from MIT. NR 23 TC 5 Z9 5 U1 4 U2 8 PU OPTICAL SOC AMER PI WASHINGTON PA 2010 MASSACHUSETTS AVE NW, WASHINGTON, DC 20036 USA SN 1094-4087 J9 OPT EXPRESS JI Opt. Express PD MAR 7 PY 2016 VL 24 IS 5 BP 5555 EP 5564 DI 10.1364/OE.24.005555 PG 10 WC Optics SC Optics GA DF5ZZ UT WOS:000371435000115 ER PT J AU Burkart, AM Tan, K Warren, L Iovino, S Hughes, KJ Kahn, CR Patti, ME AF Burkart, Alison M. Tan, Kelly Warren, Laura Iovino, Salvatore Hughes, Katelyn J. Kahn, C. Ronald Patti, Mary-Elizabeth TI Insulin Resistance in Human iPS Cells Reduces Mitochondrial Size and Function SO SCIENTIFIC REPORTS LA English DT Article ID TYPE-2 DIABETIC-PATIENTS; PLURIPOTENT STEM-CELLS; HUMAN SKELETAL-MUSCLE; ENERGY-METABOLISM; INTRAVENOUS GLUCOSE; PHYSICAL-ACTIVITY; GENE-EXPRESSION; RECEPTOR GENE; ATP SYNTHESIS; WEIGHT-LOSS AB Insulin resistance, a critical component of type 2 diabetes (T2D), precedes and predicts T2D onset. T2D is also associated with mitochondrial dysfunction. To define the cause-effect relationship between insulin resistance and mitochondrial dysfunction, we compared mitochondrial metabolism in induced pluripotent stem cells (iPSC) from 5 healthy individuals and 4 patients with genetic insulin resistance due to insulin receptor mutations. Insulin-resistant iPSC had increased mitochondrial number and decreased mitochondrial size. Mitochondrial oxidative function was impaired, with decreased citrate synthase activity and spare respiratory capacity. Simultaneously, expression of multiple glycolytic enzymes was decreased, while lactate production increased 80%. These perturbations were accompanied by an increase in ADP/ATP ratio and 3-fold increase in AMPK activity, indicating energetic stress. Insulin-resistant iPSC also showed reduced catalase activity and increased susceptibility to oxidative stress. Thus, insulin resistance can lead to mitochondrial dysfunction with reduced mitochondrial size, oxidative activity, and energy production. C1 [Patti, Mary-Elizabeth] Joslin Diabet Ctr, Integrat Physiol & Metab Res Div, Boston, MA 02215 USA. Harvard Univ, Sch Med, Boston, MA 02215 USA. RP Patti, ME (reprint author), Joslin Diabet Ctr, Integrat Physiol & Metab Res Div, Boston, MA 02215 USA. EM Mary.Elizabeth.Patti@joslin.harvard.edu FU NIH [T32DK007260]; Harold Whitworth Pierce Charitable Trust Postdoctoral Fellowship; American Diabetes Association; Novo Foundation; Joslin DRC grant [P30 DK036836]; [R37DK031036] FX The authors thank Deborah Lee, Hitomi Murao, and Mai Shirozu for technical assistance, Christopher Cahill of the Joslin DRC Advanced Microscopy Core for assistance with electron microscopy, and Christine Miller and Andrew Minotti of the Joslin DRC iPS Core. Funding was gratefully received from the NIH T32DK007260 (to AMB), the Harold Whitworth Pierce Charitable Trust Postdoctoral Fellowship (to AMB), the American Diabetes Association (to MEP), the Novo Foundation (to MEP and CRK), R37DK031036 (to CRK) and the Joslin DRC grant P30 DK036836. NR 68 TC 3 Z9 3 U1 3 U2 13 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 MAR 7 PY 2016 VL 6 AR 22788 DI 10.1038/srep22788 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DF6KU UT WOS:000371465300001 PM 26948272 ER PT J AU Jacobs, IJ Menon, U Ryan, A Gentry-Maharaj, A Burnell, M Kalsi, JK Amso, NN Apostolidou, S Benjamin, E Cruickshank, D Crump, DN Davies, SK Dawnay, A Dobbs, S Fletcher, G Ford, J Godfrey, K Gunu, R Habib, M Hallett, R Herod, J Jenkins, H Karpinskyj, C Leeson, S Lewis, SJ Liston, WR Lopes, A Mould, T Murdoch, J Oram, D Rabideau, DJ Reynolds, K Scott, I Seif, MW Sharma, A Singh, N Taylor, J Warburton, F Widschwendter, M Williamson, K Woolas, R Fallowfield, L McGuire, AJ Campbell, S Parmar, M Skates, SJ AF Jacobs, Ian J. Menon, Usha Ryan, Andy Gentry-Maharaj, Aleksandra Burnell, Matthew Kalsi, Jatinderpal K. Amso, Nazar N. Apostolidou, Sophia Benjamin, Elizabeth Cruickshank, Derek Crump, Danielle N. Davies, Susan K. Dawnay, Anne Dobbs, Stephen Fletcher, Gwendolen Ford, Jeremy Godfrey, Keith Gunu, Richard Habib, Mariam Hallett, Rachel Herod, Jonathan Jenkins, Howard Karpinskyj, Chloe Leeson, Simon Lewis, Sara J. Liston, William R. Lopes, Alberto Mould, Tim Murdoch, John Oram, David Rabideau, Dustin J. Reynolds, Karina Scott, Ian Seif, Mourad W. Sharma, Aarti Singh, Naveena Taylor, Julie Warburton, Fiona Widschwendter, Martin Williamson, Karin Woolas, Robert Fallowfield, Lesley McGuire, Alistair J. Campbell, Stuart Parmar, Mahesh Skates, Steven J. TI Ovarian cancer screening and mortality in the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS): a randomised controlled trial SO LANCET LA English DT Article ID PROPORTIONAL-HAZARDS; POSTMENOPAUSAL WOMEN; RISK; PROSTATE; ALGORITHM; MODELS; LUNG; MULTICENTER; ULTRASOUND; PREVENTION AB Background Ovarian cancer has a poor prognosis, with just 40% of patients surviving 5 years. We designed this trial to establish the effect of early detection by screening on ovarian cancer mortality. rvlethods In this randomised controlled trial, we recruited postmenopausal women aged 50-74 years from 13 centres in National Health Service Trusts in England, Wales, and Northern Ireland. Exclusion criteria were previous bilateral oophorectomy or ovarian malignancy, increased risk of familial ovarian cancer, and active non-ovarian malignancy. The trial management system confirmed eligibility and randomly allocated participants in blocks of 32 using computer generated random numbers to annual multimodal screening (MMS) with serum CA125 interpreted with use of the risk of ovarian cancer algorithm, annual transvaginal ultrasound screening (USS), or no screening, in a 1:1:2 ratio. The primary outcome was death due to ovarian cancer by Dec 31, 2014, comparing MMS and USS separately with no screening, ascertained by an outcomes committee masked to randomisation group. All analyses were by modified intention to screen, excluding the small number of women we discovered after randomisation to have a bilateral oophorectomy, have ovarian cancer, or had exited the registry before recruitment. Investigators and participants were aware of screening type. This trial is registered with ClinicalTrials.gov, number NCT00058032. Findings Between June 1, 2001, and Oct 21, 2005, we randomly allocated 202 638 women: 50 640 (25.0%) to MMS, 50 639 (25.0%) to USS, and 101359 (50.0%) to no screening. 202 546 (>99.9%) women were eligible for analysis: 50 624 (>99.9%) women in the MMS group, 50 623 (>99.9%) in the USS group, and 101 299 (>99.9%) in the no screening group. Screening ended on Dec 31, 2011, and included 345 570 MMS and 3 27 775 USS annual screening episodes. At a median follow-up of 11.1 years (IQR 10.0-12.0), we diagnosed ovarian cancer in 1282 (0.6%) women: 338 (0.7%) in the MMS group, 314 (0.6%) in the USS group, and 630 (0.6%) in the no screening group. Of these women, 148 (0.29%) women in the MMS group, 154 (0.30%) in the USS group, and 347 (0.34%) in the no screening group had died of ovarian cancer. The primary analysis using a Cox proportional hazards model gave a mortality reduction over years 0-14 of 15% (95% CI 3 to 30; p=0.10) with MMS and 11% (-7 to 27; p=0.21) with USS. The Royston-Parmar flexible parametric model showed that in the MMS group, this mortality effect was made up of 8% (-20 to 31) in years 0-7 and 23% (1-46) in years 7-14, and in the USS group, of 2% (-27 to 26) in years 0-7 and 21% (-2 to 42) in years 7-14. A prespecified analysis of death from ovarian cancer of MMS versus no screening with exclusion of prevalent cases showed significantly different death rates (p=0.021), with an overall average mortality reduction of 20% (-2 to 40) and a reduction of 8% (-27 to 43) in years 0-7 and 28% (-3 to 49) in years 7-14 in favour of MMS. Interpretation Although the mortality reduction was not significant in the primary analysis, we noted a significant mortality reduction with MMS when prevalent cases were excluded. We noted encouraging evidence of a mortality reduction in years 7-14, but further follow-up is needed before firm conclusions can be reached on the efficacy and cost-effectiveness of ovarian cancer screening. C1 [Jacobs, Ian J.; Menon, Usha; Ryan, Andy; Gentry-Maharaj, Aleksandra; Burnell, Matthew; Kalsi, Jatinderpal K.; Apostolidou, Sophia; Crump, Danielle N.; Davies, Susan K.; Fletcher, Gwendolen; Ford, Jeremy; Gunu, Richard; Habib, Mariam; Hallett, Rachel; Karpinskyj, Chloe; Lewis, Sara J.; Liston, William R.; Sharma, Aarti; Taylor, Julie; Warburton, Fiona; Widschwendter, Martin; Woolas, Robert] UCL, Inst Womens Hlth, Dept Womens Canc, London W1T 7DN, England. [Jacobs, Ian J.] Univ New S Wales, Sydney, NSW 2052, Australia. [Jacobs, Ian J.] Univ Manchester, Ctr Womens Hlth, Inst Human Dev, Manchester, Lancs, England. [Amso, Nazar N.] Cardiff Univ, Coll Biomed & Life Sci, Sch Med, Obstet & Gynaecol, Cardiff CF10 3AX, S Glam, Wales. [Benjamin, Elizabeth] Univ Coll London Hosp, Dept Pathol Res, Inst Canc, London, England. [Dawnay, Anne] Univ Coll London Hosp, Clin Biochem, London, England. [Mould, Tim] Univ Coll London Hosp, Dept Gynaecol Oncol, London, England. [Cruickshank, Derek] James Cook Univ Hosp, Dept Gynaecol Oncol, Middlesbrough, Cleveland, England. [Dobbs, Stephen] Belfast City Hosp, Dept Gynaecol Oncol, Belfast BT9 7AD, Antrim, North Ireland. [Ford, Jeremy] Qatari Shareholding Co, Malomatia Informat Commun & Technol QATAR, Doha, Qatar. [Godfrey, Keith; Lopes, Alberto] Queen Elizabeth Hosp, Northern Gynaecol Oncol Ctr, Gateshead, Tyne & Wear, England. [Habib, Mariam] Natl Hosp Neurol & Neurosurg, Med Res Council, Ctr Neuromuscular Dis, Queen Sq, London WC1N 3BG, England. [Hallett, Rachel] Bangor Univ, Sch Med Sci, Bangor, Gwynedd, Wales. [Herod, Jonathan] Liverpool Womens Hosp, Dept Gynaecol, Liverpool, Merseyside, England. [Herod, Jonathan] Hamad Med Corp, Womens Hosp, Doha, Qatar. [Jenkins, Howard; Scott, Ian] Royal Derby Hosp, Dept Gynaecol Oncol, Derby, England. [Leeson, Simon] Llandudno Hosp, Dept Gynaecol Oncol, Llandudno, Gwynedd, Wales. [Lopes, Alberto] Derriford Hosp, Plymouth PL6 8DH, Devon, England. [Mould, Tim] Royal Free Hosp, Dept Gynaecol Oncol, Pond St, London NW3 2QG, England. [Murdoch, John] St Michaels Hosp, Dept Gynaecol Oncol, Bristol, Avon, England. [Oram, David; Reynolds, Karina] St Bartholomews Hosp, Dept Gynaecol Oncol, London, England. [Rabideau, Dustin J.; Skates, Steven J.] Massachusetts Gen Hosp, Biostat Ctr, Boston, MA 02114 USA. [Seif, Mourad W.] St Marys Hosp, Cent Manchester Fdn Trust, Manchester M13 0JH, Lancs, England. [Seif, Mourad W.] Univ Manchester, Inst Canc Sci, Manchester, Lancs, England. [Sharma, Aarti] Univ Wales Hosp, Dept Gynaecol Oncol, Heath Pk, Cardiff, S Glam, Wales. [Singh, Naveena] Barts Hlth Natl Hlth Serv Trust, Dept Pathol, London, England. [Warburton, Fiona] Publ Hlth England, London, England. [Williamson, Karin] City Hosp Nottingham, Dept Gynaecol Oncol, Nottingham, England. [Woolas, Robert] Queen Alexandra Hosp, Dept Gynaecol Oncol, Portsmouth, Hants, England. [Fallowfield, Lesley] Univ Sussex, Sussex Hlth Outcomes Res & Educ Canc, Brighton & Sussex Med Sch, Sussex, England. [McGuire, Alistair J.] London Sch Econ, Dept Social Policy, London WC2A 2AE, England. [Campbell, Stuart] Create Hlth Clin, London, England. [Parmar, Mahesh] UCL, Clin Trials Unit, MRC, London, England. [Skates, Steven J.] Harvard Univ, Sch Med, Boston, MA USA. RP Menon, U (reprint author), UCL, Inst Womens Hlth, Dept Womens Canc, London W1T 7DN, England.; Jacobs, IJ (reprint author), Univ New S Wales, Sydney, NSW 2052, Australia. EM i.jacobs@unsw.edu.au; u.menon@ucl.ac.uk FU Medical Research Council; Cancer Research UK; Department of Health; Eve Appeal FX Medical Research Council, Cancer Research UK, Department of Health, The Eve Appeal. NR 41 TC 66 Z9 67 U1 16 U2 20 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 MAR 5 PY 2016 VL 387 IS 10022 BP 945 EP 956 DI 10.1016/S0140-6736(15)01224-6 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA DF8XP UT WOS:000371644200028 PM 26707054 ER PT J AU Yao, JC Fazio, N Singh, S Buzzoni, R Carnaghi, C Wolin, E Tomasek, J Raderer, M Lahner, H Voi, M Pacaud, LB Rouyrre, N Sachs, C Valle, JW Delle Fave, G Van Cutsem, E Tesselaar, M Shimada, Y Oh, DY Strosberg, J Kulke, MH Pavel, ME AF Yao, James C. Fazio, Nicola Singh, Simron Buzzoni, Roberto Carnaghi, Carlo Wolin, Edward Tomasek, Jiri Raderer, Markus Lahner, Harald Voi, Maurizio Pacaud, Lida Buboteishvili Rouyrre, Nicolas Sachs, Carolin Valle, Juan W. Delle Fave, Gianfranco Van Cutsem, Eric Tesselaar, Margot Shimada, Yasuhiro Oh, Do-Youn Strosberg, Jonathan Kulke, Matthew H. Pavel, Marianne E. CA RAD001 Adv Neuroendocrine Tumours Fourth Trial RADIANT-4 Study Grp TI Everolimus for the treatment of advanced, non-functional neuroendocrine tumours of the lung or gastrointestinal tract (RADIANT-4): a randomised, placebo-controlled, phase 3 study SO LANCET LA English DT Article ID MUTATIONS; SUNITINIB AB Background Effective systemic therapies for patients with advanced, progressive neuroendocrine tumours of the lung or gastrointestinal tract are scarce. We aimed to assess the efficacy and safety of everolimus compared with placebo in this patient population. Methods In the randomised, double-blind, placebo-controlled, phase 3 RADIANT-4 trial, adult patients (aged.1.8 years) with advanced, progressive, well-differentiated, non-functional neuroendocrine tumours of lung or gastrointestinal origin were enrolled from 97 centres in 25 countries worldwide. Eligible patients were randomly assigned in a 2:1 ratio by an interactive voice response system to receive everolimus 10 mg per day orally or identical placebo, both with supportive care. Patients were stratified by tumour origin, performance status, and previous somatostatin analogue treatment. Patients, investigators, and the study sponsor were masked to treatment assignment. The primary endpoint was progression-free survival assessed by central radiology review, analysed by intention to treat. Overall survival was a key secondary endpoint. This trial is registered with ClinicalTrials.gov, number NCT01524783. Findings Between April 3,2012, and Aug 23,2013, a total of 302 patients were enrolled, of whom 205 were allocated to everolimus 10 mg per day and 97 to placebo. Median progression-free survival was 11.0 months (95% CI 9.2-13.3) in the everolimus group and 3.9 months (3.6-7.4) in the placebo group. Everolimus was associated with a 52% reduction in the estimated risk of progression or death (hazard ratio [HR] 0.48 [95% CI 0.35-0.67], p<0.00001). Although not statistically significant, the results of the first pre-planned interim overall survival analysis indicated that everolimus might be associated with a reduction in the risk of death (HR 0.64 [95% CI 0.40-1.05], one-sided 13=0.037, whereas the boundary for statistical significance was 0.0002). Grade 3 or 4 drug -related adverse events were infrequent and included stomatitis (in 18 [9%] of 202 patients in the everolimus group vs 0 of 98 in the placebo group), diarrhoea (15 [7%] vs 2 [2%]), infections (14 [7%] vs 0), anaemia (8 [4%] vs 1 [1%]), fatigue (7 [3%] vs 1 [1%]), and hyperglycaemia (7 [3%] vs 0). Interpretation Treatment with everolimus was associated with significant improvement in progression -free survival in patients with progressive lung or gastrointestinal neuroendocrine tumours. The safety findings were consistent with the known side -effect profile of everolimus. Everolimus is the first targeted agent to show robust anti-tumour activity with acceptable tolerability across a broad range of neuroendocrine tumours, including those arising from the pancreas, lung, and gastrointestinal tract. C1 [Yao, James C.] Univ Texas MD Anderson Canc Ctr, 1515 Holcombe Blvd,Box 426, Houston, TX 77030 USA. [Fazio, Nicola] IRCCS, Ist Europeo Oncol, Milan, Italy. [Singh, Simron] Sunnybrook Hlth Sci Ctr, Toronto, ON M4N 3M5, Canada. [Buzzoni, Roberto] Fdn IRCCS, Ist Nazl Tumori, Milan, Italy. [Carnaghi, Carlo] IRCCS Ist Clin Humanitas, Rozzano, Italy. [Wolin, Edward] Univ Kentucky, Markey Canc Ctr, Lexington, KY USA. [Tomasek, Jiri] Masaryk Univ, Fac Med, Masaryk Mem Canc Inst, Brno, Czech Republic. [Raderer, Markus] AKH, Univ Klin Innere Med 1, Vienna, Austria. [Lahner, Harald] Univ Klinikum Essen, Zentrum Innere Med, Essen, Germany. [Voi, Maurizio] Novartis Pharmaceut, E Hanover, NJ USA. [Pacaud, Lida Buboteishvili; Rouyrre, Nicolas; Sachs, Carolin] Novartis Pharma AG, Basel, Switzerland. [Valle, Juan W.] Univ Manchester, Christie Hosp, Inst Canc Studies, Manchester, Lancs, England. [Delle Fave, Gianfranco] Univ Roma La Sapienza, Azienda Osped St Andrea, Piazzale Aldo Moro 5, I-00185 Rome, Italy. [Van Cutsem, Eric] Univ Hosp Gasthuisberg Leuven, Leuven, Belgium. [Van Cutsem, Eric] Katholieke Univ Leuven, Leuven, Belgium. [Tesselaar, Margot] Antoni van Leeuwenhoek, Nederlands Kanker Inst, Amsterdam, Netherlands. [Shimada, Yasuhiro] Natl Canc Ctr, 1-1 Tsukiji 5 chome, Tokyo, Japan. [Oh, Do-Youn] Seoul Natl Univ Hosp, Seoul 110744, South Korea. [Strosberg, Jonathan] Univ S Florida, H Lee Moffitt Canc Ctr, Tampa, FL 33682 USA. [Kulke, Matthew H.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Pavel, Marianne E.] Charite, Campus Virchow Klinikum, D-13353 Berlin, Germany. RP Yao, JC (reprint author), Univ Texas MD Anderson Canc Ctr, 1515 Holcombe Blvd,Box 426, Houston, TX 77030 USA. EM jyao@mdanderson.org OI fazio, nicola/0000-0001-6869-0704 FU Novartis Pharmaceuticals Corporation FX Novartis Pharmaceuticals Corporation. NR 20 TC 80 Z9 85 U1 16 U2 29 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 MAR 5 PY 2016 VL 387 IS 10022 BP 968 EP 977 DI 10.1016/S0140-6736(15)00817-X PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA DF8XP UT WOS:000371644200030 PM 26703889 ER PT J AU Pell, VR Chouchani, ET Murphy, MP Brookes, PS Krieg, T AF Pell, Victoria R. Chouchani, Edward T. Murphy, Michael P. Brookes, Paul S. Krieg, Thomas TI Moving Forwards by Blocking Back-Flow The Yin and Yang of MI Therapy SO CIRCULATION RESEARCH LA English DT Review DE oxygen; mitochondria; reperfusion injury; reactive oxygen species; antioxidants ID ISCHEMIA-REPERFUSION INJURY; MITOCHONDRIAL PERMEABILITY TRANSITION; TARGETED ANTIOXIDANT MITOQ; OXYGEN SPECIES GENERATION; PROTEIN S-NITROSYLATION; COMPLEX-I; OXIDATIVE STRESS; SUCCINATE-DEHYDROGENASE; CARDIAC ISCHEMIA; NITRIC-OXIDE AB Mitochondrial reactive oxygen species production has emerged as an important pathological mechanism in myocardial ischemia/reperfusion injury. Attempts at targeting reactive oxygen species by scavenging using antioxidants have, however, been clinically disappointing. This review will provide an overview of the current understanding of mitochondrial reactive oxygen species in ischemia/reperfusion injury. We will outline novel therapeutic approaches designed to directly target the mitochondrial respiratory chain and prevent excessive reactive oxygen species production and its associated pathology. This approach could lead to more effective interventions in an area where there is an urgent need for new treatments. C1 [Pell, Victoria R.; Krieg, Thomas] Univ Cambridge, Addenbrookes Hosp, Dept Med, Hills Rd, Cambridge CB2 0QQ, England. [Chouchani, Edward T.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Chouchani, Edward T.] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. [Murphy, Michael P.] MRC Mitochondrial Biol Unit, Cambridge, England. [Brookes, Paul S.] Univ Rochester, Med Ctr, Dept Anesthesiol, Rochester, NY 14642 USA. RP Krieg, T (reprint author), Univ Cambridge, Addenbrookes Hosp, Dept Med, Hills Rd, Cambridge CB2 0QQ, England. EM tk382@medschl.cam.ac.uk FU Medical Research Council (United Kingdom); British Heart Foundation FX Work in our laboratories is supported by the Medical Research Council (United Kingdom) and the British Heart Foundation. NR 105 TC 7 Z9 7 U1 3 U2 15 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0009-7330 EI 1524-4571 J9 CIRC RES JI Circ.Res. PD MAR 4 PY 2016 VL 118 IS 5 BP 898 EP 906 DI 10.1161/CIRCRESAHA.115.306569 PG 9 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA DG0IE UT WOS:000371747700016 PM 26941425 ER PT J AU Black, JC Zhang, HL Kim, J Getz, G Whetstine, JR AF Black, Joshua C. Zhang, Hailei Kim, Jaegil Getz, Gad Whetstine, Johnathan R. TI Regulation of Transient Site-specific Copy Gain by MicroRNA SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article DE chromatin; drug resistance; genomic instability; histone demethylase; microRNA (miRNA); CKS1B; JMJD2A; KDM4A; TSSG; cisplatin ID CELL LUNG-CANCER; CLINICAL-RELEVANCE; DEMETHYLASE KDM4A; MULTIPLE-MYELOMA; CKS1B EXPRESSION; DRUG-RESISTANCE; OVEREXPRESSION; NEUROBLASTOMA; PROLIFERATION; PROGRESSION AB Intra-tumor copy number heterogeneity is commonly observed in cancer; however, the molecular mechanisms that contribute to heterogeneity remain poorly understood. Up-regulation of the histone demethylase KDM4A promotes transient site-specific copy gain (TSSG) in cells; therefore, uncovering how KDM4A levels are controlled is important for understanding the regulation of copy number heterogeneity. Here, we demonstrate that KDM4A is regulated by hsa-mir-23a-3p, hsa-mir-23b-3p, and hsa-mir-137. Altering expression of these microRNAs (miRNAs) regulates KDM4A-dependent TSSG. miRNA inhibition promoted copy gains and increased expression of the drug-resistant oncogene CKS1B, which was further substantiated in primary breast tumors. Consistent with increased CKS1B expression, miRNA inhibition reduced breast cancer cell sensitivity to cisplatin. Our data identify these miRNAs as regulators of TSSG and copy gains of a drug resistance gene. C1 Massachusetts Gen Hosp, Ctr Canc, Rm 7-213,Bldg 149,13th St, Charlestown, MA 02129 USA. [Black, Joshua C.; Whetstine, Johnathan R.] Harvard Univ, Sch Med, Dept Med, Charlestown, MA 02129 USA. [Getz, Gad] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02129 USA. [Zhang, Hailei; Kim, Jaegil; Getz, Gad] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. RP Whetstine, JR (reprint author), Massachusetts Gen Hosp, Ctr Canc, Rm 7-213,Bldg 149,13th St, Charlestown, MA 02129 USA.; Whetstine, JR (reprint author), Harvard Univ, Sch Med, Dept Med, Charlestown, MA 02129 USA. EM jwhetstine@hms.harvard.edu FU American Cancer Society Grant [RSG-13-115-01-CCG]; National Institutes of Health Grants [CA059267, R01GM097360, U24CA143845]; Jane Coffin Childs Memorial Fund; Massachusetts General Hospital Executive Committee on Research Tosteson Postdoctoral Fellowship; American Lung Association Lung Cancer Discovery Award; Alex Lemonade Stand Foundation FX This work was supported in part by American Cancer Society Grant RSG-13-115-01-CCG, National Institutes of Health Grants CA059267 and R01GM097360, and a grant from The Jane Coffin Childs Memorial Fund for Medical Research. J. R. W. is a consultant for QSonica. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.; Fellow of The Jane Coffin Childs Memorial Fund for Medical Research and supported by Massachusetts General Hospital Executive Committee on Research Tosteson Postdoctoral Fellowship.; Supported by National Institutes of Health Grant U24CA143845.; Tepper Family Massachusetts General Hospital Research Scholar and Leukemia and Lymphoma Society Scholar and recipient of an American Lung Association Lung Cancer Discovery Award and an Innovation Award from Alex Lemonade Stand Foundation. To whom correspondence should be addressed: Dept. of Medicine, Harvard Medical School and Massachusetts General Hospital Cancer Center, Rm. 7-213, Bldg. 149, 13th St., Charlestown, MA 02129. Tel.: 617-643-4347; Fax: 617-724-9648; E-mail: jwhetstine@hms.harvard.edu. NR 43 TC 2 Z9 2 U1 1 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD MAR 4 PY 2016 VL 291 IS 10 BP 4862 EP 4871 DI 10.1074/jbc.M115.711648 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DF8WF UT WOS:000371640600002 PM 26755726 ER PT J AU Liu, X Liao, S Xu, ZW Zhu, L Yang, F Guo, WZ AF Liu, Xiao Liao, Shan Xu, Zhiwen Zhu, Ling Yang, Fan Guo, Wanzhu TI Identification and Analysis of the Porcine MicroRNA in Porcine Cytomegalovirus-Infected Macrophages Using Deep Sequencing SO PLOS ONE LA English DT Article ID INNATE IMMUNE-RESPONSES; EXPRESSED MICRORNAS; CELL PROLIFERATION; XENOTRANSPLANTATION; DIFFERENTIATION; INFLAMMATION; RECOGNITION; PROGRESS; VIRUS; PIGS AB Porcine cytomegalovirus (PCMV; genus Cytomegalovirus, subfamily Betaherpesvirinae, family Herpesviridae) is an immunosuppressive virus that mainly inhibits the immune function of T lymphocytes and macrophages, which has caused substantial damage in the farming industry. In this study, we obtained the miRNA expression profiles of PCMV-infected porcine macrophages via high-throughput sequencing. The comprehensive analysis of miRNA profiles showed that 239 miRNA database-annotated and 355 novel pig-encoded miRNAs were detected. Of these, 130 miRNAs showed significant differential expression between the PCMV-infected and uninfected porcine macrophages. The 10 differentially expressed pig-encoded miRNAs were further determined by stem-loop reverse-transcription polymerase chain reaction, and the results were consistent with the high-throughput sequencing. Gene Ontology analysis of the target genes of miRNAs in PCMV-infected porcine macrophages showed that the differentially expressed miRNAs are mainly involved in immune and metabolic processes. This is the first report of the miRNA transcriptome in porcine macrophages and an analysis of the miRNA regulatory mechanisms during PCMV infection. Further research into the regulatory mechanisms of miRNAs during immunosuppressive viral infections should contribute to the treatment and prevention of immunosuppressive viruses. C1 [Liu, Xiao; Liao, Shan; Xu, Zhiwen; Zhu, Ling; Yang, Fan; Guo, Wanzhu] Sichuan Agr Univ, Coll Vet Med, Anim Biotechnol Ctr, Yaan 625014, Peoples R China. [Liu, Xiao] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Liver, Boston, MA 02114 USA. [Liu, Xiao] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Gastrointestinal Div,Dept Med, Boston, MA 02114 USA. [Xu, Zhiwen] Sichuan Agr Univ, Coll Vet Med, Key Lab Anim Dis & Human Hlth, Yaan 625014, Peoples R China. RP Xu, ZW (reprint author), Sichuan Agr Univ, Coll Vet Med, Anim Biotechnol Ctr, Yaan 625014, Peoples R China.; Xu, ZW (reprint author), Sichuan Agr Univ, Coll Vet Med, Key Lab Anim Dis & Human Hlth, Yaan 625014, Peoples R China. EM abtcxzw@126.com FU Program for Changjiang Scholars and Innovative Research Team in University [IRT13083]; Program for Sichuan Youth Science and Technology and Innovation Research Team [2013TD0015]; China Scholarship Council (CSC); Excellent Doctoral Dissertation Fostering Foundation of Sichuan Agricultural University FX This study was supported by the Program for Changjiang Scholars and Innovative Research Team in University (project no: IRT13083), Program for Sichuan Youth Science and Technology and Innovation Research Team (project no: 2013TD0015), China Scholarship Council (CSC), and by the Excellent Doctoral Dissertation Fostering Foundation of Sichuan Agricultural University. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 45 TC 0 Z9 0 U1 5 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 4 PY 2016 VL 11 IS 3 AR e0150971 DI 10.1371/journal.pone.0150971 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DG0FG UT WOS:000371739400068 PM 26943793 ER PT J AU Bornholdt, ZA Turner, HL Murin, CD Li, W Sok, D Souders, CA Piper, AE Goff, A Shamblin, JD Wollen, SE Sprague, TR Fusco, ML Pommert, KBJ Cavacini, LA Smith, HL Klempner, M Reimann, KA Krauland, E Gerngross, TU Wittrup, KD Saphire, EO Burton, DR Glass, PJ Ward, AB Walker, LM AF Bornholdt, Zachary A. Turner, Hannah L. Murin, Charles D. Li, Wen Sok, Devin Souders, Colby A. Piper, Ashley E. Goff, Arthur Shamblin, Joshua D. Wollen, Suzanne E. Sprague, Thomas R. Fusco, Marnie L. Pommert, Kathleen B. J. Cavacini, Lisa A. Smith, Heidi L. Klempner, Mark Reimann, Keith A. Krauland, Eric Gerngross, Tillman U. Wittrup, Karl D. Saphire, Erica Ollmann Burton, Dennis R. Glass, Pamela J. Ward, Andrew B. Walker, Laura M. TI Isolation of potent neutralizing antibodies from a survivor of the 2014 Ebola virus outbreak SO SCIENCE LA English DT Article ID MONOCLONAL-ANTIBODIES; NONHUMAN-PRIMATES; B-CELLS; INFECTION; REARRANGEMENTS; SELECTION; MACAQUES; COCKTAIL; DISEASE AB Antibodies targeting the Ebola virus surface glycoprotein (EBOV GP) are implicated in protection against lethal disease, but the characteristics of the human antibody response to EBOV GP remain poorly understood. We isolated and characterized 349 GP-specific monoclonal antibodies (mAbs) from the peripheral B cells of a convalescent donor who survived the 2014 EBOV Zaire outbreak. Remarkably, 77% of the mAbs neutralize live EBOV, and several mAbs exhibit unprecedented potency. Structures of selected mAbs in complex with GP reveal a site of vulnerability located in the GP stalk region proximal to the viral membrane. Neutralizing antibodies targeting this site show potent therapeutic efficacy against lethal EBOV challenge in mice. The results provide a framework for the design of new EBOV vaccine candidates and immunotherapies. C1 [Bornholdt, Zachary A.; Murin, Charles D.; Sok, Devin; Fusco, Marnie L.; Pommert, Kathleen B. J.; Saphire, Erica Ollmann; Burton, Dennis R.] Scripps Res Inst, Dept Immunol & Microbial Sci, La Jolla, CA 92037 USA. [Turner, Hannah L.; Murin, Charles D.; Ward, Andrew B.] Scripps Res Inst, Dept Integrat Struct & Computat Biol, La Jolla, CA 92037 USA. [Li, Wen; Krauland, Eric; Gerngross, Tillman U.; Wittrup, Karl D.; Walker, Laura M.] Adimab, Lebanon, NH 03766 USA. [Souders, Colby A.; Cavacini, Lisa A.; Smith, Heidi L.; Klempner, Mark; Reimann, Keith A.] Univ Massachusetts, Sch Med, MassBiol, Boston, MA 02126 USA. [Piper, Ashley E.; Goff, Arthur; Shamblin, Joshua D.; Wollen, Suzanne E.; Sprague, Thomas R.; Glass, Pamela J.] US Army, Med Res Inst Infect Dis, Frederick, MD 21702 USA. [Burton, Dennis R.] MIT, Ragon Inst, Massachusetts Gen Hosp, Cambridge, MA 02142 USA. [Burton, Dennis R.] Harvard Univ, Cambridge, MA 02142 USA. RP Walker, LM (reprint author), Adimab, Lebanon, NH 03766 USA. EM laura.walker@adimab.com RI Ward, Andrew/F-9203-2014 OI Ward, Andrew/0000-0001-7153-3769 FU NIH/National Institute of Allergy and Infectious Diseases Center for Excellence in Translational Research [U19AI109762]; NSF; U.S. NIH grants [U19 AI109762, R01 AI067927]; Defense Advanced Research Projects Agency [DARPA-BAA-13-03]; Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery [UM1AI100663]; [R01AI067927] FX We thank T. Boland and M. Vasquez for assistance with antibody sequence analysis, C. Williams and S. M. Eagol for assistance with figure preparation, R. Pejchal for providing helpful comments on the manuscript, and M. Haynes for assistance with flow cytometry. All of the IgGs were sequenced by Adimab's Molecular Core and produced by the High Throughput Expression group. BLI binding experiments were performed by Adimab's protein analytics group. The ZMapp cocktail mAb 2G4 was generously provided by Mapp Biopharmaceutical. The data presented in this manuscript are tabulated in the main paper and in the supplementary materials. GenBank accession numbers for the antibody variable-region gene sequences reported in this study can be found in table S7. The cryo-EM maps have been deposited to the Electron Microscopy Data Bank (accession numbers EMD-6586, EMD-6587, EMD-6588, and EMD-6589). E.O.S., Z.A.B., M.L.F., K.B.J.P., A.B.W., H.L.T., and C.D.M. acknowledge support from the NIH/National Institute of Allergy and Infectious Diseases Center for Excellence in Translational Research Grant U19AI109762, "Consortium for Immunotherapeutics Against Viral Hemorrhagic Fevers." E.O.S. was also supported by R01AI067927. C.D.M. was supported by a predoctoral fellowship from NSF. This study was supported in part by U.S. NIH grants U19 AI109762 and R01 AI067927 awarded to E.O.S. Research was funded in part by the Defense Advanced Research Projects Agency (DARPA-BAA-13-03). D.R.B. and D.S. acknowledge support from Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery Grant UM1AI100663. This is manuscript no. 29237 from The Scripps Research Institute. Opinions, interpretations, conclusions, and recommendations are those of the authors and are not necessarily endorsed by the U.S. Army. NR 30 TC 12 Z9 12 U1 2 U2 13 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 EI 1095-9203 J9 SCIENCE JI Science PD MAR 4 PY 2016 VL 351 IS 6277 BP 1078 EP 1083 DI 10.1126/science.aad5788 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DF8HE UT WOS:000371597500043 PM 26912366 ER PT J AU Beste, LA Moseley, RH Saint, S Cornia, PB AF Beste, Lauren A. Moseley, Richard H. Saint, Sanjay Cornia, Paul B. TI Too Much of a Good Thing SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID PORTAL-HYPERTENSION; HISTORY C1 [Beste, Lauren A.] Vet Affairs VA Puget Sound Hlth Care Syst, Gen Med Serv, Seattle, WA USA. [Beste, Lauren A.] Vet Affairs VA Puget Sound Hlth Care Syst, Hlth Serv Res & Dev, Seattle, WA USA. [Beste, Lauren A.; Cornia, Paul B.] Vet Affairs VA Puget Sound Hlth Care Syst, Hosp & Specialty Med Serv, Seattle, WA USA. [Beste, Lauren A.; Cornia, Paul B.] Univ Washington, Sch Med, Dept Med, Seattle, WA 98195 USA. [Moseley, Richard H.; Saint, Sanjay] VA Ann Arbor Healthcare Syst, Med Serv, Ann Arbor, MI USA. [Moseley, Richard H.; Saint, Sanjay] Univ Michigan Hlth Syst, Dept Internal Med, Ann Arbor, MI USA. RP Beste, LA (reprint author), VA Puget Sound Hlth Care Syst, 1660 S Columbian Way S-111-GI, Seattle, WA 98108 USA. EM lab25@uw.edu FU Doximity; Jvion FX Dr. Saint reports receiving fees for serving on advisory boards from Doximity and Jvion. No other potential conflict of interest relevant to this article was reported. NR 9 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 MAR 3 PY 2016 VL 374 IS 9 BP 873 EP 878 DI 10.1056/NEJMcps1405984 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA DF2FT UT WOS:000371158400013 PM 26962907 ER PT J AU Conlon, N Silva, A Guerra, E Jelinic, P Schlappe, BA Olvera, N Mueller, JJ Tornos, C Jungbluth, AA Young, RH Oliva, E Levine, D Soslow, RA AF Conlon, Niamh Silva, Annacarolina Guerra, Esther Jelinic, Petar Schlappe, Brooke A. Olvera, Narciso Mueller, Jennifer J. Tornos, Carmen Jungbluth, Achim A. Young, Robert H. Oliva, Esther Levine, Douglas Soslow, Robert A. TI Loss of SMARCA4 Expression Is Both Sensitive and Specific for the Diagnosis of Small Cell Carcinoma of Ovary, Hypercalcemic Type SO AMERICAN JOURNAL OF SURGICAL PATHOLOGY LA English DT Article DE immunohistochemistry; hypercalcemic type; small cell carcinoma of ovary; SMARCA4 ID RHABDOID TUMOR; UNDIFFERENTIATED CARCINOMA; GERM-LINE; MUTATIONS; BRG1; CANCER; INI1; ADENOCARCINOMA; ENDOMETRIAL; UTERUS AB Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare ovarian neoplasm that occurs in young women and has a poor prognosis. The histologic diagnosis of SCCOHT can be challenging due to its rarity and relatively nonspecific histologic features, which range from the classic, first-described small cell morphology to a pattern in which there are large cells with abundant eosinophilic cytoplasm. Many entities can be in the differential diagnosis and to date, immunohistochemical stains have shown no distinctive profile and have been of limited aid. SMARCA4 (also known as BRG1) mutations have recently been reported at high frequency in these tumors. SMARCA4 is an important component of the SWI/SNF complex that regulates gene expression through alteration of nucleosome conformation. Studies to date have suggested that immunohistochemical loss of expression of SMARCA4 is associated with the presence of a SMARCA4 mutation in most cases. In this study, the sensitivity and specificity of the immunohistochemical loss of SMARCA4 expression for the diagnosis of SCCOHT is examined in the context of the differential diagnosis with other primary or metastatic ovarian tumors. All but one of the SCCOHT showed loss of SMARCA4 expression (16/17; 94%), while of 279 other tumors tested, only two tumors (one clear cell carcinoma and one ovarian melanoma) showed loss of SMARCA4 expression. We conclude that SMARCA4 immunohistochemistry is highly sensitive and specific for a diagnosis of SCCOHT and is of clinical utility in the differential diagnosis of poorly differentiated ovarian tumors. C1 [Conlon, Niamh; Jungbluth, Achim A.; Soslow, Robert A.] Mem Sloan Kettering Canc Ctr, Dept Pathol, 1275 York Ave, New York, NY 10021 USA. [Jelinic, Petar; Schlappe, Brooke A.; Olvera, Narciso; Mueller, Jennifer J.; Levine, Douglas] Mem Sloan Kettering Canc Ctr, Dept Surg, 1275 York Ave, New York, NY 10021 USA. [Tornos, Carmen] SUNY Stony Brook, Med Ctr, Dept Pathol, Stony Brook, NY USA. [Silva, Annacarolina; Guerra, Esther; Young, Robert H.; Oliva, Esther] Harvard Univ, Sch Med, Dept Pathol, Massachusetts Gen Hosp, Boston, MA 02115 USA. RP Soslow, RA (reprint author), Mem Sloan Kettering Canc Ctr, Dept Pathol, 1275 York Ave, New York, NY 10021 USA. EM gynbreast@mskcc.org OI Mueller, Jennifer/0000-0003-0365-7510 FU NCI NIH HHS [P30 CA008748] NR 35 TC 9 Z9 9 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0147-5185 EI 1532-0979 J9 AM J SURG PATHOL JI Am. J. Surg. Pathol. PD MAR 3 PY 2016 VL 40 IS 3 BP 395 EP 403 DI 10.1097/PAS.0000000000000558 PG 9 WC Pathology; Surgery SC Pathology; Surgery GA DI7UF UT WOS:000373706800013 PM 26645725 ER PT J AU Fraietta, JA Beckwith, KA Patel, PR Ruella, M Zheng, ZH Barrett, DM Lacey, SF Melenhorst, JJ McGettigan, SE Cook, DR Zhang, CF Xu, J Do, P Hulitt, J Kudchodkar, SB Cogdill, AP Gill, S Porter, DL Woyach, JA Long, MX Johnson, AJ Maddocks, K Muthusamy, N Levine, BL June, CH Byrd, JC Maus, MV AF Fraietta, Joseph A. Beckwith, Kyle A. Patel, Prachi R. Ruella, Marco Zheng, Zhaohui Barrett, David M. Lacey, Simon F. Melenhorst, Jan Joseph McGettigan, Shannon E. Cook, Danielle R. Zhang, Changfeng Xu, Jun Do, Priscilla Hulitt, Jessica Kudchodkar, Sagar B. Cogdill, Alexandria P. Gill, Saar Porter, David L. Woyach, Jennifer A. Long, Meixiao Johnson, Amy J. Maddocks, Kami Muthusamy, Natarajan Levine, Bruce L. June, Carl H. Byrd, John C. Maus, Marcela V. TI Ibrutinib enhances chimeric antigen receptor T-cell engraftment and efficacy in leukemia SO BLOOD LA English DT Article ID CHRONIC LYMPHOCYTIC-LEUKEMIA; CYTOKINE PRODUCTION; CD200 EXPRESSION; CHECKPOINT BLOCKADE; ANTITUMOR IMMUNITY; INHIBITOR; PD-1; PROLIFERATION; ACTIVATION; LYMPHOMA AB Anti-CD19 chimeric antigen receptor (CAR) T-cell therapy is highly promising but requires robust T-cell expansion and engraftment. A T-cell defect in chronic lymphocytic leukemia (CLL) due to disease and/or therapy impairs ex vivoexpansionand response to CART cells. To evaluate the effect of ibrutinib treatment on the T-cell compartment in CLL as it relates to CART-cell generation, we examined the phenotype and function of T cells in a cohort of CLL patients during their course of treatment with ibrutinib. We found that >= 5 cycles of ibrutinib therapy improved the expansion of CD19-directed CART cells (CTL019), in association with decreased expression of the immunosuppressive molecule programmed cell death 1 on T cells and of CD200 on B-CLL cells. In support of these findings, we observed that 3 CLL patients who had been treated with ibrutinib for >= 1 year at the time of T-cell collection had improved ex vivo and in vivo CTL019 expansion, which correlated positively together and with clinical response. Lastly, we show that ibrutinib exposure does not impair CAR T-cell function in vitro but does improve CAR T-cell engraftment, tumor clearance, and survival in human xenograft models of resistant acute lymphocytic leukemia and CLL when administered concurrently. Our collective findings indicate that ibrutinib enhances CAR T-cell function and suggest that clinical trials with combination therapy are warranted. Our studies demonstrate that improved T-cell function may also contribute to the efficacy of ibrutinib in CLL. These trials were registered at www.clinicaltrials.gov as #NCT01747486, #NCT01105247, and #NCT01217749. C1 [Fraietta, Joseph A.; Patel, Prachi R.; Ruella, Marco; Zheng, Zhaohui; Lacey, Simon F.; Melenhorst, Jan Joseph; McGettigan, Shannon E.; Cook, Danielle R.; Zhang, Changfeng; Xu, Jun; Kudchodkar, Sagar B.; Cogdill, Alexandria P.; Gill, Saar; Porter, David L.; Levine, Bruce L.; June, Carl H.] Univ Penn, Ctr Cellular Immunotherapies, Philadelphia, PA 19104 USA. [Fraietta, Joseph A.; Patel, Prachi R.; Ruella, Marco; Zheng, Zhaohui; Lacey, Simon F.; Melenhorst, Jan Joseph; McGettigan, Shannon E.; Cook, Danielle R.; Zhang, Changfeng; Xu, Jun; Kudchodkar, Sagar B.; Cogdill, Alexandria P.; Porter, David L.; Levine, Bruce L.; June, Carl H.] Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA. [Beckwith, Kyle A.; Do, Priscilla; Woyach, Jennifer A.; Long, Meixiao; Johnson, Amy J.; Maddocks, Kami; Muthusamy, Natarajan; Byrd, John C.] Ohio State Univ, Dept Internal Med, Div Hematol, Columbus, OH 43210 USA. [Barrett, David M.; Hulitt, Jessica] Childrens Hosp Philadelphia, Div Oncol, Philadelphia, PA 19104 USA. [Gill, Saar; Porter, David L.] Univ Penn, Dept Internal Med, Div Hematol Oncol, Philadelphia, PA 19104 USA. [Levine, Bruce L.; June, Carl H.] Univ Penn, Pathol & Lab Med, Philadelphia, PA 19104 USA. [Maus, Marcela V.] Harvard Univ, Massachusetts Gen Hosp, Ctr Canc, Sch Med, Boston, MA 02114 USA. RP Maus, MV (reprint author), Massachusetts Gen Hosp, Ctr Canc, Bldg 149,Thirteenth St, Charlestown, MA 02129 USA.; Byrd, JC (reprint author), Ohio State Univ, CCC Bldg,4th Floor,410 W 12thAve, Columbus, OH 43210 USA. EM john.byrd@osumc.edu; mvmaus@mgh.harvard.edu OI Cogdill, Alexandria/0000-0001-8917-9462 FU National Institutes of Health National Cancer Institute [T32 CA009140, K08 CA166039, P01 CA095426, K23 CA178183, R35 CA198183, R01 CA177292, R01 CA165206]; D. Warren Brown Foundation; Four Winds Foundation; Lymphoma Research Foundation; Novartis FX This work was supported by the National Institutes of Health National Cancer Institute grants T32 CA009140 (J.A.F.), K08 CA166039 (M.V.M.), P01 CA095426 (N.M. and J.C.B.), K23 CA178183 (J.A.W.), R35 CA198183 (J.C.B.), R01 CA177292 (J.C.B.), and R01 CA165206 (C.H.J. and D.L.P.); the D. Warren Brown Foundation; the Four Winds Foundation (J.C.B.); the Lymphoma Research Foundation (M.R.); and Novartis. NR 50 TC 20 Z9 21 U1 5 U2 12 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD MAR 3 PY 2016 VL 127 IS 9 BP 1117 EP 1127 DI 10.1182/blood-2015-11-679134 PG 11 WC Hematology SC Hematology GA DI3MB UT WOS:000373401700012 PM 26813675 ER PT J AU Cea, M Cagnetta, A Adamia, S Acharya, C Tai, YT Fulciniti, M Ohguchi, H Munshi, A Acharya, P Bhasin, MK Zhong, L Carrasco, R Monacelli, F Ballestrero, A Richardson, P Gobbi, M Lemoli, RM Munshi, N Hideshima, T Nencioni, A Chauhan, D Anderson, KC AF Cea, Michele Cagnetta, Antonia Adamia, Sophia Acharya, Chirag Tai, Yu-Tzu Fulciniti, Mariateresa Ohguchi, Hiroto Munshi, Aditya Acharya, Prakrati Bhasin, Manoj K. Zhong, Lei Carrasco, Ruben Monacelli, Fiammetta Ballestrero, Alberto Richardson, Paul Gobbi, Marco Lemoli, Roberto M. Munshi, Nikhil Hideshima, Teru Nencioni, Alessio Chauhan, Dharminder Anderson, Kenneth C. TI Evidence for a role of the histone deacetylase SIRT6 in DNA damage response of multiple myeloma cells SO BLOOD LA English DT Article ID STRAND BREAK REPAIR; GENOMIC INSTABILITY; TUMOR-SUPPRESSOR; GENE-EXPRESSION; IN-VIVO; CHROMATIN; METABOLISM; CANCER; SIRTUINS; KINASE AB Multiple myeloma (MM) is characterized by a highly unstable genome, with aneuploidy observed in nearly all patients. The mechanism causing this karyotypic instability is largely unknown, but recent observations have correlated these abnormalities with dysfunctional DNA damage response. Here, we show that the NAD(+)-dependent deacetylase SIRT6 is highly expressed in MM cells, as an adaptive response to genomic stability, and that high SIRT6 levels are associated with adverse prognosis. Mechanistically, SIRT6 interacts with the transcription factor ELK1 and with the ERK signaling-related gene. By binding to their promoters and deacetylating H3K9 at these sites, SIRT6 downregulates the expression of mitogen-activated protein kinase (MAPK) pathway genes, MAPK signaling, and proliferation. In addition, inactivation of ERK2/p90RSK signaling triggered by high SIRT6 levels increases DNA repair via Chk1 and confers resistance to DNA damage. Using genetic and biochemical studies in vitro and in human MM xenograft models, we show that SIRT6 depletion both enhances proliferation and confers sensitization to DNA-damaging agents. Our findings therefore provide insights into the functional interplay between SIRT6 and DNA repair mechanisms, with implications for both tumorigenesis and the treatment of MM. C1 [Cea, Michele; Cagnetta, Antonia; Adamia, Sophia; Acharya, Chirag; Tai, Yu-Tzu; Fulciniti, Mariateresa; Ohguchi, Hiroto; Munshi, Aditya; Acharya, Prakrati; Carrasco, Ruben; Richardson, Paul; Munshi, Nikhil; Hideshima, Teru; Chauhan, Dharminder; Anderson, Kenneth C.] Harvard Univ, Sch Med, LeBow Inst Myeloma Therapeut, Boston, MA USA. [Cea, Michele; Cagnetta, Antonia; Adamia, Sophia; Acharya, Chirag; Tai, Yu-Tzu; Fulciniti, Mariateresa; Ohguchi, Hiroto; Munshi, Aditya; Acharya, Prakrati; Carrasco, Ruben; Richardson, Paul; Munshi, Nikhil; Hideshima, Teru; Chauhan, Dharminder; Anderson, Kenneth C.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Jerome Lipper Ctr Multiple Myeloma Res, 44 Binney St, Boston, MA 02115 USA. [Cea, Michele; Cagnetta, Antonia; Monacelli, Fiammetta; Ballestrero, Alberto; Gobbi, Marco; Lemoli, Roberto M.; Nencioni, Alessio] Univ Genoa, Dept Internal Med, Ist Ricovero & Cura Carattere Sci,Clin Hematol, Sci Azienda Osped Univ San Martino,Ist Sci Tumori, I-16126 Genoa, Italy. [Bhasin, Manoj K.] Beth Israel Deaconess Med Ctr, Genom Prote Bioinformat & Syst Biol Ctr, Boston, MA 02215 USA. [Zhong, Lei] Harvard Univ, Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. RP Cea, M (reprint author), IRCCS AOU San Martino IST, Dept Hematol & Oncol, I-16132 Genoa, Italy.; Anderson, KC (reprint author), Dana Farber Canc Inst, Dept Med Oncol, M557,450 Brookline Ave, Boston, MA 02115 USA. EM michele.cea@unige.it; kenneth_anderson@dfci.harvard.edu FU National Institutes of Health, National Cancer Institute [R01 50947, P01 73878, P50 100707]; International Multiple Myeloma Foundation; American Italian Cancer Foundation FX This work was supported by the National Institutes of Health, National Cancer Institute (grants R01 50947, P01 73878, and P50 100707) (K.C.A.), the International Multiple Myeloma Foundation (A.C.), and the American Italian Cancer Foundation (M.C.). K.C.A. is an American Cancer Society Clinical Research Professor. NR 54 TC 4 Z9 5 U1 0 U2 2 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD MAR 3 PY 2016 VL 127 IS 9 BP 1138 EP 1150 DI 10.1182/blood-2015-06-649970 PG 13 WC Hematology SC Hematology GA DI3MB UT WOS:000373401700014 PM 26675349 ER PT J AU Wong, RL Fahs, DB Talwalkar, JS Colson, ER Desai, MM Kayingo, G Balanda, M Luczak, AG Rosenthal, MS AF Wong, Risa Liang Fahs, Deborah Bain Talwalkar, Jaideep S. Colson, Eve R. Desai, Mayur M. Kayingo, Gerald Balanda, Matthew Luczak, Anthony G. Rosenthal, Marjorie S. TI A longitudinal study of health professional students' attitudes towards interprofessional education at an American university SO JOURNAL OF INTERPROFESSIONAL CARE LA English DT Article DE Education; interprofessional collaboration; interprofessional education; interprofessional learning; surveys; teamwork; work-based learning ID SOCIAL CARE STUDENTS; QUESTIONNAIRE; PERCEPTIONS; READINESS; LESSONS; WORKING; RIPLS AB Efforts to improve interprofessional education (IPE) are informed by attitudes of health professional students, yet there are limited US data on student characteristics and experiences associated with positive attitudes towards IPE. A cohort of US medical, nursing, and physician associate students was surveyed in their first and third years, using the Readiness for Interprofessional Learning Scale and Interdisciplinary Education Perception Scale. Information was also collected on demographics and experiences during training. Health professional students differed in their attitudes towards IPE; characteristics associated with having more positive attitudes at both time points included being a nursing student, female, older, and having more previous healthcare experience. Students who participated in interprofessional extracurricular activities (particularly patient-based activities) during training reported more positive attitudes in the third year than those who did not participate in such activities. Based on these findings, schools may consider how student characteristics and participation in interprofessional extracurricular activities can affect attitudes regarding IPE. Building on the positive elements of this interprofessional extracurricular experience, schools may also want to consider service-learning models of IPE where students work together on shared goals. C1 [Wong, Risa Liang] Massachusetts Gen Hosp, Dept Internal Med, Boston, MA 02114 USA. [Fahs, Deborah Bain; Balanda, Matthew; Luczak, Anthony G.] Yale Univ, Sch Nursing, West Haven, CT USA. [Talwalkar, Jaideep S.] Yale Univ, Sch Med, Dept Gen Internal Med, Int Med Primary Care, New Haven, CT 06520 USA. [Talwalkar, Jaideep S.; Colson, Eve R.; Rosenthal, Marjorie S.] Yale Univ, Sch Med, Dept Pediat, New Haven, CT 06520 USA. [Desai, Mayur M.] Yale Univ, Sch Publ Hlth, Chron Dis Epidemiol Epidemiol & Publ Hlth, New Haven, CT 06520 USA. [Kayingo, Gerald] Univ Calif Davis, Phys Assistant Program, Sacramento, CA 95817 USA. RP Rosenthal, MS (reprint author), Yale Univ, Sch Med, Dept Pediat, Robert Wood Johnson Fdn Clin Scholars Program, 333 Cedar St, New Haven, CT 06520 USA. EM marjorie.rosenthal@yale.edu OI Fahs, Deborah/0000-0002-2997-7419 FU Yale School of Medicine Office of Student Research FX Risa Liang Wong was funded by the Yale School of Medicine Office of Student Research. Eve R. Colson was a Josiah Macy Jr. Foundation Faculty Scholar. NR 31 TC 1 Z9 1 U1 5 U2 11 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 1356-1820 EI 1469-9567 J9 J INTERPROF CARE JI J. Interprofessional Care PD MAR 3 PY 2016 VL 30 IS 2 BP 191 EP 200 DI 10.3109/13561820.2015.1121215 PG 10 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA DI8BQ UT WOS:000373726300009 PM 27026189 ER PT J AU Penman, A Hancock, H Papavasileiou, E James, M Idowu, O Riche, DM Fernandez, M Brauner, S Smith, SO Hoadley, S Richardson, C Vazquez, V Chi, C Andreoli, C Husain, D Chen, CJ Sobrin, L AF Penman, Alan Hancock, Heather Papavasileiou, Evangelia James, Maurice Idowu, Omolola Riche, Daniel M. Fernandez, Marlene Brauner, Stacey Smith, Sataria O. Hoadley, Suzanne Richardson, Cole Vazquez, Vanessa Chi, Cheryl Andreoli, Christopher Husain, Deeba Chen, Ching J. Sobrin, Lucia TI Risk Factors for Proliferative Diabetic Retinopathy in African Americans with Type 2 Diabetes SO OPHTHALMIC EPIDEMIOLOGY LA English DT Article DE diabetic retinopathy; African Americans; risk factors; proliferative diabetic retinopathy; type 2 diabetes ID UNITED-STATES; PROGRESSION; POPULATION; HEALTH; WHITES; COMPLICATIONS; ASSOCIATION; HEMOGLOBIN; PREVALENCE; BLACKS AB Purpose: To assess personal and demographic risk factors for proliferative diabetic retinopathy in African Americans with type 2 diabetes. Methods: In this prospective, non-interventional, cross-sectional case-control study, 380 African Americans with type 2 diabetes were enrolled. Participants were recruited prospectively and had to have either: (1) absence of diabetic retinopathy after >= 10 years of type 2 diabetes, or (2) presence of proliferative diabetic retinopathy when enrolled. Dilated, 7-field fundus photographs were graded using the Early Treatment Diabetic Retinopathy Study scale. Covariates including hemoglobin A(1C) (HbA(1C)), blood pressure, height, weight and waist circumference were collected prospectively. Multivariate regression models adjusted for age, sex and site were constructed to assess associations between risk factors and proliferative diabetic retinopathy. Results: Proliferative diabetic retinopathy was associated with longer duration of diabetes (odds ratio, OR, 1.62, p < 0.001), higher systolic blood pressure (OR 1.65, p < 0.001) and insulin use (OR 6.65, p < 0.001) in the multivariate regression analysis. HbA(1C) was associated with proliferative diabetic retinopathy in the univariate analysis (OR 1.31, p = 0.002) but was no longer significant in the multivariate analysis. Conclusions: In this case-control study of African Americans with type 2 diabetes, duration of diabetes, systolic hypertension and insulin use were strong risk factors for the development of proliferative diabetic retinopathy. Interestingly, HbA(1C) did not confer additional risk in this cohort. C1 [Penman, Alan; Riche, Daniel M.] Univ Mississippi, Med Ctr, Dept Med, Jackson, MS 39216 USA. [Penman, Alan] Univ Mississippi, Med Ctr, Ctr Biostat & Bioinformat, Jackson, MS 39216 USA. [Hancock, Heather; Idowu, Omolola; Smith, Sataria O.; Hoadley, Suzanne; Richardson, Cole; Chen, Ching J.] Univ Mississippi, Med Ctr, Dept Ophthalmol, Jackson, MS 39216 USA. [Papavasileiou, Evangelia; Brauner, Stacey; Husain, Deeba] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol, Boston, MA USA. [James, Maurice] St Domin Hosp, Dept Ophthalmol, Jackson, MS USA. [Fernandez, Marlene] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Vazquez, Vanessa; Chi, Cheryl] Boston Med Ctr, Dept Ophthalmol, Boston, MA USA. [Andreoli, Christopher] Harvard Vanguard Med Associates, Visual Serv Dept, Boston, MA USA. [Sobrin, Lucia] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Boston, MA USA. RP Sobrin, L (reprint author), Massachusetts Eye & Ear Infirm, 243 Charles St, Boston, MA 02114 USA. EM Lucia_sobrin@meei.harvard.edu FU American Diabetes Association Clinical Translational Research Award, Alexandria, VA [1-11-CT-51]; NEI, Bethesda, MD [K12-EY16335]; Research to Prevent Blindness Career Development Award; William & Mary Greve Special Scholar Award, New York City, NY; Harvard Catalyst \ The Harvard Clinical and Translations Science Center Faculty Fellowship, Boston, MA; Massachusetts Lions Eye Research Fund, Abington, MA; Eleanor and Miles Shore Fellowship, Boston, MA; Sara Elizabeth O'Brien Trust, Boston, MA FX This study received financial support from: the American Diabetes Association Clinical Translational Research Award 1-11-CT-51, Alexandria, VA; NEI K12-EY16335, Bethesda, MD; Research to Prevent Blindness Career Development Award and William & Mary Greve Special Scholar Award, New York City, NY; Harvard Catalyst vertical bar The Harvard Clinical and Translations Science Center Faculty Fellowship, Boston, MA; Massachusetts Lions Eye Research Fund, Abington, MA; Eleanor and Miles Shore Fellowship, Boston, MA; and the Sara Elizabeth O'Brien Trust, Boston, MA. NR 35 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 0928-6586 EI 1744-5086 J9 OPHTHAL EPIDEMIOL JI Ophthalmic Epidemiol. PD MAR 3 PY 2016 VL 23 IS 2 BP 88 EP 93 DI 10.3109/09286586.2015.1119287 PG 6 WC Ophthalmology SC Ophthalmology GA DH4FU UT WOS:000372741700004 PM 26950197 ER PT J AU Sandford, E Bird, TD Li, JZ Burmeister, M AF Sandford, Erin Bird, Thomas D. Li, Jun Z. Burmeister, Margit TI PRICKLE2 Mutations Might Not Be Involved in Epilepsy SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Letter ID PROGRESSIVE MYOCLONUS; ATAXIA; A467T; POLG C1 [Sandford, Erin; Burmeister, Margit] Univ Michigan, Mol & Behav Neurosci Inst, Ann Arbor, MI 48109 USA. [Bird, Thomas D.] Univ Washington, Dept Neurol, Seattle, WA 98195 USA. [Bird, Thomas D.] Univ Washington, Dept Med Med Genet, Seattle, WA 98195 USA. [Bird, Thomas D.] VA Puget Sound Hlth Care Syst, Geriatr Res Educ & Clin Ctr, Seattle, WA 98101 USA. [Li, Jun Z.; Burmeister, Margit] Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA. [Li, Jun Z.; Burmeister, Margit] Univ Michigan, Dept Computat Med & Bioinformat, Ann Arbor, MI 48109 USA. [Burmeister, Margit] Univ Michigan, Dept Psychiat, Ann Arbor, MI 48109 USA. RP Burmeister, M (reprint author), Univ Michigan, Mol & Behav Neurosci Inst, Ann Arbor, MI 48109 USA.; Burmeister, M (reprint author), Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA.; Burmeister, M (reprint author), Univ Michigan, Dept Computat Med & Bioinformat, Ann Arbor, MI 48109 USA.; Burmeister, M (reprint author), Univ Michigan, Dept Psychiat, Ann Arbor, MI 48109 USA. EM margit@umich.edu FU NINDS NIH HHS [R01 NS078560, R01-NS078560] NR 10 TC 1 Z9 3 U1 0 U2 0 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 MAR 3 PY 2016 VL 98 IS 3 BP 588 EP 589 DI 10.1016/j.ajhg.2016.01.009 PG 2 WC Genetics & Heredity SC Genetics & Heredity GA DG9DN UT WOS:000372383100021 PM 26942291 ER PT J AU Ariyachet, C Tovaglieri, A Xiang, GJ Lu, JQ Shah, MS Richmond, CA Verbeke, C Melton, DA Stanger, BZ Mooney, D Shivdasani, RA Mahony, S Xia, Q Breault, DT Zhou, Q AF Ariyachet, Chaiyaboot Tovaglieri, Alessio Xiang, Guanjue Lu, Jiaqi Shah, Manasvi S. Richmond, Camilla A. Verbeke, Catia Melton, Douglas A. Stanger, Ben Z. Mooney, David Shivdasani, Ramesh A. Mahony, Shaun Xia, Qing Breault, David T. Zhou, Qiao TI Reprogrammed Stomach Tissue as a Renewable Source of Functional beta Cells for Blood Glucose Regulation SO CELL STEM CELL LA English DT Article ID TRANSCRIPTION FACTOR CDX2; INSULIN-PRODUCING CELLS; PLURIPOTENT STEM-CELLS; ENTEROENDOCRINE CELLS; ENDOCRINE; GUT; LINEAGE; MOUSE; FOXO1; DIFFERENTIATION AB The gastrointestinal (GI) epithelium is a highly regenerative tissue with the potential to provide a renewable source of insulin(+) cells after undergoing cellular reprogramming. Here, we show that cells of the antral stomach have a previously unappreciated propensity for conversion into functional insulin-secreting cells. Native antral endocrine cells share a surprising degree of transcriptional similarity with pancreatic beta cells, and expression of beta cell reprogramming factors in vivo converts antral cells efficiently into insulin(+) cells with close molecular and functional similarity to beta cells. Induced GI insulin(+) cells can suppress hyperglycemia in a diabetic mouse model for at least 6 months and regenerate rapidly after ablation. Reprogramming of antral stomach cells assembled into bioengineered mini-organs in vitro yielded transplantable units that also suppressed hyperglycemia in diabetic mice, highlighting the potential for development of engineered stomach tissues as a renewable source of functional beta cells for glycemic control. C1 [Ariyachet, Chaiyaboot; Melton, Douglas A.; Zhou, Qiao] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. [Ariyachet, Chaiyaboot; Melton, Douglas A.; Shivdasani, Ramesh A.; Breault, David T.; Zhou, Qiao] Harvard Univ, Stem Cell Inst, Cambridge, MA 02138 USA. [Tovaglieri, Alessio; Shah, Manasvi S.] Boston Childrens Hosp, Div Endocrinol, Boston, MA 02115 USA. [Xiang, Guanjue; Mahony, Shaun] Penn State Univ, Dept Biochem & Mol Biol, University Pk, PA 16802 USA. [Lu, Jiaqi; Xia, Qing] Peking Univ, Dept Biol Chem, State Key Lab Nat & Biomimet Drugs, Sch Pharmaceut Sci, Beijing 100191, Peoples R China. [Shah, Manasvi S.; Richmond, Camilla A.; Breault, David T.] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Richmond, Camilla A.] Boston Childrens Hosp, Div Gastroenterol, Boston, MA 02115 USA. [Verbeke, Catia; Mooney, David] Harvard Univ, Sch Engn & Appl Sci, Cambridge, MA 02138 USA. [Stanger, Ben Z.] Univ Penn, Dept Cell & Dev Biol, Philadelphia, PA 19104 USA. [Shivdasani, Ramesh A.] Harvard Univ, Sch Med, Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. RP Zhou, Q (reprint author), Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA.; Zhou, Q (reprint author), Harvard Univ, Stem Cell Inst, Cambridge, MA 02138 USA. EM qiao_zhou@harvard.edu FU National Institute of Health; Harvard Stem Cell Institute [U01 DK089536, DP-0144-14-00]; Timothy Murphy Fund; IDDRC [P30HD18655]; HDDC [P30DK034854]; HSCI-Sternlicht Fellowship; [R01DK082889]; [R01DK084056] FX We thank Boston Children's Hospital core facility for Illumina array; Joslin Specialized Assay Core for insulin measurement; Juliana Brown for expert help with pancreatectomy; members of the Zhou lab for advice and feedback; and Gordon Weir, Susan Bonner-Weir, Andrew Leiter, Konrad Hochedlinger, and Jay Rajagopal for discussion and reading of the manuscript. This study was supported by awards from the National Institute of Health and the Harvard Stem Cell Institute (U01 DK089536 and DP-0144-14-00) to Q.Z., awards (R01DK084056, the Timothy Murphy Fund, the IDDRC P30HD18655, and the HDDC P30DK034854) to D.T.B., and R01DK082889 to R.A.S. C.A. is a recipient of HSCI-Sternlicht Fellowship. NR 49 TC 9 Z9 9 U1 6 U2 18 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1934-5909 EI 1875-9777 J9 CELL STEM CELL JI Cell Stem Cell PD MAR 3 PY 2016 VL 18 IS 3 BP 410 EP 421 DI 10.1016/j.stem.2016.01.003 PG 12 WC Cell & Tissue Engineering; Cell Biology SC Cell Biology GA DG8GX UT WOS:000372322200016 PM 26908146 ER PT J AU Sohani, AR Abramson, JS AF Sohani, Aliyah R. Abramson, Jeremy S. TI MYC/BCL2 double-expression vs. cell-of-origin classification in diffuse large B-cell lymphoma: do we need to know both? SO LEUKEMIA & LYMPHOMA LA English DT Editorial Material ID RITUXIMAB PLUS CYCLOPHOSPHAMIDE; GENE-EXPRESSION; PROTEIN EXPRESSION; BCL2; MYC; VINCRISTINE; DOXORUBICIN; PREDNISONE; SURVIVAL; TISSUE C1 [Sohani, Aliyah R.] Massachusetts Gen Hosp, Dept Pathol, 55 Fruit St,WRN 219, Boston, MA 02114 USA. [Abramson, Jeremy S.] Massachusetts Gen Hosp, Ctr Canc, Ctr Lymphoma, Boston, MA 02114 USA. RP Sohani, AR (reprint author), Massachusetts Gen Hosp, Dept Pathol, 55 Fruit St,WRN 219, Boston, MA 02114 USA. EM arsohani@mgh.harvard.edu NR 17 TC 0 Z9 0 U1 2 U2 2 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1042-8194 EI 1029-2403 J9 LEUKEMIA LYMPHOMA JI Leuk. Lymphoma PD MAR 3 PY 2016 VL 57 IS 3 BP 509 EP 511 DI 10.3109/10428194.2015.1115046 PG 3 WC Oncology; Hematology SC Oncology; Hematology GA DH0UO UT WOS:000372499800005 PM 26693593 ER PT J AU Dalamaga, M Polyzos, SA Karmaniolas, K Chamberland, J Lekka, A Triantafilli, M Migdalis, I Papadavid, E Mantzoros, CS AF Dalamaga, Maria Polyzos, Stergios A. Karmaniolas, Konstantinos Chamberland, John Lekka, Antigoni Triantafilli, Maria Migdalis, Ilias Papadavid, Evangelia Mantzoros, Christos S. TI Fetuin-A levels and free leptin index are reduced in patients with chronic lymphocytic leukemia: a hospital-based case-control study SO LEUKEMIA & LYMPHOMA LA English DT Article DE malignancy; Alpha-2-HS-glycoprotein; insulin; fetuin-A; chronic lymphocytic leukemia ID FATTY LIVER-DISEASE; OF-THE-LITERATURE; MYELODYSPLASTIC SYNDROME; INSULIN-RESISTANCE; MYELOID-LEUKEMIA; CANCER; RISK; DIAGNOSIS; CLASSIFICATION; GLYCOPROTEIN AB There are limited data on fetuin-A, soluble leptin receptor (sOB-R) and free leptin index (FLI) in patients with chronic lymphocytic leukemia (CLL). The aim of this study was to compare circulating fetuin-A, sOB-R levels and FLI between 95 patients with CLL and 95 matched controls, as well as among different stages of CLL. Circulating fetuin-A was significantly lower in cases than controls (241.9 +/- 99.2 vs. 288.8 +/- 127.7 mu g/mL; p = 0.005). Although circulating sOB-R levels were similar between groups, FLI was lower in cases than controls (0.45 +/- 0.42 vs. 0.67 +/- 0.57; p = 0.003). Furthermore, lower fetuin-A or FLI, but not sOB-R, were independently associated with CLL (p < 0.05), particularly among overweight/obese individuals. Fetuin-A, s-OB-R and FLI were similar between different stages of CLL severity, or between symptomatic and asymptomatic disease. In conclusion, circulating fetuin-A and FLI, but not sOB-R, were lower in patients with CLL than controls, a finding warranting further investigation. C1 [Dalamaga, Maria] Univ Athens, Sch Med, Dept Clin Biochem, Attikon Gen Univ Hosp, Athens 12462, Greece. [Polyzos, Stergios A.; Chamberland, John; Mantzoros, Christos S.] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Div Endocrinol Diabet & Metab, Boston, MA USA. [Karmaniolas, Konstantinos; Migdalis, Ilias] 417 Army Share Fund Gen Hosp, Dept Internal Med, Athens, Greece. [Lekka, Antigoni; Triantafilli, Maria] 417 Army Share Fund Gen Hosp, Hematol Lab, Athens, Greece. [Papadavid, Evangelia] Univ Athens, Sch Med, Dept Internal Med, Attikon Gen Univ Hosp,Dermatol Clin, Athens 12462, Greece. [Mantzoros, Christos S.] Harvard Univ, Sch Med, Endocrinol Sect, Boston VA Healthcare Syst, Boston, MA USA. RP Dalamaga, M (reprint author), Univ Athens, Sch Med, Dept Clin Biochem, 1 Rimini St, Athens 12462, Greece. EM madalamaga@med.uoa.gr OI Dalamaga, Maria/0000-0002-7008-388X NR 32 TC 0 Z9 0 U1 0 U2 1 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1042-8194 EI 1029-2403 J9 LEUKEMIA LYMPHOMA JI Leuk. Lymphoma PD MAR 3 PY 2016 VL 57 IS 3 BP 577 EP 584 DI 10.3109/10428194.2015.1075523 PG 8 WC Oncology; Hematology SC Oncology; Hematology GA DH0UO UT WOS:000372499800012 PM 26317877 ER PT J AU Narayan, R Garcia, JS Percival, MEM Berube, C Coutre, S Gotlib, J Greenberg, P Liedtke, M Hewitt, R Regan, K Williamson, C Doykan, C Cardone, MH McMillan, A Medeiros, BC AF Narayan, Rupa Garcia, Jacqueline S. Percival, Mary-Elizabeth M. Berube, Caroline Coutre, Steve Gotlib, Jason Greenberg, Peter Liedtke, Michaela Hewitt, Rhonda Regan, Kathleen Williamson, Charles Doykan, Camille Cardone, Michael H. McMillan, Alex Medeiros, Bruno C. TI Sequential azacitidine plus lenalidomide in previously treated elderly patients with acute myeloid leukemia and higher risk myelodysplastic syndrome SO LEUKEMIA & LYMPHOMA LA English DT Article DE azanucleosides; Hypomethylating agent failure; lenalidomide; azacitidine; MDS; AML ID INTRAVENOUS CLOFARABINE; HYPOMETHYLATING AGENTS; TET2 MUTATIONS; OUTCOMES; FAILURE; THERAPY; 5-AZACYTIDINE; COMBINATION; EXPRESSION; RESISTANCE AB The outcome of sequential azacitidine with lenalidomide has not been reported in previously treated patients with acute myeloid leukemia (AML) and higher risk myelodysplastic syndrome (MDS). This study describes a phase 2 study evaluating the safety and efficacy of this combination in elderly patients with AML and MDS with prior hypomethylating agent (HMA) and/or immunomodulatory agent exposure. Patients were treated on a 42-day cycle with azacitidine at 75 mg/m(2) SQ/IV daily on days 1-7, followed by lenalidomide 50 mg orally daily on days 8-28. The median number of treatment cycles on study was two (range = 1-11). Of 32 evaluable patients, the overall response rate was 25%. Neutropenic fever was the most common serious adverse event, but overall the combination was well-tolerated. The median overall survival (OS) for responders vs non-responders was 9.8 vs 4.0 months, respectively (HR = 0.36, p = 0.016). In conclusion, this combination demonstrated modest clinical activity in this poor risk population. C1 [Narayan, Rupa; Percival, Mary-Elizabeth M.; Berube, Caroline; Coutre, Steve; Gotlib, Jason; Greenberg, Peter; Liedtke, Michaela; Hewitt, Rhonda; Regan, Kathleen; Williamson, Charles; Medeiros, Bruno C.] Stanford Univ, Dept Med, Sch Med, Div Hematol, Stanford, CA 94305 USA. [Garcia, Jacqueline S.] Dana Farber Canc Inst, Dept Med Oncol, Div Hematol Malignancies, Boston, MA 02115 USA. [Doykan, Camille; Cardone, Michael H.] Eutrop Pharmaceut, Cambridge, MA USA. [McMillan, Alex] Stanford Univ, Sch Med, Dept Hlth Res & Policy, Stanford, CA 94305 USA. RP Medeiros, BC (reprint author), Stanford Univ, Dept Med, Div Hematol, 875 Blake Wilbur Dr,Room 2329, Stanford, CA 94305 USA. EM brunom@stanford.edu FU NCATS NIH HHS [KL2 TR001083, TL1 TR001084] NR 37 TC 5 Z9 5 U1 0 U2 1 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1042-8194 EI 1029-2403 J9 LEUKEMIA LYMPHOMA JI Leuk. Lymphoma PD MAR 3 PY 2016 VL 57 IS 3 BP 609 EP 615 DI 10.3109/10428194.2015.1091930 PG 7 WC Oncology; Hematology SC Oncology; Hematology GA DH0UO UT WOS:000372499800017 PM 26374199 ER PT J AU Bhola, PD Letai, A AF Bhola, Patrick D. Letai, Anthony TI Mitochondria-Judges and Executioners of Cell Death Sentences SO MOLECULAR CELL LA English DT Review ID CHRONIC LYMPHOCYTIC-LEUKEMIA; BCL-X-L; ACUTE MYELOID-LEUKEMIA; CYTOCHROME-C; MEMBRANE PERMEABILIZATION; BH3 DOMAINS; PHOSPHATIDYLSERINE EXPOSURE; CHROMOSOMAL BREAKPOINT; PROAPOPTOTIC FUNCTION; PROMOTES APOPTOSIS AB Apoptosis is a form of programmed cell death that is critical for basic human development and physiology. One of the more important surprises in cell biology in the last two decades is the extent to which mitochondria represent a physical point of convergence for many apoptosis-inducing signals in mammalian cells. Mitochondria not only adjudicate the decision of whether or not to commit to cell death, but also release toxic proteins culminating in widespread proteolysis, nucleolysis, and cell engulfment. Interactions among BCL-2 family proteins at the mitochondrial outer membrane control the release of these toxic proteins and, by extension, control cellular commitment to apoptosis. This pathway is particularly relevant to cancer treatment, as most cancer chemotherapies trigger mitochondrial-mediated apoptosis. In this Review, we discuss recent advances in the BCL-2 family interactions, their control by upstream factors, and how the mitochondria itself alters these interactions. We also highlight recent clinical insights into mitochondrial-mediated apoptosis and novel cancer therapies that exploit this pathway. C1 [Bhola, Patrick D.; Letai, Anthony] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Bhola, Patrick D.; Letai, Anthony] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. RP Letai, A (reprint author), Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA.; Letai, A (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. EM anthony_letai@dfci.harvard.edu FU NIH [P01CA066996, 1R21CA188858-01] FX We thank Emily Su for design of the figure. We acknowledge support from NIH grant P01CA066996. A.L. is a consultant for, and receives sponsored research support for, AbbVie, Astra-Zeneca, Tetralogic, and XrX. P.D.B. is supported by NIH grant 1R21CA188858-01. NR 135 TC 21 Z9 22 U1 3 U2 18 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 MAR 3 PY 2016 VL 61 IS 5 BP 695 EP 704 DI 10.1016/j.molcel.2016.02.019 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DG8IJ UT WOS:000372326800010 PM 26942674 ER PT J AU Bukhari, SIA Truesdell, SS Lee, S Kollu, S Classon, A Boukhali, M Jain, E Mortensen, RD Yanagiya, A Sadreyev, RI Haas, W Vasudevan, S AF Bukhari, Syed I. A. Truesdell, Samuel S. Lee, Sooncheol Kollu, Swapna Classon, Anthony Boukhali, Myriam Jain, Esha Mortensen, Richard D. Yanagiya, Akiko Sadreyev, Ruslan I. Haas, Wilhelm Vasudevan, Shobha TI A Specialized Mechanism of Translation Mediated by FXR1a-Associated MicroRNP in Cellular Quiescence SO MOLECULAR CELL LA English DT Article ID MESSENGER-RNA TRANSLATION; POLY(A) TAIL; POLY(A)-SPECIFIC RIBONUCLEASE; MAMMALIAN-CELLS; XENOPUS-OOCYTES; UP-REGULATION; REPRESSION; BINDING; ACTIVATION; PROTEIN AB MicroRNAs predominantly decrease gene expression; however, specific mRNAs are translationally upregulated in quiescent (G0) mammalian cells and immature Xenopus laevis oocytes by an FXR1a-associated microRNA-protein complex (microRNP) that lacks the microRNP repressor, GW182. Their mechanism in these conditions of decreased mTOR signaling, and therefore reduced canonical (cap-and-poly(A)-tail-mediated) translation, remains undiscovered. Our data reveal that mTOR inhibition in human THP1 cells enables microRNA-mediated activation. Activation requires shortened/no poly(A)tail targets; polyadenylated mRNAs are partially activated upon PAIP2 overexpression, which interferes with poly(A)-bound PABP, precluding PABP-enhanced microRNA-mediated inhibition and canonical translation. Consistently, inhibition of PARN deadenylase prevents activation. P97/DAP5, a homolog of canonical translation factor, eIF4G, which lacks PABP-and cap binding complex-interacting domains, is required for activation, and thereby for the oocyte immature state. P97 interacts with 30 UTR-binding FXR1a-associated microRNPs and with PARN, which binds mRNA 50 caps, forming a specialized complex to translate recruited mRNAs in these altered canonical translation conditions. C1 [Bukhari, Syed I. A.; Truesdell, Samuel S.; Lee, Sooncheol; Kollu, Swapna; Classon, Anthony; Boukhali, Myriam; Mortensen, Richard D.; Haas, Wilhelm; Vasudevan, Shobha] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Canc Res, Boston, MA 02114 USA. [Bukhari, Syed I. A.; Truesdell, Samuel S.; Lee, Sooncheol; Kollu, Swapna; Classon, Anthony; Jain, Esha; Mortensen, Richard D.; Vasudevan, Shobha] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Regenerat Med, Boston, MA 02114 USA. [Yanagiya, Akiko] McGill Univ, Goodman Canc Res Ctr, Dept Biochem, Montreal, PQ H3A 1A3, Canada. [Sadreyev, Ruslan I.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Mol Biol, Boston, MA 02114 USA. [Sadreyev, Ruslan I.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pathol, Boston, MA 02114 USA. [Mortensen, Richard D.] Duke Univ, Dept Biol, Durham, NC 27708 USA. RP Vasudevan, S (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Canc Res, Boston, MA 02114 USA.; Vasudevan, S (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Regenerat Med, Boston, MA 02114 USA. EM vasudevan.shobha@mgh.harvard.edu FU Cancer Research Institute; D. M-E Ryder; Leukemia & Lymphoma Society; Smith Family Foundation; NIGMS [GM100202]; Fund for Medical Discovery fellowship FX The study is funded by Cancer Research Institute, D. & M-E Ryder, Leukemia & Lymphoma Society, Smith Family Foundation & NIGMS GM100202 grants to S.V. S.L. is funded by Fund for Medical Discovery fellowship. We thank Partners Healthcare Center for Personalized Genetic Medicine facility for microarray data, M. Serra and J.M. Traverso for plasmids, O. Le Tonqueze for stable cell lines, J.A. Steitz and N. Sonenberg for comments, and E. Wahle and M. Wormington for anti-PARN. The authors declare no conflict of interest. NR 37 TC 5 Z9 5 U1 3 U2 9 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1097-2765 EI 1097-4164 J9 MOL CELL JI Mol. Cell PD MAR 3 PY 2016 VL 61 IS 5 BP 760 EP 773 DI 10.1016/j.molcel.2016.02.013 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DG8IJ UT WOS:000372326800015 PM 26942679 ER PT J AU McGowan, SK Espejo, EP Balliett, N Werdowatz, EA AF McGowan, Sarah Kate Espejo, Emmanuel P. Balliett, Noelle Werdowatz, Emily A. TI The Effects of Transdiagnostic Group CBT for Anxiety on Insomnia Symptoms SO COGNITIVE BEHAVIOUR THERAPY LA English DT Article DE Anxiety; insomnia; anxious arousal; cognitive behavior therapy ID COGNITIVE-BEHAVIOR THERAPY; SLEEP DISTURBANCES; PANIC DISORDER; METAANALYSIS; DEPRESSION; PSYCHOTHERAPY; EPIDEMIOLOGY; EXPOSURE; IMPACT; MODEL AB Insomnia is a common feature among individuals with anxiety disorders. Studies of cognitive behavioral therapy (CBT) for anxiety report moderate effects on concomitant insomnia symptoms, but further research is still needed especially toward understanding how CBT for anxiety renders beneficial effects on insomnia. The current study examined changes in insomnia symptoms reported by 51 Veterans who participated in a group-based transdiagnostic CBT for anxiety intervention. In addition, insomnia symptoms were examined in relation to symptoms of general distress (GD), anhedonic depression (AD), and anxious arousal (AA) pre- to post-treatment. Results revealed a small, though statistically significant (p<.05) beneficial effect on insomnia symptoms. When changes in GD, AD, and AA were simultaneously examined in relation to changes in insomnia, change in AA was the only significant predictor of insomnia symptoms. The current study highlights the role of AA in the relationship between anxiety disorders and insomnia and demonstrates that reductions in insomnia during transdiagnostic CBT for anxiety can be largely attributed to changes in AA. C1 [McGowan, Sarah Kate; Espejo, Emmanuel P.] VA San Diego Healthcare Syst, Psychol Serv, San Diego, CA USA. [Balliett, Noelle] VA Puget Sound Hlth Care Syst, Psychol, Tacoma, WA USA. [Werdowatz, Emily A.] VA San Diego Healthcare Syst, Res Serv, San Diego, CA USA. RP Espejo, EP (reprint author), VA San Diego Healthcare Syst, Psychol Serv, San Diego, CA USA. EM eespejo@ucsd.edu FU Clinical Scientist Training Initiative Award FX Training in transdiagnostic group cognitive-behavioral therapy of anxiety by Dr. Peter Norton was supported by a Clinical Scientist Training Initiative Award issued to the VA San Diego Psychology Service by the Society for a Science of Clinical Psychology. The contents do not reflect the views of the Department of Veterans Affairs or the United States Government. There are no conflicts to report. We would like to thank Dr. Peter Norton for providing training in his transdiagnostic group cognitive-behavioral therapy of anxiety protocol and for providing materials to assist in the delivery of the group treatment and the conduct of this research study. We would also like to thank Natalie Castriotta, Ph.D., Kim Roser-Kedward, LCSW, Lesley Boutah, LCSW, Kathryn Seay, M.A., and Alexandrea Harmell, M.A. who assisted with co-leading the anxiety groups included in this study. NR 48 TC 0 Z9 0 U1 3 U2 8 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 1650-6073 EI 1651-2316 J9 COGN BEHAV THERAPY JI Cogn. Behav. Ther. PD MAR 3 PY 2016 VL 45 IS 2 BP 163 EP 175 DI 10.1080/16506073.2015.1134639 PG 13 WC Behavioral Sciences; Psychology, Clinical SC Behavioral Sciences; Psychology GA DG4JE UT WOS:000372037700006 PM 26838091 ER PT J AU Lin, HJ Yue, YR Maidana, DE Bouzika, P Atik, A Matsumoto, H Miller, JW Vavvas, DG AF Lin, Haijiang Yue, Yueran Maidana, Daniel E. Bouzika, Peggy Atik, Alp Matsumoto, Hidetaka Miller, Joan W. Vavvas, Demetrios G. TI Drug Delivery Nanoparticles: Toxicity Comparison in Retinal Pigment Epithelium and Retinal Vascular Endothelial Cells SO SEMINARS IN OPHTHALMOLOGY LA English DT Review DE subcellular localization; pegylation; PEG-PLGA; nanoparticle; retina; Cellular uptake ID CELLULAR UPTAKE; POLYETHYLENE-GLYCOL; PARTICLE-SIZE; PEPTIDE; THERAPEUTICS; PEGYLATION; PATHWAYS; APTAMER; CANCER; TISSUE AB Multiple synthetic polymer nanoparticles (NPs) have been widely used as drug delivery systems. However, their toxicity to the retinal pigment epithelium and retinal endothelium remains unclear. In this study, we analyze the cytotoxic effects of three different kinds of NPs, made of poly lactic-co-glycolic acid (PLGA), polycaprolactone (PCL), and PEGylated PLGA (PEG-PLGA), in a retinal pigment epithelium cell line (ARPE-19) and in primary human retinal vascular endothelial cells (RVEC). PEG-PLGA NPs presented the lowest cytotoxicity on ARPE-19 cells and RVEC as assessed by MTT viability assay. While PLGA and PCL exhibited variable amounts of toxicity, no significant toxicity was observed when incubating cells with high PEG-PLGA concentrations (100 mu g/ml), for up to 6 days. On both transmission electron microscopy and confocal microscopy, Rhodamine 6G-loaded PEG-PLGA NPs were observed intracellularly in multiple subcellular organelles. PEG-PLGA NPs are a potentially viable option for the treatment of eye diseases. C1 [Lin, Haijiang; Yue, Yueran; Maidana, Daniel E.; Bouzika, Peggy; Atik, Alp; Matsumoto, Hidetaka; Miller, Joan W.; Vavvas, Demetrios G.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Retina Serv,Angiogenesis Lab, Boston, MA USA. RP Vavvas, DG (reprint author), Massachusetts Eye & Ear Infirm, 243 Charles St, Boston, MA 02114 USA. EM Demetrios_Vavvas@meei.harvard.edu FU NEI [R21EY023079-01A1]; Yeatts Family Foundation; Loefflers Family Fund; Macula Society Research Grant award; Research to Prevent Blindness Foundation; NEI (MEEI Core Grant), Bayer Healthcare Global Ophthalmology Award [EY014104]; Physician Scientist Award FX This study was supported by an NEI grant R21EY023079-01A1 (DGV); the Yeatts Family Foundation (DGV, JWM); the Loefflers Family Fund (DGV, JWM); the 2013 Macula Society Research Grant award (DGV); a Physician Scientist Award (DGV), an unrestricted grant (JWM) from the Research to Prevent Blindness Foundation; and an NEI grant EY014104 (MEEI Core Grant), Bayer Healthcare 2013 Global Ophthalmology Award (DEM). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the article. NR 28 TC 1 Z9 1 U1 10 U2 22 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 0882-0538 EI 1744-5205 J9 SEMIN OPHTHALMOL JI Semin. Ophthalmol. PD MAR 3 PY 2016 VL 31 IS 1-2 SI SI BP 1 EP 9 DI 10.3109/08820538.2015.1114865 PG 9 WC Ophthalmology SC Ophthalmology GA DG5NZ UT WOS:000372126400001 PM 26959123 ER PT J AU Modjtahedi, BS Bose, N Papakostas, TD Morse, L Vavvas, DG Kishan, AU AF Modjtahedi, Bobeck S. Bose, Namrata Papakostas, Thanos D. Morse, Lawrence Vavvas, Demetrios G. Kishan, Amar U. TI Lipids and Diabetic Retinopathy SO SEMINARS IN OPHTHALMOLOGY LA English DT Review DE lipid metabolism; Diabetic retinopathy; statins; fibrates; lipoprotein ID LOW-DENSITY-LIPOPROTEIN; APOLIPOPROTEIN-A-I; PIGMENT EPITHELIAL-CELLS; RANDOMIZED CONTROLLED-TRIAL; SEVERE VISUAL-LOSS; MACULAR EDEMA; SERUM-LIPIDS; RISK-FACTORS; PITTSBURGH EPIDEMIOLOGY; VITREOUS FLUID AB The relationship between lipids and the development and/or severity of diabetic retinopathy (DR) is complex. Large epidemiologic studies suggest an inconsistent and overall modest association between serum triglycerides or major cholesterol species and the severity of DR; however, certain specific lipoprotein species may have stronger associations with DR severity, suggesting a pathophysiological role for lipoproteins analogous to that seen in atherosclerosis. In this lipoprotein-mediated DR pathogenesis model, damage to the blood-retinal barrier allows extravasation of lipoprotein species, which are modified in the intraretinal environment, creating substantial local damage. Additionally, hypolipidemic therapy with statins and fibrates-particularly the latter-have been shown to modulate DR in large-scale studies. Since serum lipid profile changes do not necessarily correlate with DR modulation, the efficacy of these agents may be due to their tissue-specific changes in lipoproteins and/or their anti-inflammatory, antioxidative, antiangiogenic, and antiapoptotic functions. C1 [Modjtahedi, Bobeck S.; Papakostas, Thanos D.; Vavvas, Demetrios G.] Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Retina Serv, Boston, MA 02114 USA. [Bose, Namrata] Univ So Calif, Keck Sch Med, Dept Endocrinol, Los Angeles, CA 90033 USA. [Morse, Lawrence] Univ Calif Davis, Sch Med, Dept Ophthalmol & Vis Sci, Davis, CA 95616 USA. [Kishan, Amar U.] Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Vavvas, DG (reprint author), Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, Retina Serv,Dept Ophthalmol, 243 Charles St, Boston, MA 02114 USA. EM demetrios_vavvas@meei.harvard.edu OI Morse, Lawrence/0000-0002-1758-2348 FU Heed Ophthalmic Foundation FX Dr. Modjtahedi received research support from the Heed Ophthalmic Foundation. NR 101 TC 2 Z9 2 U1 1 U2 5 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 0882-0538 EI 1744-5205 J9 SEMIN OPHTHALMOL JI Semin. Ophthalmol. PD MAR 3 PY 2016 VL 31 IS 1-2 SI SI BP 10 EP 18 DI 10.3109/08820538.2015.1114869 PG 9 WC Ophthalmology SC Ophthalmology GA DG5NZ UT WOS:000372126400002 PM 26959124 ER PT J AU Abdulaal, M Haddad, NMN Sun, JK Silva, PS AF Abdulaal, Marwan Haddad, Nour Maya N. Sun, Jennifer K. Silva, Paolo S. TI The Role of Plasma Kallikrein-Kinin Pathway in the Development of Diabetic Retinopathy: Pathophysiology and Therapeutic Approaches SO SEMINARS IN OPHTHALMOLOGY LA English DT Review DE Diabetic macular edema; diabetic retinopathy; plasma kallikrein-kinin ID MACULAR EDEMA; FACTOR-XII; LASER PHOTOCOAGULATION; VASCULAR-PERMEABILITY; DEFERRED LASER; B-1 RECEPTORS; SYSTEM; RANIBIZUMAB; PREKALLIKREIN; ACTIVATION AB Diabetic retinal disease is characterized by a series of retinal microvascular changes and increases in retinal vascular permeability that lead to development of diabetic retinopathy (DR) and diabetic macular edema (DME), respectively. Current treatment strategies for DR and DME are mostly limited to vascular endothelial growth factor (VEGF) inhibitors and laser photocoagulation. These treatment modalities are not universally effective in all patients, and potential side effects persist in a significant portion of patients. The plasma kallikrein-kinin system (KKS) is one of the pathways that has been identified in the vitreous in proliferative DR and DME. Preclinical studies have shown that the activation of intraocular KKS induces retinal vascular permeability, vasodilation, and retinal thickening. Proteomic analysis from vitreous of eyes with DME has shown that KKS and VEGF pathways are potentially independent biologic pathways. Furthermore, proteins associated with DME in the vitreous were significantly more correlated with the KKS pathway compared to VEGF pathway. Preclinical experiments on diabetic animals showed that inhibition of KKS components was found to be an effective approach to decrease retinal vascular permeability. An initial phase I human trial of a novel plasma kallikrein inhibitor for the treatment of DME is currently ongoing to test the safety of this approach and serves as an initial step in the translation of basic science discovery into an innovative clinical intervention. C1 [Abdulaal, Marwan; Haddad, Nour Maya N.; Sun, Jennifer K.; Silva, Paolo S.] Joslin Diabet Ctr, Beetham Eye Inst, Boston, MA 02215 USA. [Abdulaal, Marwan; Haddad, Nour Maya N.; Sun, Jennifer K.; Silva, Paolo S.] Harvard Univ, Sch Med, Dept Ophthalmol, Boston, MA 02215 USA. RP Silva, PS (reprint author), Harvard Univ, Sch Med, Joslin Diabet Ctr, Beetham Eye Inst, One Joslin Pl, Boston, MA 02215 USA. EM PaoloAntonio.Silva@joslin.harvard.edu NR 47 TC 0 Z9 0 U1 2 U2 4 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 0882-0538 EI 1744-5205 J9 SEMIN OPHTHALMOL JI Semin. Ophthalmol. PD MAR 3 PY 2016 VL 31 IS 1-2 SI SI BP 19 EP 24 DI 10.3109/08820538.2015.1114829 PG 6 WC Ophthalmology SC Ophthalmology GA DG5NZ UT WOS:000372126400003 PM 26959125 ER PT J AU Sachdeva, MM Eliott, D AF Sachdeva, Mira M. Eliott, Dean TI Stem Cell-Based Therapy for Diseases of the Retinal Pigment Epithelium: From Bench to Bedside SO SEMINARS IN OPHTHALMOLOGY LA English DT Review DE transplantation; stem cells; stargardt's macular dystrophy; retinal pigment epithelium; Age-related macular degeneration ID HUMAN SOMATIC-CELLS; LONG-TERM SAFETY; MACULAR DEGENERATION; DIRECTED DIFFERENTIATION; GEOGRAPHIC ATROPHY; DEFINED FACTORS; CHOROID GRAFT; TRANSPLANTATION; INHIBITION; NEOVASCULARIZATION AB Age-related macular degeneration (AMD) represents a leading cause of blindness in the elderly, and Stargardt's macular dystrophy (SMD) is the most common form of juvenile-onset macular degeneration. Dry AMD and SMD share an underlying pathophysiology, namely dysfunction and ultimately loss of the retinal pigment epithelium (RPE), suggesting that RPE transplantation may offer a potential treatment strategy for both patient populations. Stem cells have emerged as a promising source of replacement RPE. During the past 15 years, extraordinary strides have been made in the identification, characterization, and differentiation of stem cells. Recently, this large body of basic science and preclinical research has been translated to patient care with the publication of results from Phase 1/2 trials demonstrating safety of transplantation of human embryonic stem cell (hESC)-derived RPE into patients with AMD and SMD. While significant challenges remain before dry AMD and SMD become treatable diseases, the goal has become more tangible. C1 [Sachdeva, Mira M.; Eliott, Dean] Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. RP Sachdeva, MM (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Retina Serv, 243 Charles St, Boston, MA 02114 USA. EM Mira_Sachdeva@meei.harvard.edu NR 39 TC 0 Z9 0 U1 4 U2 5 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 0882-0538 EI 1744-5205 J9 SEMIN OPHTHALMOL JI Semin. Ophthalmol. PD MAR 3 PY 2016 VL 31 IS 1-2 SI SI BP 25 EP 29 DI 10.3109/08820538.2015.1115253 PG 5 WC Ophthalmology SC Ophthalmology GA DG5NZ UT WOS:000372126400004 PM 26959126 ER PT J AU Brader, HS Young, LHY AF Brader, Hilary S. Young, Lucy H. Y. TI Subthreshold Diode Micropulse Laser: A Review SO SEMINARS IN OPHTHALMOLOGY LA English DT Review DE subvisible; photocoagulation; non-damaging; Minimum-intensity ID DIABETIC MACULAR EDEMA; CENTRAL SEROUS CHORIORETINOPATHY; RETINAL VEIN OCCLUSION; OPTICAL COHERENCE TOMOGRAPHY; ONE-YEAR OUTCOMES; PIGMENT-EPITHELIUM; GRID LASER; 810 NM; TRANSPUPILLARY THERMOTHERAPY; PANRETINAL PHOTOCOAGULATION AB The subthreshold diode micropulse laser is a form of non-damaging thermal laser therapy which has shown efficacy in multiple retinal conditions. The purpose of this article is to review the use of subthreshold diode micropulse laser as an emerging treatment modality for the treatment of retinal disease. The proposed mechanisms of action, safety, efficacy, recommended laser treatment parameters, and clinical applications for which the use of subthreshold diode micropulse laser has been studied will be reviewed. C1 [Brader, Hilary S.; Young, Lucy H. Y.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Boston, MA 02114 USA. RP Brader, HS (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Retina Serv, 243 Charles St, Boston, MA 02114 USA. EM hilary.brader@gmail.com NR 76 TC 0 Z9 0 U1 3 U2 10 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 0882-0538 EI 1744-5205 J9 SEMIN OPHTHALMOL JI Semin. Ophthalmol. PD MAR 3 PY 2016 VL 31 IS 1-2 SI SI BP 30 EP 39 DI 10.3109/08820538.2015.1114837 PG 10 WC Ophthalmology SC Ophthalmology GA DG5NZ UT WOS:000372126400005 PM 26959127 ER PT J AU Ajlan, RS Silva, PS Sun, JK AF Ajlan, Radwan S. Silva, Paolo S. Sun, Jennifer K. TI Vascular Endothelial Growth Factor and Diabetic Retinal Disease SO SEMINARS IN OPHTHALMOLOGY LA English DT Review DE Diabetic macular edema; diabetic retinopathy; vascular endothelial growth factor ID INTRAVITREAL BEVACIZUMAB AVASTIN; MACULAR EDEMA; IRIS NEOVASCULARIZATION; RETINOPATHY SEVERITY; PERMEABILITY FACTOR; DEFERRED LASER; RANIBIZUMAB; AFLIBERCEPT; INHIBITION; DURATION AB Diabetic retinal disease remains a leading cause of blindness among working-aged adults around the world. Until this decade, laser photocoagulation for both proliferative diabetic retinopathy and diabetic macular edema had been the standard of care for millions of patients. The introduction of vascular endothelial growth factor inhibitors (anti-VEGF) and subsequent clinical trials demonstrating their efficacy for treatment of diabetic eye disease have established a new standard in treatment of center-involved diabetic macular edema that is highly specific to the pathologic process and highly effective in preserving and improving vision. This review focuses on clinically relevant developments that led to the shift from focal/grid laser photocoagulation to anti-VEGF injections in the treatment of center-involved diabetic macular edema (DME), with an overview of the disease pathophysiology, clinical disease course, and available anti-VEGF agents. This article also reviews the scientific evidence exploring the use of anti-VEGF agents in nonproliferative and proliferative diabetic retinopathy. C1 [Ajlan, Radwan S.; Silva, Paolo S.; Sun, Jennifer K.] Harvard Univ, Sch Med, Joslin Diabet Ctr, Beetham Eye Inst, One Joslin Pl, Boston, MA 02215 USA. RP Silva, PS (reprint author), Harvard Univ, Sch Med, Joslin Diabet Ctr, Beetham Eye Inst, One Joslin Pl, Boston, MA 02215 USA. EM PaoloAntonio.Silva@joslin.harvard.edu NR 45 TC 2 Z9 2 U1 4 U2 10 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 0882-0538 EI 1744-5205 J9 SEMIN OPHTHALMOL JI Semin. Ophthalmol. PD MAR 3 PY 2016 VL 31 IS 1-2 SI SI BP 40 EP 48 DI 10.3109/08820538.2015.1114833 PG 9 WC Ophthalmology SC Ophthalmology GA DG5NZ UT WOS:000372126400006 PM 26959128 ER PT J AU Hafler, BP Comander, J DiFranco, CW Place, EM Pierce, EA AF Hafler, Brian P. Comander, Jason DiFranco, Carol Weigel Place, Emily M. Pierce, Eric A. TI Course of Ocular Function in PRPF31 Retinitis Pigmentosa SO SEMINARS IN OPHTHALMOLOGY LA English DT Review DE Inherited retinal degeneration; retinitis pigmentosa; RNA splicing factor ID OPTICAL COHERENCE TOMOGRAPHY; MESSENGER-RNA; MUTATIONS; ELECTRORETINOGRAM; VARIABILITY; PENETRANCE AB Mutations in pre-mRNA splicing factors are the second most common cause of autosomal dominant retinitis pigmentosa, and a major cause of vision loss. The development of gene augmentation therapy for disease caused by mutations in PRPF31 necessitates defining pretreatment characteristics and disease progression of patients with PRPF31-related retinitis pigmentosa. We show rates of decline of visual field area -6.9% per year and 30-Hz flicker cone response of -9.2% per year, which are both similar to observed rates for retinitis pigmentosa. We hypothesize that RNA splicing factor retinitis pigmentosa will be amenable to treatment by AAV-mediated gene therapy, and that understanding the clinical progression rates of PRPF31 retinitis pigmentosa will help with the design of gene therapy clinical trials. C1 [Hafler, Brian P.; Comander, Jason; DiFranco, Carol Weigel; Place, Emily M.; Pierce, Eric A.] Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Boston, MA 02114 USA. RP Hafler, BP (reprint author), Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Boston, MA 02114 USA. EM brian_hafler@meei.harvard.edu OI Pierce, Eric/0000-0002-2354-4102 FU NEI NIH HHS [R01 EY020902, K12 EY016335] NR 17 TC 0 Z9 0 U1 3 U2 6 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 0882-0538 EI 1744-5205 J9 SEMIN OPHTHALMOL JI Semin. Ophthalmol. PD MAR 3 PY 2016 VL 31 IS 1-2 SI SI BP 49 EP 52 DI 10.3109/08820538.2015.1114856 PG 4 WC Ophthalmology SC Ophthalmology GA DG5NZ UT WOS:000372126400007 PM 26959129 ER PT J AU Glass, LD Sullivan, R Freitag, SK AF Glass, Lora Dagi Sullivan, Ryan Freitag, Suzanne K. TI New Translational Research in the Medical Management of Orbital Melanoma SO SEMINARS IN OPHTHALMOLOGY LA English DT Review DE vemurafinib; ipilimumab; Dabrafenib; trametinib; nivolumab; pembrolizumab ID BRAF-MUTATED MELANOMA; METASTATIC MELANOMA; MEK INHIBITION; OPEN-LABEL; MALIGNANT-MELANOMA; IMPROVED SURVIVAL; PHASE-2 TRIAL; IPILIMUMAB; VEMURAFENIB; NIVOLUMAB AB New translational research has paved the way for more optimistic management of melanoma. Medications targeting oncogenic signaling cascades and immune regulatory molecules have significantly improved overall survival for patients with metastatic melanoma. While isolated, operable orbital melanoma may still benefit from surgery, there potentially is an opportunity to provide patients with neoadjuvant systemic therapy with sustainable long-term effects. Additionally, patients with non-resectable orbital melanoma can benefit from systemic treatment. C1 [Glass, Lora Dagi; Freitag, Suzanne K.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Ophthalm Plast Surg Serv,Dept Ophthalmol, Boston, MA USA. [Sullivan, Ryan] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Canc, Boston, MA USA. RP Glass, LD (reprint author), Ophthalm Plast Surg Serv, 243 Charles St,10th Floor, Boston, MA 02114 USA. EM lora_dagiglass@meei.harvard.edu NR 40 TC 0 Z9 0 U1 2 U2 2 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 0882-0538 EI 1744-5205 J9 SEMIN OPHTHALMOL JI Semin. Ophthalmol. PD MAR 3 PY 2016 VL 31 IS 1-2 SI SI BP 53 EP 58 DI 10.3109/08820538.2015.1114849 PG 6 WC Ophthalmology SC Ophthalmology GA DG5NZ UT WOS:000372126400008 ER PT J AU Goyal, S Hamrah, P AF Goyal, Sunali Hamrah, Pedram TI Understanding Neuropathic Corneal Pain-Gaps and Current Therapeutic Approaches SO SEMINARS IN OPHTHALMOLOGY LA English DT Review DE corneal neural anatomy; in vivo confocal microscopy; neuropathic pain; corneal pain; Autologous serum drops; dry eye ID VIVO-CONFOCAL-MICROSCOPY; DRY-EYE DISEASE; MEIBOMIAN GLAND DYSFUNCTION; HERPES-ZOSTER OPHTHALMICUS; PERIPHERAL NERVOUS-SYSTEM; PRIMARY SJOGRENS-SYNDROME; IN-SITU KERATOMILEUSIS; SENSORY NEURONS; THERMAL-STIMULATION; TOPICAL APPLICATION AB The richly innervated corneal tissue is one of the most powerful pain generators in the body. Corneal neuropathic pain results from dysfunctional nerves causing perceptions such as burning, stinging, eye-ache, and pain. Various inflammatory diseases, neurological diseases, and surgical interventions can be the underlying cause of corneal neuropathic pain. Recent efforts have been made by the scientific community to elucidate the pathophysiology and neurobiology of pain resulting from initially protective physiological reflexes, to a more persistent chronic state. The goal of this clinical review is to briefly summarize the pathophysiology of neuropathic corneal pain, describe how to systematically approach the diagnosis of these patients, and finally summarizing our experience with current therapeutic approaches for the treatment of corneal neuropathic pain. C1 [Goyal, Sunali; Hamrah, Pedram] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Cornea & Refract Surg Serv,Dept Ophthalmol, Boston, MA USA. [Hamrah, Pedram] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Ocular Surface Imaging Ctr,Dept Ophthalmol, Boston, MA USA. [Hamrah, Pedram] New England Eye Ctr, Boston Image Reading Ctr, Boston, MA USA. [Hamrah, Pedram] New England Eye Ctr, Cornea Serv, Boston, MA USA. [Hamrah, Pedram] Tufts Univ, Sch Med, Tufts Med Ctr, Dept Ophthalmol, Boston, MA 02111 USA. RP Hamrah, P (reprint author), Tufts Univ, Sch Med, Tufts Med Ctr, Cornea Serv,New England Eye Ctr, 800 Washington St, Boston, MA 02111 USA. EM phamrah@tuftsmedicalcenter.org FU NIH [R01-EY022695]; Research to Prevent Blindness Career Development Award; Falk Medical Research Trust FX This study was supported by NIH R01-EY022695 (PH), Research to Prevent Blindness Career Development Award (PH), and Falk Medical Research Trust (PH). The funding organizations had no role in the design or conduct of this research. NR 112 TC 1 Z9 1 U1 1 U2 4 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 0882-0538 EI 1744-5205 J9 SEMIN OPHTHALMOL JI Semin. Ophthalmol. PD MAR 3 PY 2016 VL 31 IS 1-2 SI SI BP 59 EP 70 DI 10.3109/08820538.2015.1114853 PG 12 WC Ophthalmology SC Ophthalmology GA DG5NZ UT WOS:000372126400009 PM 26959131 ER PT J AU Odorcic, S Sabeti, S Haas, W Durand, ML Dohlman, CH AF Odorcic, Silvia Sabeti, Saama Haas, Wolfgang Durand, Marlene L. Dohlman, Claes H. TI Fungal Infections in Boston Keratoprosthesis Patients: Lessons Learned and Novel Developments on the Horizon SO SEMINARS IN OPHTHALMOLOGY LA English DT Review DE yeast; prophylaxis; mold; keratitis; Endophthalmitis; translational research ID TYPE-1 KERATOPROSTHESIS; MICROBIAL KERATITIS; CONJUNCTIVAL SAC; CONTACT-LENS; BACTERIAL-KERATITIS; RESISTANCE PATTERNS; RISK-FACTORS; IN-VITRO; ENDOPHTHALMITIS; FLORA AB The Boston Keratoprosthesis (B-KPro) is a widely accepted modality of corneal restoration in eyes where traditional penetrating keratoplasty has little chance of success. It is the most commonly used keratoprosthesis worldwide. While the introduction of broad-spectrum antibiotic prophylaxis has virtually eliminated cases of bacterial endophthalmitis, fungal colonization and infections are a growing concern. This review of the literature summarizes risk factors for fungal infections in KPro eyes, rates of fungal infection and colonization, clinical presentation, causative organisms, management, and outcomes. We also focus on current recommendations for antifungal prophylaxis, and highlight the role of translational research at the Massachusetts Eye and Ear Infirmary (MEEI, Boston, USA) with its aim of developing novel strategies for reducing rates of fungal infections in KPro patients. C1 [Odorcic, Silvia; Haas, Wolfgang; Durand, Marlene L.; Dohlman, Claes H.] Massachusetts Eye & Ear Infirm, Dept Ophthalmol, 243 Charles St, Boston, MA 02114 USA. [Sabeti, Saama] Univ Ottawa, Ottawa Hosp, Inst Eye, Dept Ophthalmol, Ottawa, ON, Canada. [Durand, Marlene L.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. RP Odorcic, S (reprint author), Massachusetts Eye & Ear Infirm, Dept Ophthalmol, 243 Charles St, Boston, MA 02114 USA. EM silvia.odorcic@gmail.com NR 55 TC 0 Z9 0 U1 0 U2 1 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 0882-0538 EI 1744-5205 J9 SEMIN OPHTHALMOL JI Semin. Ophthalmol. PD MAR 3 PY 2016 VL 31 IS 1-2 SI SI BP 71 EP 84 DI 10.3109/08820538.2015.1114871 PG 14 WC Ophthalmology SC Ophthalmology GA DG5NZ UT WOS:000372126400010 PM 26959132 ER PT J AU Saeed, HN Chodosh, J AF Saeed, Hajirah N. Chodosh, James TI Immunologic Mediators in Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis SO SEMINARS IN OPHTHALMOLOGY LA English DT Review DE granzyme B; granulysin; Fas; perforin; ocular immunology; immunomodulators ID SOLUBLE FAS LIGAND; CUTANEOUS ADVERSE-REACTIONS; CYTOTOXIC T-CELLS; INTRAVENOUS IMMUNOGLOBULIN; GRANZYME-B; GRANULYSIN; INVOLVEMENT; THERAPY; INHIBITION; MANAGEMENT AB Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are a spectrum of T-cell mediated immune disorders. While the contributory mechanisms leading to the apoptosis of epidermal cells in SJS/TEN remain unproven, the keratinocyte apoptosis seen in SJS/TEN is thought to occur through the T-cell mediated Fas-Fas ligand (FasL), perforin/granzyme B, and other immune mediators. Most recently, emphasis has been placed on the granulysin pathway as being the primary mediator of apoptosis and widespread epidermal necrosis in SJS/TEN. This article aims to review the proposed mechanisms by which these pathways work and the immunomodulatory therapies that have been developed in an attempt to target them. C1 [Saeed, Hajirah N.; Chodosh, James] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol, 243 Charles St, Boston, MA 02114 USA. RP Chodosh, J (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol, 243 Charles St, Boston, MA 02114 USA. EM James_Chodosh@meei.harvard.edu NR 71 TC 0 Z9 1 U1 5 U2 5 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 0882-0538 EI 1744-5205 J9 SEMIN OPHTHALMOL JI Semin. Ophthalmol. PD MAR 3 PY 2016 VL 31 IS 1-2 SI SI BP 85 EP 90 DI 10.3109/08820538.2015.1115255 PG 6 WC Ophthalmology SC Ophthalmology GA DG5NZ UT WOS:000372126400011 PM 26959133 ER PT J AU Khan-Farooqi, H Chodosh, J AF Khan-Farooqi, Haumith Chodosh, James TI Autologous Limbal Stem Cell Transplantation: The Progression of Diagnosis and Treatment SO SEMINARS IN OPHTHALMOLOGY LA English DT Review DE limbus; epithelium; Cornea; transplant; limbal stem cell deficiency ID CORNEAL EPITHELIAL MAINTENANCE; OCULAR SURFACE DISORDERS; CONJUNCTIVAL TRANSPLANTATION; XERODERMA-PIGMENTOSUM; DEFICIENCY; RECONSTRUCTION; REGENERATION; NEOPLASIA; AUTOGRAFT; SURGERIES AB Though the corneoscleral limbus has been studied for more than 150 years, our ability to successfully treat those with limbal stem cell deficiency (LSCD) is still a work in progress. Today, the only definitive cure for LSCD is stem cell transplantation. This review briefly discusses the evolution of our understanding of limbal stem cell function, provides an outline of the history of autologous limbal stem cell (LSC) transplantation, and discusses current techniques and future strategies for LSCD treatment. C1 [Khan-Farooqi, Haumith; Chodosh, James] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol, 243 Charles St, Boston, MA 02114 USA. RP Khan-Farooqi, H (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol, 243 Charles St, Boston, MA 02114 USA. EM Haumith_Khan-Farooqi@meei.harvard.edu FU Research to Prevent Blindness, New York, NY FX This work was supported in part by an unrestricted grant to the Department of Ophthalmology at Harvard Medical School from Research to Prevent Blindness, New York, NY. NR 69 TC 0 Z9 0 U1 4 U2 6 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 0882-0538 EI 1744-5205 J9 SEMIN OPHTHALMOL JI Semin. Ophthalmol. PD MAR 3 PY 2016 VL 31 IS 1-2 SI SI BP 91 EP 98 DI 10.3109/08820538.2015.1114862 PG 8 WC Ophthalmology SC Ophthalmology GA DG5NZ UT WOS:000372126400012 PM 26959134 ER PT J AU Peeler, C Cestari, DM AF Peeler, Crandall Cestari, Dean M. TI Non-Arteritic Anterior Ischemic Optic Neuropathy (NAION): A Review and Update on Animal Models SO SEMINARS IN OPHTHALMOLOGY LA English DT Review DE Neuroprotection; primate models; rodent models; optic nerve vasculature; optic nerve ischemia ID NOCTURNAL ARTERIAL-HYPOTENSION; SINGLE INTRAVITREAL INJECTION; NERVE SHEATH DECOMPRESSION; IMPROVE VISUAL FUNCTION; RETINAL GANGLION-CELLS; HEAD BLOOD-FLOW; PRIMATE MODEL; RODENT MODEL; DISC DRUSEN; SUSTAINED NEUROPROTECTION AB Non-arteritic anterior ischemic optic neuropathy (NAION) is a relatively common optic neuropathy in adults over the age of 50, typically causing sudden, painless, unilateral vision loss and always resulting in swelling of the optic nerve head. Though several anatomic and vascular risk factors have been identified, much remains unknown about its pathophysiology and there is no proven treatment. This article reviews the risk factors, clinical presentation, and therapies that have been investigated for NAION. In addition, we provide an update from recent rodent and primate models, which offer new insight into the pathophysiology of this disease and provide a platform for treatment trials. C1 [Peeler, Crandall; Cestari, Dean M.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Neuroophthalmol Serv, Boston, MA USA. RP Peeler, C (reprint author), Massachusetts Eye & Ear Infirm, 243 Charles St, Boston, MA 02114 USA. EM crandall.peeler@gmail.com NR 103 TC 0 Z9 0 U1 0 U2 1 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 0882-0538 EI 1744-5205 J9 SEMIN OPHTHALMOL JI Semin. Ophthalmol. PD MAR 3 PY 2016 VL 31 IS 1-2 SI SI BP 99 EP 106 DI 10.3109/08820538.2015.1115248 PG 8 WC Ophthalmology SC Ophthalmology GA DG5NZ UT WOS:000372126400013 PM 26959135 ER PT J AU Rasool, N Lessell, S Cestari, DM AF Rasool, Nailyn Lessell, Simmons Cestari, Dean M. TI Leber Hereditary Optic Neuropathy: Bringing the Lab to the Clinic SO SEMINARS IN OPHTHALMOLOGY LA English DT Review DE Leber hereditary optic neuropathy; Hereditary optic neuropathy; mitochondrial optic neuropathy; optic neuropathy ID MITOCHONDRIAL-DNA MUTATION; COMPLEX-I DYSFUNCTION; GENE-THERAPY; VISUAL RECOVERY; MATERNAL INHERITANCE; PEDIGREE ANALYSIS; IDENTICAL-TWINS; RAT MODEL; IDEBENONE; DISEASE AB Leber hereditary optic neuropathy (LHON) was the first clinically characterized mitochondrial disorder. Since its first description in 1871, much has been discovered regarding the genetics and pathophysiology of the disease. This has enabled the development of in vitro cell and animal models that can be used to try to determine not only the effects of the genetic mutation upon the clinical phenotype but to also test potential novel therapies. Treatments for LHON have ranged from vitamins and minerals to immunosuppressants and, more recently, targeted gene therapy. This article reviews the pathophysiology and clinical features of LHON with a focus on translational research. C1 [Rasool, Nailyn; Lessell, Simmons; Cestari, Dean M.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Neuroophthalmol Serv, Boston, MA USA. RP Cestari, DM (reprint author), 243 Charles St, Boston, MA 02114 USA. EM Dean_cestari@meei.harvard.edu NR 98 TC 2 Z9 2 U1 2 U2 4 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 0882-0538 EI 1744-5205 J9 SEMIN OPHTHALMOL JI Semin. Ophthalmol. PD MAR 3 PY 2016 VL 31 IS 1-2 SI SI BP 107 EP 116 DI 10.3109/08820538.2015.1115251 PG 10 WC Ophthalmology SC Ophthalmology GA DG5NZ UT WOS:000372126400014 PM 26959136 ER PT J AU Boudreault, K Durand, ML Rizzo, JF AF Boudreault, Katherine Durand, Marlene L. Rizzo, Joseph F., III TI Investigation-Directed Approach to Inflammatory Optic Neuropathies SO SEMINARS IN OPHTHALMOLOGY LA English DT Review DE Lyme borreliosis; lupus; myelin oligodendrocyte glycoprotein (MOG); Atypical optic neuritis; neuromyelitis optica (NMO); sarcoidosis ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; NEURITIS TREATMENT TRIAL; RELAPSING NEUROMYELITIS-OPTICA; LYME-DISEASE; BORRELIA-BURGDORFERI; NERVOUS-SYSTEM; SPECTRUM DISORDERS; MULTIPLE-SCLEROSIS; OCULAR SYPHILIS; FOLLOW-UP AB Any presentation of an optic neuropathy with features that suggest inflammation should be addressed promptly because of blindness and the potential for effective treatment in some cases. A step-wise approach, including laboratory testing and imaging, is often informative, although the diagnosis may remain elusive despite detailed investigation. C1 Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Neuroophthalmol Serv, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Rizzo, JF (reprint author), Massachusetts Eye & Ear Infirm, Neuroophthalmol Serv, 243 Charles St, Boston, MA 02114 USA. EM joseph_rizzo@meei.harvard.edu NR 113 TC 2 Z9 2 U1 1 U2 7 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 0882-0538 EI 1744-5205 J9 SEMIN OPHTHALMOL JI Semin. Ophthalmol. PD MAR 3 PY 2016 VL 31 IS 1-2 SI SI BP 117 EP 130 DI 10.3109/08820538.2015.1114835 PG 14 WC Ophthalmology SC Ophthalmology GA DG5NZ UT WOS:000372126400015 PM 26959137 ER PT J AU Guy, AH Wiggs, JL Turalba, A Pasquale, LR AF Guy, Ann H. Wiggs, Janey L. Turalba, Angela Pasquale, Louis R. TI Translating the Low Translaminar Cribrosa Pressure Gradient Hypothesis into the Clinical Care of Glaucoma SO SEMINARS IN OPHTHALMOLOGY LA English DT Review DE intraocular pressure; primary open angle glaucoma; Intracranial pressure ID CEREBROSPINAL-FLUID PRESSURE; OPEN-ANGLE GLAUCOMA; IDIOPATHIC INTRACRANIAL HYPERTENSION; OPTIC DISC EDEMA; LAMINA-CRIBROSA; PSEUDOTUMOR CEREBRI; OCULAR HYPERTENSION; TRABECULECTOMY; DISPLACEMENT; PAPILLEDEMA AB Glaucoma is an optic neuropathy with multiple known risk factors, including age, race, family history, and intraocular pressure. Unfortunately, the only currently modifiable risk factor in treating the disease is intraocular pressure (IOP). Recent studies have investigated intracranial pressure (ICP) and the translaminar cribrosa pressure gradient as a potential explanation for glaucomatous optic nerve vulnerability across a range of IOP values. The difference between these two pressures across the lamina cribrosa may have an effect on the optic nerve, which could provide another modifiable parameter in the battle against glaucoma. In order for modification of the translaminar pressure gradient to be considered in the treatment of glaucoma, noninvasive methods to accurately measure ICP need to be developed. The translaminar pressure gradient could be therapeutically adjusted by either further lowering the IOP or raising the ICP when it is pathologically low, if possible. C1 [Guy, Ann H.; Wiggs, Janey L.; Turalba, Angela; Pasquale, Louis R.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Glaucoma Serv,Dept Ophthalmol, Boston, MA 02114 USA. [Pasquale, Louis R.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Channing Div Network Med,Dept Med, Boston, MA 02114 USA. RP Guy, AH (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol, 243 Charles St, Boston, MA 02114 USA. EM hollyguy1@gmail.com FU Glaucoma Center of Excellence; Harvard Medical School Ophthalmology Scholar award FX No author has any financial interests in the material discussed here. Drs. Pasquale and Wiggs are supported by the Glaucoma Center of Excellence. Dr. Pasquale is also supported by a Harvard Medical School Ophthalmology Scholar award. NR 48 TC 0 Z9 0 U1 2 U2 2 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 0882-0538 EI 1744-5205 J9 SEMIN OPHTHALMOL JI Semin. Ophthalmol. PD MAR 3 PY 2016 VL 31 IS 1-2 SI SI BP 131 EP 139 DI 10.3109/08820538.2015.1114855 PG 9 WC Ophthalmology SC Ophthalmology GA DG5NZ UT WOS:000372126400016 PM 26959138 ER PT J AU Dewundara, SS Wiggs, JL Sullivan, DA Pasquale, LR AF Dewundara, Samantha S. Wiggs, Janey L. Sullivan, David A. Pasquale, Louis R. TI Is Estrogen a Therapeutic Target for Glaucoma? SO SEMINARS IN OPHTHALMOLOGY LA English DT Review DE Estrogen; reproductive hormones; optic nerve degeneration; postmenopausal hormones; glaucoma; sex differences ID OPEN-ANGLE GLAUCOMA; HORMONE REPLACEMENT THERAPY; NITRIC-OXIDE SYNTHASE; FEMALE REPRODUCTIVE FACTORS; VISUAL-FIELD ANALYSIS; GANGLION-CELL LOSS; OCULAR BLOOD-FLOW; INTRAOCULAR-PRESSURE; MENSTRUAL-CYCLE; POSTMENOPAUSAL WOMEN AB This article's objective is to provide an overview of the association between estrogen and glaucoma. A literature synthesis was conducted of articles published in peer-reviewed journals screened through May 5, 2015, using the PubMed database. Keywords used were "estrogen and glaucoma," "reproductive factors and glaucoma," and "estrogen, nitric oxide and eye." Forty-three journal articles were included. Results indicated that markers for lifetime estrogen exposure have been measured by several studies and show that the age of menarche onset, oral contraceptive (OC) use, bilateral oophorectomy, age of menopause onset and duration between menarche to menopause are associated with primary open-angle glaucoma (POAG) risk. The Blue Mountain Eye Study found a significantly increased POAG risk with later (>13 years) compared with earlier (<= 12 years) age of menarche. Nurses' Health Study (NHS) investigators found that OC use of greater than 5 years was associated with a 25% increased risk of POAG. The Mayo Clinic Cohort Study of Oophorectomy and Aging found that women who underwent bilateral oophorectomy before age 43 years had an increased risk of glaucoma. The Rotterdam Study found that women who went through menopause before reaching the age of 45 years had a higher risk of open-angle glaucoma (2.6-fold increased risk), while the NHS showed a reduced risk of POAG among women older than 65 who entered menopause after age >= 54 years. Increased estrogen states may confer a reduced risk of glaucoma or glaucoma-related traits such as reduced intraocular pressure (IOP). Pregnancy, a hyperestrogenemic state, is associated with decreased IOP during the third trimester. Though the role of postmenopausal hormone (PMH) use in the reduction of IOP is not fully conclusive, PMH use may reduce the risk of POAG. From a genetic epidemiologic perspective, estrogen metabolic pathway single nucleotide polymorphisms (SNPs) were associated with POAG in women and polymorphisms in endothelial nitric oxide synthase, a gene receptive to estrogen regulation, are associated with glaucoma. The study concluded that increasing evidence suggests that lifetime exposure to estrogen may alter the pathogenesis of glaucoma. Estrogen exposure may have a neuroprotective effect on the progression of POAG but further studies need to confirm this finding. The role of sex-specific preventive and therapeutic treatment may be on the horizon. C1 [Dewundara, Samantha S.; Wiggs, Janey L.; Sullivan, David A.; Pasquale, Louis R.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol, Boston, MA USA. [Sullivan, David A.] Massachusetts Eye & Ear Infirm, Schepens Eye Res Inst, Boston, MA 02114 USA. [Pasquale, Louis R.] Brigham & Womens Hosp, Div Network Med, 75 Francis St, Boston, MA 02115 USA. RP Pasquale, LR (reprint author), Massachusetts Eye & Ear Infirm, 243 Charles St, Boston, MA 02114 USA. EM Louis_Pasquale@meei.harvard.edu FU NIH [R01 EY015473, R01 EY05612]; Harvard Glaucoma Center of Excellence FX This work is supported in part by NIH R01 EY015473 and NIH R01 EY05612. Drs. Pasquale and Wiggs are supported by the Harvard Glaucoma Center of Excellence and Dr. Sullivan is supported by the Margaret S. Sinon Scholar in Ocular Surface Research fund. NR 84 TC 0 Z9 1 U1 0 U2 2 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 0882-0538 EI 1744-5205 J9 SEMIN OPHTHALMOL JI Semin. Ophthalmol. PD MAR 3 PY 2016 VL 31 IS 1-2 SI SI BP 140 EP 146 DI 10.3109/08820538.2015.1114845 PG 7 WC Ophthalmology SC Ophthalmology GA DG5NZ UT WOS:000372126400017 PM 26959139 ER PT J AU Kamat, SS Gregory, MS Pasquale, LR AF Kamat, Shivani S. Gregory, Meredith S. Pasquale, Louis R. TI The Role of the Immune System in Glaucoma: Bridging the Divide Between Immune Mechanisms in Experimental Glaucoma and the Human Disease SO SEMINARS IN OPHTHALMOLOGY LA English DT Review DE innate immunity; adaptive immunity; Glaucoma; TNF alpha ID OPTIC-NERVE HEAD; NORMAL-PRESSURE GLAUCOMA; NORMAL-TENSION GLAUCOMA; NECROSIS-FACTOR-ALPHA; OPEN-ANGLE GLAUCOMA; MOUSE MODEL; SHOCK PROTEINS; COMPLEMENT; TRIAL; AUTOANTIBODIES AB Glaucoma is one of the leading causes of visual impairment worldwide. Classically, clinicians have evaluated patients through a full ophthalmological examination including gonioscopy, measurement of intraocular pressure (IOP), and assessment of the optic nerve. New imaging modalities have further enhanced our ability to evaluate glaucoma; however, our treatments have not evolved as much. Whether one uses medical treatment with topical ocular antihypertensives, laser trabeculoplasty, or filtering surgery, the mainstay of treatment is to lower IOP. However, as our understanding of the disease evolves, mechanisms other than elevated IOP have been implicated in glaucoma pathogenesis. Recent animal model studies have shown a possible role of the immune system in the pathophysiology of glaucoma. This article explores the current understanding of immune reactions in glaucoma, which could lead to a new paradigm of treatment for human disease. C1 [Kamat, Shivani S.; Pasquale, Louis R.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol, Boston, MA USA. [Gregory, Meredith S.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Schepens Eye Res Inst,Dept Ophthalmol, Boston, MA USA. [Pasquale, Louis R.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Channing Div Network Med, Boston, MA 02115 USA. RP Pasquale, LR (reprint author), Massachusetts Eye & Ear Infirm, Glaucoma Serv, 243 Charles St, Boston, MA 02114 USA. EM Louis_pasquale@meei.harvard.edu NR 33 TC 0 Z9 0 U1 2 U2 9 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 0882-0538 EI 1744-5205 J9 SEMIN OPHTHALMOL JI Semin. Ophthalmol. PD MAR 3 PY 2016 VL 31 IS 1-2 SI SI BP 147 EP 154 DI 10.3109/08820538.2015.1114858 PG 8 WC Ophthalmology SC Ophthalmology GA DG5NZ UT WOS:000372126400018 PM 26959140 ER PT J AU Mishra, A Jackson, ML AF Mishra, Anuradha Jackson, Mary Lou TI Translational Vision Rehabilitation: From Eccentric Fixation to Reading Rehabilitation SO SEMINARS IN OPHTHALMOLOGY LA English DT Review DE microperimetry; Biofeed; oculomotor control ID PREFERRED RETINAL LOCUS; ABSOLUTE CENTRAL SCOTOMA; MACULAR DEGENERATION; STARGARDT-DISEASE; BIOFEEDBACK; STABILITY; MP-1; REORGANIZATION; AMD; MICROPERIMETRY AB Eccentric fixation is a commonly used adaptive strategy in patients with central vision loss. A common complaint in patients with central vision loss is reading difficulty. The mechanisms as to how and why eccentric fixation develops comprise an exciting area of research. As we better understand this phenomenon, we may apply these findings to the clinical setting and in particular to reading rehabilitation. Biofeedback is a new technique that can be applied to eccentric fixation and may have a role in reading rehabilitation. C1 [Mishra, Anuradha] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol, Boston, MA USA. [Jackson, Mary Lou] Univ British Columbia, Ophthalmol & Vis Sci, Vancouver, BC V5Z 1M9, Canada. RP Mishra, A (reprint author), Massachusetts Eye & Ear Infirm, Vis Rehabil Ctr, 243 Charles St,8th Floor, Boston, MA 02114 USA. EM amishra83@gmail.com NR 53 TC 1 Z9 1 U1 1 U2 2 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 0882-0538 EI 1744-5205 J9 SEMIN OPHTHALMOL JI Semin. Ophthalmol. PD MAR 3 PY 2016 VL 31 IS 1-2 SI SI BP 169 EP 177 DI 10.3109/08820538.2015.1114867 PG 9 WC Ophthalmology SC Ophthalmology GA DG5NZ UT WOS:000372126400022 PM 26959144 ER PT J AU Chang, VS Chodosh, J Papaliodis, GN AF Chang, Victoria S. Chodosh, James Papaliodis, George N. TI Chronic Ocular Complications of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis: The Role of Systemic Immunomodulatory Therapy SO SEMINARS IN OPHTHALMOLOGY LA English DT Review DE chronic disease; autoimmune bullous diseases; drug therapy; eye diseases; Anti-inflammatory agents ID INTRAVENOUS IMMUNOGLOBULIN THERAPY; CUTANEOUS LUPUS-ERYTHEMATOSUS; NECROSIS-FACTOR-ALPHA; DRY EYE SYNDROME; TNF-ALPHA; MYCOPHENOLATE-MOFETIL; CONJUNCTIVAL INFLAMMATION; IMMUNOSUPPRESSIVE THERAPY; CYCLOSPORINE TREATMENT; ADVERSE-REACTIONS AB Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare, but potentially blinding diseases that affect the skin and mucous membranes. Although the cutaneous manifestations tend to be self-limited and resolve without sequelae, the chronic ocular complications associated with SJS/TEN can persist despite local therapy. Poor understanding of the underlying pathophysiology and lack of a standardized clinical approach have resulted in a paucity of data in regards to suitable treatment options. Inflammatory cellular infiltration and elevated levels of ocular surface cytokines in the conjunctival specimens of affected patients give credence to an underlying immunogenic etiology. Furthermore, the presence of ongoing ocular surface inflammation and progressive conjunctival fibrosis in the absence of exogenous aggravating factors suggest a possible role for systemic immunomodulatory therapy (IMT). We review in detail the proposed immunogenesis underlying chronic ocular SJS/TEN and the possible utility of systemic IMT. C1 [Chang, Victoria S.; Chodosh, James; Papaliodis, George N.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol, Boston, MA USA. RP Chang, VS (reprint author), Massachusetts Eye & Ear Infirm, 243 Charles St, Boston, MA 02114 USA. EM victoriaschang@gmail.com NR 109 TC 2 Z9 2 U1 1 U2 1 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 0882-0538 EI 1744-5205 J9 SEMIN OPHTHALMOL JI Semin. Ophthalmol. PD MAR 3 PY 2016 VL 31 IS 1-2 SI SI BP 178 EP 187 DI 10.3109/08820538.2015.1114841 PG 10 WC Ophthalmology SC Ophthalmology GA DG5NZ UT WOS:000372126400023 PM 26959145 ER PT J AU Stagner, AM Jakobiec, FA AF Stagner, Anna M. Jakobiec, Frederick A. TI Updates on the Molecular Pathology of Selected Ocular and Ocular Adnexal Tumors: Potential Targets for Future Therapy SO SEMINARS IN OPHTHALMOLOGY LA English DT Review DE MYCN; retinoblastoma; molecular genetics; LIN28A; HER2; Eye; sebaceous carcinoma; microRNA; medulloepithelioma ID MUIR-TORRE-SYNDROME; DNA MISMATCH REPAIR; CILIARY BODY MEDULLOEPITHELIOMA; EYELID SEBACEOUS CARCINOMAS; INTRAOCULAR MEDULLOEPITHELIOMA; GENE-EXPRESSION; CELL-CARCINOMA; N-MYC; RETINOBLASTOMA; CANCER AB Ophthalmic pathologic studies of retinoblastoma first definitively elucidated a genetic etiology for cancer three decades ago. Advances in DNA sequencing, protein expression profiling, and the exploration of epigenetics have since led to categorization of tumors and clinical prognostication based on genetic aberrancy. There are now many neoplasms that are defined by a characteristic genetic signature. In the past several years alone, much has been discovered in regard to the original tumor-suppressor gene initially defined in retinoblastoma as well as in other intraocular tumors such as medulloepithelioma. Our further understanding of ocular adnexal tumors that result in substantial morbidity and mortality, such as sebaceous carcinoma, has also benefited from a genetic approach. In this article, we review the clinicopathologic features of the foregoing three entities-retinoblastoma, medulloepithelioma, and sebaceous carcinoma-in order to highlight discoveries in their underlying abnormal molecular genetic functioning. C1 Massachusetts Eye & Ear Infirm, David G Cogan Ophthalm Pathol Lab, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Ophthalmol, Boston, MA USA. RP Jakobiec, FA (reprint author), Massachusetts Eye & Ear Infirm, David G Cogan Lab Ophthalm Pathol, 243 Charles St,Suite 328, Boston, MA 02114 USA. EM Fred_Jakobiec@meei.harvard.edu NR 62 TC 0 Z9 0 U1 0 U2 1 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 0882-0538 EI 1744-5205 J9 SEMIN OPHTHALMOL JI Semin. Ophthalmol. PD MAR 3 PY 2016 VL 31 IS 1-2 SI SI BP 188 EP 196 DI 10.3109/08820538.2015.1115257 PG 9 WC Ophthalmology SC Ophthalmology GA DG5NZ UT WOS:000372126400024 PM 26959146 ER PT J AU Pearlman, RA Foglia, MB Fox, E Cohen, JH Chanko, BL Berkowitz, KA AF Pearlman, Robert A. Foglia, Mary Beth Fox, Ellen Cohen, Jennifer H. Chanko, Barbara L. Berkowitz, Kenneth A. TI Ethics Consultation Quality Assessment Tool: A Novel Method for Assessing the Quality of Ethics Case Consultations Based on Written Records SO AMERICAN JOURNAL OF BIOETHICS LA English DT Article DE professional ethics; organizational ethics; clinical ethics; ethics consultation ID CLINICAL-ETHICS; SERVICE AB Although ethics consultation is offered as a clinical service in most hospitals in the United States, few valid and practical tools are available to evaluate, ensure, and improve ethics consultation quality. The quality of ethics consultation is important because poor quality ethics consultation can result in ethically inappropriate outcomes for patients, other stakeholders, or the health care system. To promote accountability for the quality of ethics consultation, we developed the Ethics Consultation Quality Assessment Tool (ECQAT). ECQAT enables raters to assess the quality of ethics consultations based on the written record. Through rigorous development and preliminary testing, we identified key elements of a quality ethics consultation (ethics question, consultation-specific information, ethical analysis, and conclusions and/or recommendations), established scoring criteria, developed training guidelines, and designed a holistic assessment process. This article describes the development of the ECQAT, the resulting product, and recommended future testing and potential uses for the tool. C1 [Pearlman, Robert A.; Foglia, Mary Beth; Cohen, Jennifer H.; Chanko, Barbara L.; Berkowitz, Kenneth A.] Natl Ctr Eth Hlth Care, Dept Vet Affairs, Zurich, Switzerland. [Fox, Ellen] Fox Eth Consulting, Zurich, Switzerland. RP Pearlman, RA (reprint author), VA Puget Sound Hlth Care Syst, Natl Ctr Eth Hlth Care, S-182 GEC,1660 South Columbian Way, Seattle, WA 98108 USA. EM Robert.Pearlman@va.gov NR 34 TC 12 Z9 12 U1 6 U2 6 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 1526-5161 EI 1536-0075 J9 AM J BIOETHICS JI Am. J. Bioeth. PD MAR 3 PY 2016 VL 16 IS 3 BP 3 EP 14 DI 10.1080/15265161.2015.1134704 PG 12 WC Ethics; Medical Ethics; Social Issues; Social Sciences, Biomedical SC Social Sciences - Other Topics; Medical Ethics; Social Issues; Biomedical Social Sciences GA DF7NJ UT WOS:000371544100002 PM 26913651 ER PT J AU Pearlman, RA Foglia, MB Cohen, JH Chanko, BL Berkowitz, KA AF Pearlman, Robert A. Foglia, Mary Beth Cohen, Jennifer H. Chanko, Barbara L. Berkowitz, Kenneth A. TI Response to Open Peer Commentaries on "Ethics Consultation Quality Assessment Tool: A Novel Method for Assessing the Quality of Ethics Case Consultations Based on Written Records" SO AMERICAN JOURNAL OF BIOETHICS LA English DT Letter C1 [Pearlman, Robert A.; Foglia, Mary Beth; Cohen, Jennifer H.; Chanko, Barbara L.; Berkowitz, Kenneth A.] Natl Ctr Eth Hlth Care, Dept Vet Affairs, Seattle, WA 98108 USA. RP Pearlman, RA (reprint author), Natl Ctr Eth Hlth Care, VA Puget Sound Hlth Care Syst, S 182-GEC,1660 South Columbian Way, Seattle, WA 98108 USA. EM Robert.Pearlman@va.gov NR 2 TC 0 Z9 0 U1 0 U2 0 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 1526-5161 EI 1536-0075 J9 AM J BIOETHICS JI Am. J. Bioeth. PD MAR 3 PY 2016 VL 16 IS 3 BP W1 EP W2 DI 10.1080/15265161.2016.1150532 PG 2 WC Ethics; Medical Ethics; Social Issues; Social Sciences, Biomedical SC Social Sciences - Other Topics; Medical Ethics; Social Issues; Biomedical Social Sciences GA DF7NO UT WOS:000371544600001 PM 26913669 ER PT J AU Davis, RW Brannen, AD Hossain, MJ Monsma, S Bock, PE Nahrendorf, M Mead, D Lodes, M Liles, MR Panizzi, P AF Davis, Richard W. Brannen, Andrew D. Hossain, Mohammad J. Monsma, Scott Bock, Paul E. Nahrendorf, Matthias Mead, David Lodes, Michael Liles, Mark R. Panizzi, Peter TI Complete genome of Staphylococcus aureus Tager 104 provides evidence of its relation to modern systemic hospital-acquired strains SO BMC GENOMICS LA English DT Article ID SUBSYSTEMS TECHNOLOGY; BACTERIAL PATHOGENS; ENDOCARDITIS; SEQUENCE; STAPHYLOCOAGULASE; PROTHROMBIN; EVOLUTION; RAST; MRSA; SUSCEPTIBILITY AB Background: Staphylococcus aureus (S. aureus) infections range in severity due to expression of certain virulence factors encoded on mobile genetic elements (MGE). As such, characterization of these MGE, as well as single nucleotide polymorphisms, is of high clinical and microbiological importance. To understand the evolution of these dangerous pathogens, it is paramount to define reference strains that may predate MGE acquisition. One such candidate is S. aureus Tager 104, a previously uncharacterized strain isolated from a patient with impetigo in 1947. Results: We show here that S. aureus Tager 104 can survive in the bloodstream and infect naive organs. We also demonstrate a procedure to construct and validate the assembly of S. aureus genomes, using Tager 104 as a proof-of-concept. In so doing, we bridged confounding gap regions that limited our initial attempts to close this 2.82 Mb genome, through integration of data from Illumina Nextera paired-end, PacBio RS, and Lucigen NxSeq mate-pair libraries. Furthermore, we provide independent confirmation of our segmental arrangement of the Tager 104 genome by the sole use of Lucigen NxSeq libraries filled by paired-end MiSeq reads and alignment with SPAdes software. Genomic analysis of Tager 104 revealed limited MGE, and vSa beta island configuration that is reminiscent of other hospital acquired S. aureus genomes. Conclusions: Tager 104 represents an early-branching ancestor of certain hospital-acquired strains. Combined with its earlier isolation date and limited content of MGE, Tager 104 can serve as a viable reference for future comparative genome studies. C1 [Davis, Richard W.; Brannen, Andrew D.; Panizzi, Peter] Auburn Univ, Harrison Sch Pharm, Dept Drug Discovery & Dev, 4306 Walker Bldg, Auburn, AL 36849 USA. [Hossain, Mohammad J.; Liles, Mark R.] Auburn Univ, Dept Biol Sci, 101 Rouse Life Sci Bldg, Auburn, AL 36849 USA. [Monsma, Scott; Mead, David; Lodes, Michael] Lucigen Corp, 2905 Parmenter St, Middleton, WI 53562 USA. [Bock, Paul E.] Vanderbilt Univ, Med Ctr, Dept Pathol Microbiol & Immunol, Nashville, TN 37232 USA. [Nahrendorf, Matthias] Massachusetts Gen Hosp, Ctr Syst Biol, Simches Res Bldg,185 Cambridge St, Boston, MA 02114 USA. [Nahrendorf, Matthias] Harvard Univ, Sch Med, Simches Res Bldg,185 Cambridge St, Boston, MA 02114 USA. RP Panizzi, P (reprint author), Auburn Univ, Harrison Sch Pharm, Dept Drug Discovery & Dev, 4306 Walker Bldg, Auburn, AL 36849 USA. EM panizzi@auburn.edu OI Panizzi, Peter/0000-0003-0141-8807 FU National Institutes of Health through National Heart, Lung, and Blood Institute [R00HL094533, R01HL114477, R01 HL071544]; National Institute of Allergy and Infectious Diseases grant [2R44AI085840 02] FX Supported by the National Institutes of Health through grants provided by the National Heart, Lung, and Blood Institute, R00HL094533 (to P.P.), R01HL114477 (to P.P. and M.N.), R01 HL071544 (to P.E.B). Support also provided by the National Institute of Allergy and Infectious Diseases grant 2R44AI085840 02 (to D.M., P.P. and M.R.L.). The authors also wish to thank the Alabama Supercomputer Authority for access to the Alabama Supercomputer. NR 49 TC 1 Z9 1 U1 2 U2 8 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2164 J9 BMC GENOMICS JI BMC Genomics PD MAR 3 PY 2016 VL 17 AR 179 DI 10.1186/s12864-016-2433-8 PG 15 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA DF8GI UT WOS:000371595000005 PM 26940863 ER PT J AU Arokiaraj, MC De Santis, G De Beule, M Palacios, IF AF Arokiaraj, Mark C. De Santis, Gianluca De Beule, Matthieu Palacios, Igor F. TI A Novel Tram Stent Method in the Treatment of Coronary Bifurcation Lesions - Finite Element Study SO PLOS ONE LA English DT Article ID SIDE-BRANCH; KISSING BALLOON; NUMERICAL SIMULATIONS; SHEAR-STRESS; MAIN VESSEL; INTERVENTION; INSIGHTS; DISEASE; ATHEROSCLEROSIS; CLASSIFICATION AB A novel stent was designed for the treatment of coronary bifurcation lesion, and it was investigated for its performance by finite element analysis. This study was performed in search of a novel method of treatment of bifurcation lesion with provisional stenting. A bifurcation model was created with the proximal vessel of 3.2 mm diameter, and the distal vessel after the side branch (2.3 mm) was 2.7 mm. A novel stent was designed with connection links that had a profile of a tram. Laser cutting and shape setting of the stent was performed, and thereafter it was crimped and deployed over a balloon. The contact pressure, stresses on the arterial wall, stresses on the stent, the maximal principal log strain of the main artery and the side-branch were studied. The study was performed in Abaqus, Simulia. The stresses on the main branch and the distal branch were minimally increased after deployment of this novel stent. The side branch was preserved, and the stresses on the side branch were lesser; and at the confluence of bifurcation on either side of the side branch origin the von-Mises stress was marginally increased. The stresses and strain at the bifurcation were significantly lesser than the stresses and strain of the currently existing techniques used in the treatment of bifurcation lesions though the study was primarily focused only on the utility of the new technology. There is a potential for a novel Tram-stent method in the treatment of coronary bifurcation lesions. C1 [Arokiaraj, Mark C.] Pondicherry Inst Med Sci, Cardiol, Pondicherry, India. [De Santis, Gianluca; De Beule, Matthieu] FEops Nv, Technol Pk 3, Ghent, Belgium. [Palacios, Igor F.] Massachusetts Gen Hosp, Cardiol, Boston, MA 02114 USA. [Arokiaraj, Mark C.] 36 Montorsier St, Pondicherry, India. RP Arokiaraj, MC (reprint author), Pondicherry Inst Med Sci, Cardiol, Pondicherry, India.; Arokiaraj, MC (reprint author), 36 Montorsier St, Pondicherry, India. EM christomark@gmail.com FU FEops bvba FX The authors received no specific funding for this work. Authors Gianluca De Santis and Mathieu De Beule are employed by FEops bvba. FEops bvba provided support in the form of salaries for authors Gianluca De Santis and Mathieu De Beule, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the 'author contributions' section. NR 53 TC 0 Z9 0 U1 4 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 MAR 3 PY 2016 VL 11 IS 3 AR e0149838 DI 10.1371/journal.pone.0149838 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DG0EB UT WOS:000371735200037 PM 26937643 ER PT J AU Tanuma, J Lee, KH Haneuse, S Matsumoto, S Nguyen, DT Nguyen, DTH Do, CD Pham, TT Nguyen, KV Oka, S AF Tanuma, Junko Lee, Kyu Ha Haneuse, Sebastien Matsumoto, Shoko Dung Thi Nguyen Dung Thi Hoai Nguyen Cuong Duy Do Thuy Thanh Pham Kinh Van Nguyen Oka, Shinichi TI Incidence of AIDS-Defining Opportunistic Infections and Mortality during Antiretroviral Therapy in a Cohort of Adult HIV-Infected Individuals in Hanoi, 2007-2014 SO PLOS ONE LA English DT Article ID HIV-1-INFECTED PATIENTS; COLLABORATIVE ANALYSIS; RISKS DATA; 1ST YEAR; DEATH; INITIATION; AGE AB Background Although the prognosis for HIV-infected individuals has improved after antiretroviral therapy (ART) scale-up, limited data exist on the incidence of AIDS-defining opportunistic infections (ADIs) and mortality during ART in resource-limited settings. Methods HIV-infected adults in two large hospitals in urban Hanoi were enrolled to the prospective cohort, from October 2007 through December 2013. Those who started ART less than one year before enrollment were assigned to the survival analysis. Data on ART history and ADIs were collected retrospectively at enrollment and followed-up prospectively until April 2014. Results Of 2,070 cohort participants, 1,197 were eligible for analysis and provided 3,446 person-years (PYs) of being on ART. Overall, 161 ADIs episodes were noted at a median of 3.20 months after ART initiation (range 0.03-75.8) with an incidence 46.7/1,000 PYs (95% confidence interval [CI] 39.8-54.5). The most common ADI was tuberculosis with an incidence of 29.9/1,000 PYs. Mortality after ART initiation was 8.68/1,000 PYs and 45% (19/45) died of AIDS-related illnesses. Age over 50 years at ART initiation was significantly associated with shorter survival after controlling for baseline CD4 count, but neither having injection drug use (IDU) history nor previous ADIs were associated with poor survival. Semi-competing risks analysis in 951 patients without ADIs history prior to ART showed those who developed ADIs after starting ART were at higher risk of death in the first six months than after six months. Conclusion ADIs were not rare in spite of being on effective ART. Age over 50 years, but not IDU history, was associated with shorter survival in the cohort. This study provides in-depth data on the prognosis of patients on ART in Vietnam during the first decade of ART scale-up. C1 [Tanuma, Junko; Matsumoto, Shoko; Oka, Shinichi] Natl Ctr Global Hlth & Med, AIDS Clin Ctr, Tokyo, Japan. [Tanuma, Junko] Harvard Univ, TH Chan Sch Publ Hlth, Takemi Program Int Hlth, Boston, MA USA. [Lee, Kyu Ha] Forsyth Inst, Epidemiol & Biostat Core, Cambridge, MA USA. [Haneuse, Sebastien] Harvard Univ, TH Chan Sch Publ Hlth, Biostat, Boston, MA USA. [Dung Thi Nguyen; Dung Thi Hoai Nguyen; Kinh Van Nguyen] Natl Hosp Trop Dis, HIV Dept, Hanoi, Vietnam. [Cuong Duy Do; Thuy Thanh Pham] Bach Mai Hosp, Dept Infect Dis, Hanoi, Vietnam. RP Tanuma, J (reprint author), Natl Ctr Global Hlth & Med, AIDS Clin Ctr, Tokyo, Japan.; Tanuma, J (reprint author), Harvard Univ, TH Chan Sch Publ Hlth, Takemi Program Int Hlth, Boston, MA USA. EM junkotanuma2014@gmail.com FU Japan Initiative for Global Research Network on Infectious Diseases from Japan Agency for Medical Research and development [15fm0108001h0001]; Takemi Program in International Health FX This research was funded by the Japan Initiative for Global Research Network on Infectious Diseases from Japan Agency for Medical Research and development [15fm0108001h0001] (http://www.amed.go.jp/en/). SO was the receiver as the primary investigator. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.; The authors greatly thank Ms. Nguyen Thi Yen, Ms. Nguyen Thi Tien, Ms. Nguyen Lan Phuong, Ms. Ms. Le Thi Hoa, Mr. Pham Hong Hai, Dr. Nguyen Thi Ngoc Chi and Dr. Dang Thi Bich for collecting data, Ms. Keiko Saito and Ms. Nguyen Thi Huyen for their assistance in study operation. Junko Tanuma gratefully acknowledges the support of the Takemi Program in International Health and thanks participants in the Takemi Seminar for their valuable comments. NR 40 TC 0 Z9 0 U1 1 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 MAR 3 PY 2016 VL 11 IS 3 AR e0150781 DI 10.1371/journal.pone.0150781 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DG0EB UT WOS:000371735200144 PM 26939050 ER PT J AU Willenbacher, E Weger, R Rochau, U Siebert, U Willenbacher, W AF Willenbacher, Ella Weger, Roman Rochau, Ursula Siebert, Uwe Willenbacher, Wolfgang CA Austrian Myeloma Registry TI Real-World Use of 3rd Line Therapy for Multiple Myeloma in Austria: An Austrian Myeloma Registry (AMR) Analysis of the Therapeutic Landscape and Clinical Outcomes prior to the Use of Next Generation Myeloma Therapeutics SO PLOS ONE LA English DT Article ID RISK AB Objective Clinical trials demonstrate improving survival in patients with multiple myeloma (MM) after treatment. However, it is unclear whether increased survival translates to a similar benefit in a real world setting. Methods We analyzed the overall survival of 347 multiple myeloma patients in Austria by means of a national registry (AMR), focused on results from 3rd and later lines of therapy. This benchmark was chosen to define a baseline prior to the broad application of upcoming 2nd generation drugs (carfilzomib, pomalidomide). Results Projected 10 years survival for patients with MM in Austria is estimated to be 56% in patients diagnosed in between the years 2011-2014, 21% in patients with a diagnosis made between 2000-2005, and 39% in those with a diagnosis made between 2006-2010). For the same intervals a significant increase in the use of both bortezomib, lenalidomide and thalidomide-so called IMiDs (from 2005 onwards) and their simultaneous use in combination therapies (from 2010 onwards) could be shown. The use of autologous transplantation (ASCT) remained more or less constant at similar to 35% of patients in the 1st line setting over the whole period, comparing well to international practice patterns, while the use of 2nd line ASCT increased from 5.5% to 18.7% of patients. Patients in 3rd or later line treatment (n = 105), showed that even in relapsed and refractory disease median survival was 27 months with a considerable proportion of long-term survivors (similar to 20%). Conclusion & Perspective With the expected emergence of additional active anti-myeloma compounds, we aim to assess survival in patients with relapsed and refractory MM. C1 [Willenbacher, Ella; Willenbacher, Wolfgang] Med Univ Innsbruck, Internal Med Hematol & Oncol 5, A-6020 Innsbruck, Austria. [Willenbacher, Ella; Weger, Roman; Rochau, Ursula; Siebert, Uwe; Willenbacher, Wolfgang] ONCOTYROL Ctr Personalized Canc Med, Area Hlth Technol Assessment & Bioinformat 4, Innsbruck, Austria. [Rochau, Ursula; Siebert, Uwe] UMIT Univ Hlth Sci Med Informat & Technol, Dept Publ Hlth Hlth Serv Res & Hlth Technol Asses, Inst Publ Hlth Med Decis Making & Hlth Technol As, Hall In Tirol, Austria. [Siebert, Uwe] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Inst Technol Assessment, Boston, MA USA. [Siebert, Uwe] Harvard Univ, Sch Med, Dept Radiol, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Siebert, Uwe] Harvard Univ, Ctr Hlth Decis Sci, Dept Hlth Policy & Management, TH Chan Sch Publ Hlth, Boston, MA 02115 USA. RP Willenbacher, W (reprint author), Med Univ Innsbruck, Internal Med Hematol & Oncol 5, A-6020 Innsbruck, Austria.; Willenbacher, W (reprint author), ONCOTYROL Ctr Personalized Canc Med, Area Hlth Technol Assessment & Bioinformat 4, Innsbruck, Austria. EM Wolfgang.Willenbacher@tirol-kliniken.at FU European Union [278570]; COMET Center ONCOTYROL FX The research leading to these results has received funding from the European Union Seventh Framework Program (FP7/2007-2013) OPTATIO (WW, RW) under grant agreement no278570" [http://ec.europa.eu/research/fp7/], as well as by the COMET Center ONCOTYROL (EW, RW, UR)-[http://www.oncotyrol.at/]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 17 TC 1 Z9 1 U1 2 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 MAR 3 PY 2016 VL 11 IS 3 AR e0147381 DI 10.1371/journal.pone.0147381 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DG0EB UT WOS:000371735200005 PM 26937956 ER PT J AU Zhang, C Ding, H He, M Liu, LN Liu, LP Li, G Niu, B Zhong, XW AF Zhang, Chi Ding, Hui He, Miao Liu, Lina Liu, Liangping Li, Gang Niu, Bing Zhong, Xingwu TI Comparison of Early Changes in Ocular Surface and Inflammatory Mediators between Femtosecond Lenticule Extraction and Small-Incision Lenticule Extraction SO PLOS ONE LA English DT Article ID IN-SITU KERATOMILEUSIS; NERVE GROWTH-FACTOR; DRY-EYE DISEASE; TEAR FILM STABILITY; CORNEAL SENSATION; FACTOR-BETA; PHOTOREFRACTIVE KERATECTOMY; TGF-BETA; FACTOR-ALPHA; EPI-LASIK AB Purpose To evaluate the short-term changes in ocular surface measures and tear inflammatory mediators after femtosecond lenticule extraction (FLEx) and small-incision lenticule extraction (SMILE) procedures. Methods Eighteen subjects (18 eyes) underwent FLEx and 23 subjects (23 eyes) underwent SMILE in this single-center and prospective study. Central corneal sensitivity, Schirmer I test (SIT), noninvasive tear breakup time (NI-TBUT), tear meniscus height, corneal fluorescein (FL) staining, and ocular surface disease index (OSDI) were assessed in all patients. Concentrations of interleukin-1 alpha (IL-1 alpha), tumor necrosis factor-alpha (TNF-alpha), nerve growth factor (NGF), interferon-gamma (IFN-gamma), transforming growth factor-beta 1 (TGF-beta 1) and matrix metalloproteinase-9 (MMP-9) in collected tears were measured by multiplex antibody microarray. Results Central corneal sensitivity was reduced in both groups, but the scores in the SMILE group were higher than those in the FLEx group at all time points postoperatively (P<0.01). Lower FL scores and longer NI-BUT were observed in the SMILE group 1 week after surgery (P<0.05). OSDI scores in both groups increased rapidly at 1 day and 1 week postoperatively, then returned to their preoperative levels within 1 month (P<0.05). There were no significant differences in SIT or tear meniscus height between the two groups. Lower and faster recovery of tear NGF, TGF-beta 1 and IL-1 alpha concentration were found in the SMILE group compared to the FLEx group postoperatively. No significant difference was found in tear TNF-alpha, IFN-gamma and MMP-9 for either group before or after surgery. Tear NGF, TGF-beta 1 and IL-1 alpha show a correlation with ocular surface changes after FLEx or SMILE surgery. Conclusion SMILE has superiority over FLEx in early ocular surface changes and NGF, TGF-beta 1 and IL-1 alpha may contribute to the process of ocular surface recovery. C1 [Zhang, Chi; He, Miao; Liu, Liangping; Zhong, Xingwu] Sun Yat Sen Univ, Zhongshan Ophthalm Ctr, Guangzhou 510060, Guangdong, Peoples R China. [Zhang, Chi; He, Miao; Liu, Liangping; Zhong, Xingwu] Sun Yat Sen Univ, State Key Lab Ophthalmol, Guangzhou 510060, Guangdong, Peoples R China. [Zhang, Chi] First Peoples Hosp Foshan, Dept Ophthalmol, Foshan 528000, Peoples R China. [Ding, Hui; Liu, Lina; Li, Gang; Zhong, Xingwu] Sun Yat Sen Univ, Hainan Eye Hosp, Zhongshan Ophthalm Ctr, Haikou 570311, Peoples R China. [Niu, Bing] Shanghai Univ, Sch Life Sci, Shanghai Key Lab Bioenergy Crops, Shanghai 200444, Peoples R China. [Niu, Bing] Harvard Univ, Sch Med, Schepens Eye Res Inst, Massachusetts Eye & Ear Infirm,Dept Ophthalmol, Boston, MA 02114 USA. RP Zhong, XW (reprint author), Sun Yat Sen Univ, Zhongshan Ophthalm Ctr, Guangzhou 510060, Guangdong, Peoples R China.; Zhong, XW (reprint author), Sun Yat Sen Univ, State Key Lab Ophthalmol, Guangzhou 510060, Guangdong, Peoples R China.; Zhong, XW (reprint author), Sun Yat Sen Univ, Hainan Eye Hosp, Zhongshan Ophthalm Ctr, Haikou 570311, Peoples R China. EM zhongxwu@mail.sysu.edu.cn FU National Natural Science Foundation of China [81371046]; Science and Technology Planning Project of Guangdong Province [2013B090200057] FX This work was supported by grants from the National Natural Science Foundation of China (81371046) and Science and Technology Planning Project of Guangdong Province (2013B090200057). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 67 TC 1 Z9 1 U1 4 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 MAR 3 PY 2016 VL 11 IS 3 AR e0149503 DI 10.1371/journal.pone.0149503 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DG0EB UT WOS:000371735200026 PM 26937680 ER PT J AU Ramsey, JL Neupert, SD Mroczek, DK Spiro, A AF Ramsey, Jennifer L. Neupert, Shevaun D. Mroczek, Daniel K. Spiro, Avron, III TI The effects of daily co-occurrence of affect on older adults' reactivity to health stressors SO PSYCHOLOGY & HEALTH LA English DT Article DE daily co-occurrence of affect; health stress; negative affect; aging ID EMOTIONAL EXPERIENCE; AFFECT OPTIMIZATION; AFFECT COMPLEXITY; NEGATIVE AFFECT; LIFE-SPAN; AGE; RESILIENCE AB Objectives: The present study examined age differences among older adults in the daily co-occurrence of affect and its potential role in buffering the negative effects of health stressors.Design: Participants were from the Veterans Affairs Normative Aging Study and included 249 young-old adults (age=60-79years, M=71.6) and 64 old-old adults (age=80-89, M=82.9) who completed questionnaires assessing stressors, physical health symptoms, and positive and negative affect for eight consecutive days.Results: An independent samples t-test showed young-old and old-old adults did not significantly differ in their mean levels of daily co-occurrence of affect. The between-person relationships among stressors, health and daily co-occurrence of affect revealed that neither stressors nor health were significantly related to daily co-occurrence of affect. However, results from a multilevel model revealed a three-way cross-level interaction (health stressor x age group x co-occurrence of affect) where old-old adults with higher levels of co-occurrence of affect were less emotionally reactive to health stressors than young-old adults.Conclusion: These findings provide support for the assertion that co-occurrence of affect functions in an adaptive capacity and highlight the importance of examining domain-specific stressors. C1 [Ramsey, Jennifer L.; Neupert, Shevaun D.] N Carolina State Univ, Dept Psychol, Raleigh, NC 27695 USA. [Mroczek, Daniel K.] Nortwestern Univ, Dept Psychol, Evanston, IL USA. [Spiro, Avron, III] VA Boston Healthcare Syst, Massachusetts Vet Epidemiol Res & Informat Ctr MA, Boston, MA USA. [Spiro, Avron, III] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Spiro, Avron, III] Boston Univ, Sch Med, Dept Psychiat, Boston, MA 02118 USA. RP Ramsey, JL (reprint author), N Carolina State Univ, Dept Psychol, Raleigh, NC 27695 USA. EM Jlramsey@ncsu.edu FU National Institute of Aging [R01-AG18436]; Research Service of the Department of Veterans Affairs; Cooperative Studies Program/ERIC, US Department of Veterans Affairs FX The current study was supported by a grant from the National Institute of Aging (R01-AG18436) to Dan Mroczek, and by the Research Service of the Department of Veterans Affairs. The VA Normative Aging Study (NAS) is supported by the Cooperative Studies Program/ERIC, US Department of Veterans Affairs, and is a research component of the Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC). NR 40 TC 1 Z9 1 U1 0 U2 1 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 0887-0446 EI 1476-8321 J9 PSYCHOL HEALTH JI Psychol. Health PD MAR 3 PY 2016 VL 31 IS 3 BP 364 EP 378 DI 10.1080/08870446.2015.1111368 PG 15 WC Public, Environmental & Occupational Health; Psychology, Multidisciplinary SC Public, Environmental & Occupational Health; Psychology GA DG1EM UT WOS:000371808400009 PM 26518259 ER PT J AU Shura, RD Miskey, HM Rowland, JA Yoash-Gantz, RE Denning, JH AF Shura, Robert D. Miskey, Holly M. Rowland, Jared A. Yoash-Gantz, Ruth E. Denning, John H. TI Embedded Performance Validity Measures with Postdeployment Veterans: Cross-Validation and Efficiency with Multiple Measures SO APPLIED NEUROPSYCHOLOGY-ADULT LA English DT Article DE multiple measures; veteran; neuropsychological assessment; Word Memory Test; performance validity ID TRAUMATIC BRAIN-INJURY; WORD MEMORY TEST; COMPLEX FIGURE TEST; TEST FAILURE; MALINGERING DETECTION; EVALUATION CONTEXT; LIKELIHOOD RATIOS; INADEQUATE EFFORT; SUSPECT EFFORT; RESPONSE BIAS AB Embedded validity measures support comprehensive assessment of performance validity. The purpose of this study was to evaluate the accuracy of individual embedded measures and to reduce them to the most efficient combination. The sample included 212 postdeployment veterans (average age=35 years, average education=14 years). Thirty embedded measures were initially identified as predictors of Green's Word Memory Test (WMT) and were derived from the California Verbal Learning Test-Second Edition (CVLT-II), Conners' Continuous Performance Test-Second Edition (CPT-II), Trail Making Test, Stroop, Wisconsin Card Sorting Test-64, the Wechsler Adult Intelligence Scale-Third Edition Letter-Number Sequencing, Rey Complex Figure Test (RCFT), Brief Visuospatial Memory Test-Revised, and the Finger Tapping Test. Eight nonoverlapping measures with the highest area-under-the-curve (AUC) values were retained for entry into a logistic regression analysis. Embedded measure accuracy was also compared to cutoffs found in the existing literature. Twenty-one percent of the sample failed the WMT. Previously developed cutoffs for individual measures showed poor sensitivity (SN) in the current sample except for the CPT-II (Total Errors, SN=.41). The CVLT-II (Trials 1-5 Total) showed the best overall accuracy (AUC=.80). After redundant measures were statistically eliminated, the model included the RCFT (Recognition True Positives), CPT-II (Total Errors), and CVLT-II (Trials 1-5 Total) and increased overall accuracy compared with the CVLT-II alone (AUC=.87). The combination of just 3 measures from the CPT-II, CVLT-II, and RCFT was the most accurate/efficient in predicting WMT performance. C1 [Shura, Robert D.; Miskey, Holly M.; Rowland, Jared A.; Yoash-Gantz, Ruth E.] WG Bill Hefner Vet Affairs Med Ctr, Mid Atlantic Mental Illness Res Educ & Clin Ctr, Salisbury, Wilts, England. [Shura, Robert D.; Miskey, Holly M.; Rowland, Jared A.; Yoash-Gantz, Ruth E.] WG Bill Hefner Vet Affairs Med Ctr, Mental Hlth & Behav Sci Serv Line, Salisbury, Wilts, England. [Shura, Robert D.; Miskey, Holly M.; Yoash-Gantz, Ruth E.] Wake Forest Sch Med, Dept Psychiat & Behav Sci, Winston Salem, NC USA. [Rowland, Jared A.] Wake Forest Sch Med, Dept Psychiat & Behav Sci, Dept Anat & Neurobiol, Winston Salem, NC USA. [Denning, John H.] Alvin C York Vet Affairs Med Ctr, Tennessee Valley Healthcare Syst, Murfreesboro, TN USA. [Denning, John H.] Ralph H Johnson VA Med Ctr, Charleston, SC USA. RP Shura, RD (reprint author), Hefner VAMC, 11M-2 MH BS,1601 Brenner Ave, Salisbury, NC 28144 USA. EM robert.shura2@va.gov OI Miskey, Holly/0000-0002-5139-4586 FU W. G. "Bill" Hefner Veterans Affairs Medical Center; Mid-Atlantic Mental Illness Research Education and Clinical Center; Department of Veterans Affairs Office of Academic Affiliations Advanced Fellowship Program in Mental Illness Research and Treatment FX This work was supported by the This research was supported by resources of the W. G. "Bill" Hefner Veterans Affairs Medical Center, the Mid-Atlantic Mental Illness Research Education and Clinical Center, and the Department of Veterans Affairs Office of Academic Affiliations Advanced Fellowship Program in Mental Illness Research and Treatment.. NR 57 TC 1 Z9 1 U1 2 U2 3 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 2327-9095 EI 2327-9109 J9 APPL NEUROPSYCH-ADUL JI Appl. Neuropsychol.-Adult PD MAR 3 PY 2016 VL 23 IS 2 BP 94 EP 104 DI 10.1080/23279095.2015.1014556 PG 11 WC Clinical Neurology; Psychology SC Neurosciences & Neurology; Psychology GA DE4TK UT WOS:000370623000003 PM 26375185 ER PT J AU Gaines, KD Soper, HV Berenji, GR AF Gaines, Katy D. Soper, Henry V. Berenji, Gholam R. TI Executive Functioning of Combat Mild Traumatic Brain Injury SO APPLIED NEUROPSYCHOLOGY-ADULT LA English DT Article DE traumatic brain injury; mild TBI; military; psychology; neuropsychology; executive ID HEAD-INJURY; SELF-AWARENESS; DYSFUNCTION; METAANALYSIS; CONCUSSION; NEUROSCIENCE; COGNITION; SYMPTOMS; RECOVERY; SEQUELAE AB This study investigates neuropsychological deficits in recently deployed veterans with mild traumatic brain injury (mTBI). Veterans discharged from 2007 to 2012 were recruited from Veterans Affairs clinics. Independent groups of participants with mTBI (n=57) and those without TBI (n=57) were administered the Beck Depression Inventory-II, Combat Exposure Scale, Word Memory Test, and the Self-Awareness of Deficits Interview. Neuropsychological instruments included the Rey-Osterrieth Complex Figure Test, Letter and Category Fluency, Trail-Making Test-Parts A and B, Christiansen H-abbreviated, Soper Neuropsychology Screen, Wechsler Memory Scale subtests Logical Memory I and II, and the Street Completion Test. The mTBI group performed significantly worse on all of the executive and nonexecutive measurements with the exception of Category Fluency, after controlling for age, depression effort, and combat exposure. Depression and combat exposure were greater for the mTBI group. The mTBI group scored poorer on effort, but only the Multiple Choice subtest was significant. The mTBI group had good awareness of their deficits. C1 [Gaines, Katy D.; Berenji, Gholam R.] Vet Affairs Greater Los Angeles Healthcare Syst, Nucl Med, 11301 Wilshire Blvd, Los Angeles, CA 90073 USA. [Soper, Henry V.] Fielding Grad Univ, Sch Psychol, Santa Barbara, CA USA. RP Gaines, KD (reprint author), Vet Affairs Greater Los Angeles Healthcare Syst, Nucl Med, 11301 Wilshire Blvd, Los Angeles, CA 90073 USA. EM drdgaines@gmail.com FU Veterans Affairs of Greater Los Angeles Health Care System [PCC2011-070727] FX This work was supported by the This work was supported by the Veterans Affairs of Greater Los Angeles Health Care System [PCC2011-070727].. NR 79 TC 0 Z9 1 U1 1 U2 16 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 2327-9095 EI 2327-9109 J9 APPL NEUROPSYCH-ADUL JI Appl. Neuropsychol.-Adult PD MAR 3 PY 2016 VL 23 IS 2 BP 115 EP 124 DI 10.1080/23279095.2015.1012762 PG 10 WC Clinical Neurology; Psychology SC Neurosciences & Neurology; Psychology GA DE4TK UT WOS:000370623000005 PM 26496530 ER PT J AU Samanta, S Sun, H Goel, HL Pursell, B Chang, C Khan, A Greiner, DL Cao, S Lim, E Shultz, LD Mercurio, AM AF Samanta, S. Sun, H. Goel, H. L. Pursell, B. Chang, C. Khan, A. Greiner, D. L. Cao, S. Lim, E. Shultz, L. D. Mercurio, A. M. TI IMP3 promotes stem-like properties in triple-negative breast cancer by regulating SLUG SO ONCOGENE LA English DT Article ID SQUAMOUS-CELL CARCINOMA; REPRESSES E-CADHERIN; SELF-RENEWAL; STEM/PROGENITOR CELLS; TUMOR INITIATION; GENE-EXPRESSION; TGF-BETA; ER-BETA; SOX2; PHENOTYPE AB IMP3 (insulin-like growth factor-2 mRNA binding protein 3) is an oncofetal protein whose expression is prognostic for poor outcome in several cancers. Although IMP3 is expressed preferentially in triple-negative breast cancer (TNBC), its function is poorly understood. We observed that IMP3 expression is significantly higher in tumor initiating than in non-tumor initiating breast cancer cells and we demonstrate that IMP3 contributes to self-renewal and tumor initiation, properties associated with cancer stem cells (CSCs). The mechanism by which IMP3 contributes to this phenotype involves its ability to induce the stem cell factor SOX2. IMP3 does not interact with SOX2 mRNA significantly or regulate SOX2 expression directly. We discovered that IMP3 binds avidly to SNAI2 (SLUG) mRNA and regulates its expression by binding to the 5' UTR. This finding is significant because SLUG has been implicated in breast CSCs and TNBC. Moreover, we show that SOX2 is a transcriptional target of SLUG. These data establish a novel mechanism of breast tumor initiation involving IMP3 and they provide a rationale for its association with aggressive disease and poor outcome. C1 [Samanta, S.; Sun, H.; Goel, H. L.; Pursell, B.; Chang, C.; Mercurio, A. M.] Univ Massachusetts, Sch Med, Dept Mol Cell & Canc Biol, Lazare Res Bldg,364 Plantat St, Worcester, MA 01605 USA. [Khan, A.] Univ Massachusetts, Sch Med, Dept Pathol, Lazare Res Bldg,364 Plantat St, Worcester, MA 01605 USA. [Greiner, D. L.] Univ Massachusetts, Sch Med, Program Mol Med, Lazare Res Bldg,364 Plantat St, Worcester, MA 01605 USA. [Cao, S.; Lim, E.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Shultz, L. D.] Jackson Lab, 600 Main St, Bar Harbor, ME 04609 USA. RP Mercurio, AM (reprint author), Univ Massachusetts, Sch Med, Dept Mol Cell & Canc Biol, Lazare Res Bldg,364 Plantat St, Worcester, MA 01605 USA. EM arthur.mercurio@umassmed.edu OI /0000-0003-1726-3037 FU Megan Lally Memorial Fund; NIH [CA168464, CA034196, AI46629] FX We thank Dr Chung-Cheng Hsieh (University of Massachusetts Medical School) for statistical analysis of our in vivo data. This work was supported by the Megan Lally Memorial Fund and NIH Grants CA168464, CA034196 and AI46629. NR 50 TC 5 Z9 5 U1 2 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 EI 1476-5594 J9 ONCOGENE JI Oncogene PD MAR 3 PY 2016 VL 35 IS 9 BP 1111 EP 1121 DI 10.1038/onc.2015.164 PG 11 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA DF4WH UT WOS:000371351700005 PM 25982283 ER PT J AU Bruinsma, BG Sridharan, GV Weeder, PD Avruch, JH Saeidi, N Ozer, S Geerts, S Porte, RJ Heger, M van Gulik, TM Martins, PN Markmann, JF Yeh, H Uygun, K AF Bruinsma, Bote G. Sridharan, Gautham V. Weeder, Pepijn D. Avruch, James H. Saeidi, Nima Oezer, Sinan Geerts, Sharon Porte, Robert J. Heger, Michal van Gulik, Thomas M. Martins, Paulo N. Markmann, James F. Yeh, Heidi Uygun, Korkut TI Metabolic profiling during ex vivo machine perfusion of the human liver SO SCIENTIFIC REPORTS LA English DT Article ID ISCHEMIA-REPERFUSION INJURY; DONOR LIVER; REACTIVE OXYGEN; FATTY LIVER; RAT-LIVER; HEPATIC ISCHEMIA; ORGAN VIABILITY; CARDIAC DEATH; TRANSPLANTATION; PRESERVATION AB As donor organ shortages persist, functional machine perfusion is under investigation to improve preservation of the donor liver. The transplantation of donation after circulatory death (DCD) livers is limited by poor outcomes, but its application may be expanded by ex vivo repair and assessment of the organ before transplantation. Here we employed subnormothermic (21 degrees C) machine perfusion of discarded human livers combined with metabolomics to gain insight into metabolic recovery during machine perfusion. Improvements in energetic cofactors and redox shifts were observed, as well as reversal of ischemia-induced alterations in selected pathways, including lactate metabolism and increased TCA cycle intermediates. We next evaluated whether DCD livers with steatotic and severe ischemic injury could be discriminated from 'transplantable' DCD livers. Metabolomic profiling was able to cluster livers with similar metabolic patterns based on the degree of injury. Moreover, perfusion parameters combined with differences in metabolic factors suggest variable mechanisms that result in poor energy recovery in injured livers. We conclude that machine perfusion combined with metabolomics has significant potential as a clinical instrument for the assessment of preserved livers. C1 [Bruinsma, Bote G.; Sridharan, Gautham V.; Weeder, Pepijn D.; Saeidi, Nima; Oezer, Sinan; Geerts, Sharon; Uygun, Korkut] Harvard Univ, Sch Med, Dept Surg, Ctr Engn Med,Massachusetts Gen Hosp, Boston, MA 02115 USA. [Bruinsma, Bote G.; Heger, Michal; van Gulik, Thomas M.] Univ Amsterdam, Acad Med Ctr, Dept Expt Surg, Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands. [Weeder, Pepijn D.; Porte, Robert J.] Univ Groningen, Univ Med Ctr Groningen, Dept Surg, Sect Hepatobiliary Surg & Liver Transplantat, Groningen, Netherlands. [Avruch, James H.; Markmann, James F.; Yeh, Heidi] Massachusetts Gen Hosp, Dept Surg, Transplant Ctr, Boston, MA 02114 USA. [Martins, Paulo N.] Univ Massachusetts, Dept Surg, Transplant Div, Worcester, MA 01605 USA. RP Uygun, K (reprint author), Harvard Univ, Sch Med, Dept Surg, Ctr Engn Med,Massachusetts Gen Hosp, Boston, MA 02115 USA. EM korkut.uygun@mgh.harvard.edu FU US National Institutes of Health [R01EB008678, R01DK096075, R01DK084053, F32 DK103500, R21EB020819]; CIMIT Project [12-1732]; Shriners Hospitals for Children; New England Organ Bank (NEOB) FX Funding from the US National Institutes of Health (grants R01EB008678, R01DK096075, R01DK084053, F32 DK103500 and R21EB020819), CIMIT Project No. 12-1732 and the Shriners Hospitals for Children is gratefully acknowledged. We would like to gratefully acknowledge the New England Organ Bank (NEOB) for supporting this work. NR 47 TC 0 Z9 1 U1 3 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD MAR 3 PY 2016 VL 6 AR 22415 DI 10.1038/srep22415 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DF3EN UT WOS:000371226800001 PM 26935866 ER PT J AU Fei, P Lee, J Packard, RRS Sereti, KI Xu, H Ma, JG Ding, YC Kang, H Chen, H Sung, K Kulkarni, R Ardehali, R Kuo, CCJ Xu, XL Ho, CM Hsiai, TK AF Fei, Peng Lee, Juhyun Packard, Rene R. Sevag Sereti, Konstantina-Ioanna Xu, Hao Ma, Jianguo Ding, Yichen Kang, Hanul Chen, Harrison Sung, Kevin Kulkarni, Rajan Ardehali, Reza Kuo, C. -C. Jay Xu, Xiaolei Ho, Chih-Ming Hsiai, Tzung K. TI Cardiac Light-Sheet Fluorescent Microscopy for Multi-Scale and Rapid Imaging of Architecture and Function SO SCIENTIFIC REPORTS LA English DT Article ID PLANE ILLUMINATION MICROSCOPY; RESOLUTION; ZEBRAFISH; HEART; TOMOGRAPHY; EMBRYOS; FETAL; RECONSTRUCTION; MYOCARDIUM; DIFFUSION AB Light Sheet Fluorescence Microscopy (LSFM) enables multi-dimensional and multi-scale imaging via illuminating specimens with a separate thin sheet of laser. It allows rapid plane illumination for reduced photo-damage and superior axial resolution and contrast. We hereby demonstrate cardiac LSFM (c-LSFM) imaging to assess the functional architecture of zebrafish embryos with a retrospective cardiac synchronization algorithm for four-dimensional reconstruction (3-D space + time). By combining our approach with tissue clearing techniques, we reveal the entire cardiac structures and hypertrabeculation of adult zebrafish hearts in response to doxorubicin treatment. By integrating the resolution enhancement technique with c-LSFM to increase the resolving power under a large field-of-view, we demonstrate the use of low power objective to resolve the entire architecture of large-scale neonatal mouse hearts, revealing the helical orientation of individual myocardial fibers. Therefore, our c-LSFM imaging approach provides multi-scale visualization of architecture and function to drive cardiovascular research with translational implication in congenital heart diseases. C1 [Fei, Peng] Huazhong Univ Sci & Technol, Sch Opt & Elect Informat, Wuhan 430074, Peoples R China. [Fei, Peng; Ho, Chih-Ming] Univ Calif Los Angeles, Dept Mech & Aerosp Engn, Los Angeles, CA USA. [Lee, Juhyun; Packard, Rene R. Sevag; Chen, Harrison; Sung, Kevin; Hsiai, Tzung K.] Univ Calif Los Angeles, Dept Bioengn, Los Angeles, CA USA. [Packard, Rene R. Sevag; Hsiai, Tzung K.] Univ Calif Los Angeles, Dept Mol Cellular & Integrat Physiol, Los Angeles, CA USA. [Packard, Rene R. Sevag; Sereti, Konstantina-Ioanna; Ma, Jianguo; Ding, Yichen; Kang, Hanul; Kulkarni, Rajan; Ardehali, Reza; Hsiai, Tzung K.] Univ Calif Los Angeles, Div Cardiol, Los Angeles, CA USA. [Xu, Hao; Kuo, C. -C. Jay] Univ So Calif, Dept Elect Engn, Los Angeles, CA 90089 USA. [Kang, Hanul; Hsiai, Tzung K.] Vet Affairs Greater Los Angeles Healthcare Syst, Div Cardiol, Los Angeles, CA USA. [Xu, Xiaolei] Mayo Clin, Dept Biochem & Mol Biol, Rochester, MN USA. RP Hsiai, TK (reprint author), Univ Calif Los Angeles, Dept Bioengn, Los Angeles, CA USA.; Hsiai, TK (reprint author), Univ Calif Los Angeles, Dept Mol Cellular & Integrat Physiol, Los Angeles, CA USA.; Hsiai, TK (reprint author), Univ Calif Los Angeles, Div Cardiol, Los Angeles, CA USA.; Hsiai, TK (reprint author), Vet Affairs Greater Los Angeles Healthcare Syst, Div Cardiol, Los Angeles, CA USA. EM THsiai@mednet.ucla.edu OI Packard, Rene/0000-0002-8520-5843 FU National Institutes of Health [HL083015, HL111437, HL129727, HL81753, HL127728, T32HL007895]; UCLA STAR Program; AHA Pre-Doctoral Fellowship [15PRE21400019] FX This study was supported by National Institutes of Health HL083015 (T.K.H.), HL111437 (T.K.H.), HL129727 (T.K.H.), HL81753 (X.X.), HL127728 (R.A.), T32HL007895 (R.R.S.P.), UCLA STAR Program (R.R.S.P.) and AHA Pre-Doctoral Fellowship 15PRE21400019 (J.L.). NR 36 TC 3 Z9 3 U1 3 U2 19 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 MAR 3 PY 2016 VL 6 AR 22489 DI 10.1038/srep22489 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DF3FS UT WOS:000371230000001 PM 26935567 ER PT J AU Wang, W Wang, WH Azadzoi, KM Su, N Dai, P Sun, JB Wang, Q Liang, P Zhang, WT Lei, XY Yan, Z Yang, JH AF Wang, Wei Wang, Wei-Hua Azadzoi, Kazem M. Su, Ning Dai, Peng Sun, Jianbin Wang, Qin Liang, Ping Zhang, Wentao Lei, Xiaoying Yan, Zhen Yang, Jing-Hua TI Activation of innate antiviral immune response via double-stranded RNA-dependent RLR receptor-mediated necroptosis SO SCIENTIFIC REPORTS LA English DT Article ID PROGRAMMED CELL-DEATH; OVARIAN-CANCER CELLS; I-LIKE RECEPTORS; RIG-I; APAF-1 CARD; DNA VIRUSES; APOPTOSIS; NECROSIS; CASPASE-9; PATHWAY AB Viruses induce double-stranded RNA (dsRNA) in the host cells. The mammalian system has developed dsRNA-dependent recognition receptors such as RLRs that recognize the long stretches of dsRNA as PAMPs to activate interferon-mediated antiviral pathways and apoptosis in severe infection. Here we report an efficient antiviral immune response through dsRNA-dependent RLR receptor-mediated necroptosis against infections from different classes of viruses.We demonstrated that virus-infected A549 cells were efficiently killed in the presence of a chimeric RLR receptor, dsCARE. It measurably suppressed the interferon antiviral pathway but promoted IL-10 production. Canonical cell death analysis by morphologic assessment, phosphatidylserine exposure, caspase cleavage and chemical inhibition excluded the involvement of apoptosis and consistently suggested RLR receptor-mediated necroptosis as the underlying mechanism of infected cell death. The necroptotic pathway was augmented by the formation of RIP1-RIP3 necrosome, recruitment of MLKL protein and the activation of cathepsin D. Contributing roles of RIP1 and RIP3 were confirmed by gene knockdown. Furthermore, the necroptosis inhibitor necrostatin-1 but not the pan-caspase inhibitor zVAD impeded dsCAREdependent infected cell death. Our data provides compelling evidence that the chimeric RLR receptor shifts the common interferon antiviral responses of infected cells to necroptosis and leads to rapid death of the virus-infected cells. This mechanism could be targeted as an efficient antiviral strategy. C1 [Wang, Wei; Wang, Wei-Hua; Dai, Peng; Sun, Jianbin; Wang, Qin; Liang, Ping; Zhang, Wentao; Lei, Xiaoying; Yan, Zhen] Fourth Mil Med Univ, Sch Pharm, Dept Pharmacogen, State Key Lab Canc Biol, Xian 710032, Peoples R China. [Azadzoi, Kazem M.; Yang, Jing-Hua] Boston Univ, Sch Med, Dept Surg, VA Boston Healthcare Syst, Boston, MA USA. [Azadzoi, Kazem M.; Yang, Jing-Hua] Boston Univ, Sch Med, Dept Urol, VA Boston Healthcare Syst, Boston, MA USA. [Su, Ning] Xijing & Tangdu Hosp, Dept Neurosurg, Xian, Peoples R China. [Su, Ning] Xijing & Tangdu Hosp, Dept Oncol, Xian, Peoples R China. [Su, Ning; Yang, Jing-Hua] Shandong Univ, Sch Med, Canc Res Ctr, Jinan 250012, Peoples R China. RP Yan, Z (reprint author), Fourth Mil Med Univ, Sch Pharm, Dept Pharmacogen, State Key Lab Canc Biol, Xian 710032, Peoples R China.; Yang, JH (reprint author), Boston Univ, Sch Med, Dept Surg, VA Boston Healthcare Syst, Boston, MA USA.; Yang, JH (reprint author), Boston Univ, Sch Med, Dept Urol, VA Boston Healthcare Syst, Boston, MA USA.; Yang, JH (reprint author), Shandong Univ, Sch Med, Canc Res Ctr, Jinan 250012, Peoples R China. EM yanzhen@fmmu.edu.cn; jyang@bu.edu FU National Natural Science Foundation of China [30928031, 81071369, 81200055, 81272276, 31471322]; Important National Science & Technology Specific Projects [2009ZX09301-009-BD23]; China Postdoctoral Science Foundation [2012M521866]; Grant BLR&D MERIT from the US. Department of Veterans Affairs [1I01BX001428] FX We thank Guocheng Zhang and Xiaolei Yang for RSV virus preparation, Zhenglu Wang and Jingrong Zhao for technical assistance, Zhou Fei and Haichuan Su for discussion, and Alice Alexander for English poof reading. This work was supported by grants from National Natural Science Foundation of China (30928031, 81071369, 81200055, 81272276, and31471322), Important National Science & Technology Specific Projects (2009ZX09301-009-BD23), China Postdoctoral Science Foundation (2012M521866) and Grant BLR&D MERIT 1I01BX001428 from the US. Department of Veterans Affairs. This is the result of work partially supported with resources and the use of facilities at VA Boston Healthcare System, USA, and Shandong University Cancer Research Center, China. NR 50 TC 0 Z9 0 U1 2 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 MAR 3 PY 2016 VL 6 AR 225501 DI 10.1038/srep22550 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DF2XE UT WOS:000371206900001 PM 26935990 ER PT J AU Pursley, AJ Saunders, GH AF Pursley, Alyssa J. Saunders, Gabrielle H. TI Knowledge, attitudes, behaviors, and noise exposure of baristas SO INTERNATIONAL JOURNAL OF AUDIOLOGY LA English DT Article DE questionnaires; cafes; Hearing conservation; health belief model; noise-induced hearing loss ID HEARING-LOSS PREVENTION; HEALTH PROMOTION MODEL; PROTECTION AB Objective: To examine the daily noise exposure of baristas working in cafes, and to measure their knowledge, attitudes, and behaviors regarding hearing conservation and perceptions of noise in their work environment. Design: Fifteen baristas from six cafes in Portland completed the Knowledge, Attitudes and Behaviors questionnaire, a sound disturbance survey, and a structured interview to document perceptions of noise in the work environment. To measure daily noise exposure, a subset of eight participants wore a personal dosimeter for three different work shifts. Study sample: A total of 11 females and four males, aged between 19 and 36 years old (mean: 26.3, SD: 4.6) recruited from independently owned cafes in the Portland metro area. Results: Dosimetry measurements revealed Leq measurements between 71 and 83 dBA, with noise doses ranging from 4% to 74%, indicating that baristas are not exposed to sound levels above the regulatory criterion. Questionnaire results indicated that baristas have low awareness about the hazards of noise, are not opposed to hearing conservation, and rarely use hearing protection when engaged in noisy activities. Conclusions: Baristas here lacked the pertinent education and motivation to commit to invaluable hearing conservation practices. C1 [Pursley, Alyssa J.] Washington Univ, Sch Med, Program Audiol & Commun Sci, 660 S Euclid Ave,Campus Box 8042, St Louis, MO 63110 USA. [Saunders, Gabrielle H.] Portland VA Med Ctr, NCRAR, Portland, OR USA. RP Pursley, AJ (reprint author), Washington Univ, Sch Med, Program Audiol & Commun Sci, 660 S Euclid Ave,Campus Box 8042, St Louis, MO 63110 USA. EM alyssa.pursley@wustl.edu FU NIH National Institute on Deafness and other Communicative Disorders Predoctoral Short-term Training Grant [DC008764, T-35] FX This study was supported by a NIH National Institute on Deafness and other Communicative Disorders T-35 Predoctoral Short-term Training Grant (Grant number DC008764). Portions of this work were presented at the American Auditory Society Annual Conference, Phoenix, USA (March 6, 2015), the Missouri Academy of Audiology Annual Conference, Saint Louis, USA (September 12, 2014), and the International Hearing Aid Research Conference, Lake Tahoe, USA (August 14, 2014). NR 16 TC 0 Z9 0 U1 3 U2 5 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1499-2027 EI 1708-8186 J9 INT J AUDIOL JI Int. J. Audiol. PD MAR 3 PY 2016 VL 55 IS 3 BP 184 EP 188 DI 10.3109/14992027.2015.1124295 PG 5 WC Audiology & Speech-Language Pathology; Otorhinolaryngology SC Audiology & Speech-Language Pathology; Otorhinolaryngology GA DE5BO UT WOS:000370646000007 PM 26795371 ER PT J AU Luo, C Puigserver, P AF Luo, Chi Puigserver, Pere TI Dietary fat promotes intestinal dysregulation SO NATURE LA English DT Editorial Material ID STEM-CELL AB In mice, a high-fat diet has now been found to induce intestinal progenitor cells to adopt a more stem-cell-like fate, altering the size of the gut and increasing tumour incidence. C1 [Luo, Chi; Puigserver, Pere] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. [Luo, Chi; Puigserver, Pere] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. RP Puigserver, P (reprint author), Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA.; Puigserver, P (reprint author), Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. EM pere_puigserver@dfci.harvard.edu NR 11 TC 1 Z9 1 U1 2 U2 10 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 MAR 3 PY 2016 VL 531 IS 7592 BP 42 EP 43 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DF2YW UT WOS:000371211900034 PM 26935693 ER PT J AU Beyaz, S Mana, MD Roper, J Kedrin, D Saadatpour, A Hong, SJ Bauer-Rowe, KE Xifaras, ME Akkad, A Arias, E Pinello, L Katz, Y Shinagare, S Abu-Remaileh, M Mihaylova, MM Lamming, DW Dogum, R Guo, GJ Bell, GW Selig, M Nielsen, GP Gupta, N Ferrone, CR Deshpande, V Yuan, GC Orkin, SH Sabatini, DM Yilmaz, OH AF Beyaz, Semir Mana, Miyeko D. Roper, Jatin Kedrin, Dmitriy Saadatpour, Assieh Hong, Sue Jean Bauer-Rowe, Khristian E. Xifaras, Michael E. Akkad, Adam Arias, Erika Pinello, Luca Katz, Yarden Shinagare, Shweta Abu-Remaileh, Monther Mihaylova, Maria M. Lamming, Dudley W. Dogum, Rizkullah Guo, Guoji Bell, George W. Selig, Martin Nielsen, G. Petur Gupta, Nitin Ferrone, Cristina R. Deshpande, Vikram Yuan, Guo-Cheng Orkin, Stuart H. Sabatini, David M. Yilmaz, Oemer H. TI High-fat diet enhances stemness and tumorigenicity of intestinal progenitors SO NATURE LA English DT Article ID ACTIVATED-RECEPTOR-DELTA; COLORECTAL-CANCER; GENETIC DISRUPTION; IN-VITRO; CELLS; PROGRESSION; EXPRESSION; LGR5; MECHANISMS; PLASTICITY AB Little is known about how pro-obesity diets regulate tissue stem and progenitor cell function. Here we show that high-fat diet (HFD)-induced obesity augments the numbers and function of Lgr5(+) intestinal stem cells of the mammalian intestine. Mechanistically, a HFD induces a robust peroxisome proliferator-activated receptor delta (PPAR-delta) signature in intestinal stem cells and progenitor cells (non-intestinal stem cells), and pharmacological activation of PPAR-delta recapitulates the effects of a HFD on these cells. Like a HFD, ex vivo treatment of intestinal organoid cultures with fatty acid constituents of the HFD enhances the self-renewal potential of these organoid bodies in a PPAR-delta-dependent manner. Notably, HFD- and agonist-activated PPAR-delta signalling endow organoid-initiating capacity to progenitors, and enforced PPAR-delta signalling permits these progenitors to form in vivo tumours after loss of the tumour suppressor Apc. These findings highlight how diet-modulated PPAR-delta activation alters not only the function of intestinal stem and progenitor cells, but also their capacity to initiate tumours. C1 [Beyaz, Semir; Mana, Miyeko D.; Roper, Jatin; Kedrin, Dmitriy; Bauer-Rowe, Khristian E.; Xifaras, Michael E.; Akkad, Adam; Arias, Erika; Shinagare, Shweta; Abu-Remaileh, Monther; Mihaylova, Maria M.; Dogum, Rizkullah; Sabatini, David M.; Yilmaz, Oemer H.] MIT, Dept Biol, David H Koch Inst Integrat Canc Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Beyaz, Semir; Guo, Guoji; Orkin, Stuart H.] Boston Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USA. [Beyaz, Semir; Guo, Guoji; Orkin, Stuart H.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pediat Oncol,Howard Hughes Med Inst,Harvard, 44 Binney St, Boston, MA 02115 USA. [Roper, Jatin] Tufts Med Ctr, Div Gastroenterol, Boston, MA 02111 USA. [Roper, Jatin] Tufts Med Ctr, Mol Oncol Res Inst, Boston, MA 02111 USA. [Kedrin, Dmitriy; Selig, Martin; Nielsen, G. Petur; Ferrone, Cristina R.; Deshpande, Vikram; Yilmaz, Oemer H.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Kedrin, Dmitriy; Selig, Martin; Nielsen, G. Petur; Ferrone, Cristina R.; Deshpande, Vikram; Yilmaz, Oemer H.] Massachusetts Gen Hosp, Dept Gastroenterol, Boston, MA 02114 USA. [Kedrin, Dmitriy; Selig, Martin; Nielsen, G. Petur; Ferrone, Cristina R.; Deshpande, Vikram; Yilmaz, Oemer H.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Kedrin, Dmitriy; Selig, Martin; Nielsen, G. Petur; Ferrone, Cristina R.; Deshpande, Vikram; Yilmaz, Oemer H.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Saadatpour, Assieh; Pinello, Luca; Yuan, Guo-Cheng] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Saadatpour, Assieh; Pinello, Luca; Yuan, Guo-Cheng] Harvard Univ, TH Chan Sch Publ Hlth, Boston, MA 02115 USA. [Hong, Sue Jean; Abu-Remaileh, Monther; Mihaylova, Maria M.; Bell, George W.; Sabatini, David M.] MIT, Dept Biol, Howard Hughes Med Inst, Whitehead Inst Biomed Res, 77 Massachusetts Ave, Cambridge, MA 02142 USA. [Katz, Yarden; Sabatini, David M.; Yilmaz, Oemer H.] Broad Inst Harvard & MIT, Cambridge, MA 02142 USA. [Lamming, Dudley W.] Univ Wisconsin, Dept Med, Madison, WI 53705 USA. [Gupta, Nitin] Univ Mississippi, Med Ctr, Div Digest Dis, Jackson, MS 39216 USA. RP Sabatini, DM; Yilmaz, OH (reprint author), MIT, Dept Biol, David H Koch Inst Integrat Canc Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA.; Yilmaz, OH (reprint author), Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA.; Yilmaz, OH (reprint author), Massachusetts Gen Hosp, Dept Gastroenterol, Boston, MA 02114 USA.; Yilmaz, OH (reprint author), Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA.; Sabatini, DM (reprint author), MIT, Dept Biol, Howard Hughes Med Inst, Whitehead Inst Biomed Res, 77 Massachusetts Ave, Cambridge, MA 02142 USA.; Sabatini, DM; Yilmaz, OH (reprint author), Broad Inst Harvard & MIT, Cambridge, MA 02142 USA. EM sabatini@wi.mit.edu; ohyilmaz@mit.edu RI Abu-Remaileh, Monther/M-3747-2016; Gupta, Nitin/A-1076-2016; OI Gupta, Nitin/0000-0002-4471-2363; Roper, Jatin/0000-0002-8851-1352; Lamming, Dudley/0000-0002-0079-4467; Beyaz, Semir/0000-0003-4730-4012 FU Howard Hughes Medical Institute; Ellison Medical Foundation Aging; NIH [R01 CA103866, A147389, K08 CA198002, ROD AG045144, ROD AG041765]; Department of Defense PRCRP Career Development Award [CA120198]; Center for the Study of Inflammatory Bowel Diseases from the Massachusetts General Hospital NIH [DK043351]; NIH Cancer Center Support [P30-CA14051]; Kathy and Curt Marble Cancer Research Fund; American Federation of Aging Research (AFAR); V Foundation Scholar grant; Koch MIT Ludwig Center; MGH [T32DK007191]; Damon Runyon Cancer Research Foundation; Hope Babette Tang Histology Facility and Kathleen Cormier FX This work was supported by the Howard Hughes Medical Institute (S.H.O. and D.M.S.), Ellison Medical Foundation Aging grant (D.M.S.), NIH (R01 CA103866 and A147389; D.M.S.), NIH (K08 CA198002; J.R.), Department of Defense PRCRP Career Development Award CA120198 (J.R.), NIH (ROD AG045144; O.H.Y.), NIH (ROD AG041765; D.W.L.), Center for the Study of Inflammatory Bowel Diseases from the Massachusetts General Hospital NIH (DK043351; O.H.Y.), NIH Cancer Center Support (core) grant P30-CA14051 (O.H.Y.), Kathy and Curt Marble Cancer Research Fund (O.H.Y.), American Federation of Aging Research (AFAR; O.H.Y.), and V Foundation Scholar grant (J.R. and O.H.Y.). M.G.M. is supported by a Koch MIT Ludwig Center post-doctoral fellowship, D.K. receives fellowship support from MGH (T32DK007191), and M.M.M. is a Robert Black Fellow of the Damon Runyon Cancer Research Foundation. We thank the Koch Institute Swanson Biotechnology Center (SBC) for technical support specifically the Hope Babette Tang (1983) Histology Facility and Kathleen Cormier. We thank S. Holder for superior histology and help with special stains. We thank P. Wisniewski and G. Paradis of the Whitehead flow cytometry and Koch core facilities, respectively, for their expertise in cell sorting We thank members of the Yilmaz laboratory for discussions. NR 48 TC 24 Z9 25 U1 21 U2 58 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 MAR 3 PY 2016 VL 531 IS 7592 BP 53 EP + DI 10.1038/nature17173 PG 19 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DF2YW UT WOS:000371211900038 PM 26935695 ER PT J AU Motzer, RJ Escudier, B Choueiri, TK AF Motzer, Robert J. Escudier, Bernard Choueiri, Toni K. TI Treatment of Advanced Renal-Cell Carcinoma Reply SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter ID CABOZANTINIB C1 [Motzer, Robert J.] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. [Escudier, Bernard] Inst Gustave Roussy, Villejuif, France. [Choueiri, Toni K.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Motzer, RJ (reprint author), Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. EM motzerr@mskcc.org NR 5 TC 2 Z9 2 U1 0 U2 1 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD MAR 3 PY 2016 VL 374 IS 9 BP 889 EP 890 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA DF2FT UT WOS:000371158400021 PM 26962911 ER PT J AU Pecoraro, A Pacciolla, A O'Cleirigh, C Mimiaga, M Kwiatek, P Blokhina, E Verbitskaya, E Krupitsky, E Woody, GE AF Pecoraro, Anna Pacciolla, Aureliano O'Cleirigh, Conall Mimiaga, Matthew Kwiatek, Piotr Blokhina, Elena Verbitskaya, Elena Krupitsky, Evgeny Woody, George E. TI Proactive coping and spirituality among patients who left or remained in antiretroviral treatment in St Petersburg, Russian Federation SO AIDS CARE-PSYCHOLOGICAL AND SOCIO-MEDICAL ASPECTS OF AIDS/HIV LA English DT Article DE AIDS; retention; Russian Federation; HIV; attrition; positive psychology; spirituality ID POSITIVE PSYCHOLOGY; HIV; MEDICATIONS; ADHERENCE; THERAPY AB Positive Psychology, the study of "positive" factors or strengths and evidence-based interventions to increase them, is a rapidly developing field that is beginning to be applied to HIV care. Proactive coping and spirituality are two positive characteristics that have been examined in multiple chronic serious health conditions. In the present study, lost-to-care (LTCs; did not attend treatment for >= 12 months; n = 120) and engaged-in-care HIV clinic patients (EICs; attended treatment for >= 12 months and adherent with antiretrovirals; n = 120) in Leningrad Oblast, Russian Federation were compared on the Proactive Coping Inventory and View of God Scale. EICs had higher scores in proactive coping [t(229) = 3.69; p = .001] and instrumental [t(232) = 2.17; p = .03] and emotional [t(233) = 2.33; p = .02] support, indicating that they engage in autonomous goal setting and self-regulate their thoughts and behaviors; obtain advice and support from their social network; and cope with emotional distress by turning to others. LTCs had higher scores in avoidance coping [t(236) = -2.31; p = .02]. More EICs were spiritual, religious, or both [ chi(2)(1, N = 239) = 7.49, p = .006]. EICs were more likely to believe in God/Higher Power [chi(2)(1, N = 239 = 8.89, p = .002] and an afterlife [ chi(2)(1, N = 236) = 5.11, p = .024]; have a relationship with God/Higher Power [ chi(2)(1, N = 237) = 12.76, p = .000]; and call on God/Higher Power for help, healing, or protection [ chi(2)(1, N = 239) = 9.61]. EICs had more positive [t(238) = 2.78; p = .006] and less negative [t(236) = -2.38; p = .002] views of God. Similar proportions, but slightly more EICs than LTCs were members of a faith community; members of a12-step group; or attended religious or spiritual services, meetings, or activities. More EICs than LTCs engaged in private spiritual or religious activities, such as prayer or meditation [ chi(2)(1, N = 239) = 9.226, p = .002]. C1 [Pecoraro, Anna; Woody, George E.] Univ Penn, Dept Psychiat, Perelman Sch Med, Philadelphia, PA 19104 USA. [Pecoraro, Anna; Woody, George E.] NIDA Clin Trials Network, Delaware Valley Node, Philadelphia, PA USA. [Pacciolla, Aureliano] LUMSA, Dipartimento Sci Umane, Rome, Italy. [O'Cleirigh, Conall; Mimiaga, Matthew] Harvard Univ, Sch Med, Boston, MA USA. [O'Cleirigh, Conall] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Mimiaga, Matthew] Harvard Univ, Sch Publ Hlth, 665 Huntington Ave, Boston, MA 02115 USA. [Kwiatek, Piotr] Pontifical Salesian Univ, Univ Pontificia Salesiana, Dipartimento Psicol, Rome, Italy. [Blokhina, Elena; Verbitskaya, Elena; Krupitsky, Evgeny] First Pavlov State Med Sch, Valdman Inst Pharmacol, St Petersburg, Russia. [Krupitsky, Evgeny] Bekhterev Res Psychoneurol Inst, St Petersburg, Russia. RP Pecoraro, A (reprint author), Univ Penn, Dept Psychiat, Perelman Sch Med, Philadelphia, PA 19104 USA.; Pecoraro, A (reprint author), NIDA Clin Trials Network, Delaware Valley Node, Philadelphia, PA USA. EM annp@mail.med.upenn.edu OI Verbitskaya, Elena/0000-0003-3770-993X FU Office of the US Global AIDS Coordinator through the PEPFAR program [PEPFAR] [R01-DA026336] FX This study was supported by funding from the Office of the US Global AIDS Coordinator through the PEPFAR program [PEPFAR Supplement to R01-DA026336]. NR 22 TC 0 Z9 0 U1 1 U2 6 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 0954-0121 EI 1360-0451 J9 AIDS CARE JI Aids Care-Psychol. Socio-Med. Asp. Aids-Hiv PD MAR 3 PY 2016 VL 28 IS 3 BP 334 EP 338 DI 10.1080/09540121.2015.1096895 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 DE5PD UT WOS:000370682600010 PM 26461806 ER PT J AU Williams, NR Hopkins, TR Short, EB Sahlem, GL Snipes, J Revuelta, GJ George, MS Takacs, I AF Williams, Nolan R. Hopkins, Thomas R. Short, E. Baron Sahlem, Gregory L. Snipes, Jonathan Revuelta, Gonzalo J. George, Mark S. Takacs, Istvan TI Reward circuit DBS improves Parkinson's gait along with severe depression and OCD SO NEUROCASE LA English DT Article DE Deep brain stimulation; Parkinson's disease; depression; apathy; obsessive-compulsive disorder ID OBSESSIVE-COMPULSIVE DISORDER; DEEP BRAIN-STIMULATION; SUBTHALAMIC NUCLEUS STIMULATION; DISEASE; STRIATUM AB A 59-year-old Caucasian man with a past history of Parkinson's disease (PD) status post-bilateral subthalamic nucleus (STN) deep brain stimulation (DBS), who also had treatment-resistant (TR) obsessive-compulsive disorder (OCD), and treatment-resistant depression (TRD), presented for further evaluation and management of his TR OCD. After an unsuccessful attempt to treat his OCD by reprogramming his existing STN DBS, he was offered bilateral ventral capsule/ventral striatum (VC/VS) DBS surgery. In addition to the expected improvement in OCD symptoms, he experienced significant improvement in both PD-related apathy and depression along with resolution of suicidal ideation. Furthermore, the patient's festinating gait dramatically improved. This case demonstrates that DBS of both the STN and VC/VS appears to have an initial signal of safety and tolerability. This is the first instance where both the STN and the VC/VS DBS targets have been implanted in an individual and the first case where a patient with PD has received additional DBS in mood-regulatory circuitry. C1 [Williams, Nolan R.] Stanford Univ, Dept Psychiat, Stanford, CA 94305 USA. [Hopkins, Thomas R.; Short, E. Baron; Sahlem, Gregory L.; Snipes, Jonathan; George, Mark S.] Med Univ S Carolina, Dept Psychiat & Behav Sci, 171 Ashley Ave, Charleston, SC 29425 USA. [Revuelta, Gonzalo J.; George, Mark S.; Takacs, Istvan] Med Univ S Carolina, Dept Neurosci, Charleston, SC 29425 USA. [George, Mark S.] Ralph H Johnson VA Med Ctr, Charleston, SC USA. RP Williams, NR (reprint author), Stanford Univ, Dept Psychiat, Stanford, CA 94305 USA. EM nolrywillia@gmail.com OI Williams, Nolan/0000-0003-4368-3203 FU National Institute of Drug Abuse [R25 DA020537] FX NRW and TRH are both funded through National Institute of Drug Abuse [grant number R25 DA020537]. NR 18 TC 3 Z9 3 U1 3 U2 18 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 1355-4794 EI 1465-3656 J9 NEUROCASE JI Neurocase PD MAR 3 PY 2016 VL 22 IS 2 BP 201 EP 204 DI 10.1080/13554794.2015.1112019 PG 4 WC Clinical Neurology; Psychiatry; Psychology SC Neurosciences & Neurology; Psychiatry; Psychology GA DD2RR UT WOS:000369770400011 PM 26644268 ER PT J AU Darby, RR Caplan, D AF Darby, R. Ryan Caplan, David TI "Cat-gras" delusion: a unique misidentification syndrome and a novel explanation SO NEUROCASE LA English DT Article DE Delusional misidentification syndrome; Capgras; confabulation; episodic memory; identity ID CAPGRAS DELUSION; REDUPLICATIVE PARAMNESIA; FACE RECOGNITION; PROSOPAGNOSIA; FAMILIARITY AB ABSRACTCapgras syndrome is a distressing delusion found in a variety of neurological and psychiatric diseases where a patient believes that a family member, friend, or loved one has been replaced by an imposter. Patients recognize the physical resemblance of a familiar acquaintance but feel that the identity of that person is no longer the same. Here we describe a 73-year-old male with right posterior frontal and bilateral anterior-medial frontal damage from prior brain trauma with a similar delusion of an imposter replacing his pet cat. Misidentification syndromes for animals, as opposed to humans, have been rarely reported. Neuropsychological testing showed deficits in executive processing and memory retrieval with prominent intrusions and false positive responses. The delusional belief content in Capgras syndrome has been hypothesized to result from loss of an emotional or autonomic response to familiar stimuli, from theory of mind deficits, or from loss of self-environment distinctions. We instead propose that Capgras delusions result from a dysfunction in linking external stimuli with retrieved internal autobiographical memories pertaining to that object. This leads to an erroneously learned identity that persists as a specific delusional belief. C1 [Darby, R. Ryan; Caplan, David] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Darby, R. Ryan] Brigham & Womens Hosp, Dept Neurol, 75 Francis St, Boston, MA 02115 USA. [Darby, R. Ryan; Caplan, David] Harvard Univ, Sch Med, Boston, MA USA. RP Darby, RR (reprint author), Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA.; Darby, RR (reprint author), Brigham & Womens Hosp, Dept Neurol, 75 Francis St, Boston, MA 02115 USA.; Darby, RR (reprint author), Harvard Univ, Sch Med, Boston, MA USA. EM darby.ryan@gmail.com NR 27 TC 2 Z9 2 U1 5 U2 14 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 1355-4794 EI 1465-3656 J9 NEUROCASE JI Neurocase PD MAR 3 PY 2016 VL 22 IS 2 BP 251 EP 256 DI 10.1080/13554794.2015.1136335 PG 6 WC Clinical Neurology; Psychiatry; Psychology SC Neurosciences & Neurology; Psychiatry; Psychology GA DD2RR UT WOS:000369770400019 PM 26765326 ER PT J AU Scioli, A Scioli-Salter, ER Sykes, K Anderson, C Fedele, M AF Scioli, Anthony Scioli-Salter, Erica R. Sykes, Keith Anderson, Christina Fedele, Michael TI The positive contributions of hope to maintaining and restoring health: An integrative, mixed-method approach SO JOURNAL OF POSITIVE PSYCHOLOGY LA English DT Article DE hope; health; stages of change; cancer survivors ID COLORECTAL-CANCER SURVIVORS; VEGETABLE CONSUMPTION; INDIVIDUAL-DIFFERENCES; DEPRESSIVE SYMPTOMS; BREAST-CANCER; DAILY-LIFE; WOMEN; FRUIT; ASSOCIATIONS; ADHERENCE AB A link between hope and physical well-being has long been suspected. To shed further light on this issue, an integrative theory of hope was used to design three health-related studies. In studies one and two, an integrative hope scale was used. In study one, greater hope was associated with depth of commitment to a healthier diet and regular exercise. In study two, the integrative hope scale was associated with a wider array of health behaviors as compared to a standard goal-oriented hope scale. In study three, a hope-centered content analysis of testimonies provided by long-term breast cancer survivors revealed a strong reliance on attachment and spirituality, dimensions typically neglected in psychological studies of this [hope] construct. An integrative approach to hope offers a framework for further research on hope and health as well as a blueprint for developing positive interventions to sustain and restore physical well-being. C1 [Scioli, Anthony; Sykes, Keith; Anderson, Christina; Fedele, Michael] Univ Syst New Hampshire, Keene State Coll, Dept Psychol, Keene, NH 03435 USA. [Scioli-Salter, Erica R.] VA Boston Healthcare Syst, Div Res, Boston, MA 02130 USA. RP Scioli, A (reprint author), Univ Syst New Hampshire, Keene State Coll, Dept Psychol, 233 Rhodes Hall,229 Main St, Keene, NH 03435 USA. EM tscioli@keene.edu FU Department of Veterans Affairs, Veterans Health Administration, and Rehabilitation Research and Development Service Award [1IK2RX000704-01A2]; Women's Health Sciences Division, National Center for PTSD FX The research described here was supported in part by a grant to the second author via the Department of Veterans Affairs, Veterans Health Administration, and Rehabilitation Research and Development Service Award (1IK2RX000704-01A2), as well as by the Women's Health Sciences Division, National Center for PTSD. NR 87 TC 0 Z9 0 U1 4 U2 21 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 1743-9760 EI 1743-9779 J9 J POSIT PSYCHOL JI J. Posit. Psychol. PD MAR 3 PY 2016 VL 11 IS 2 BP 135 EP 148 DI 10.1080/17439760.2015.1037858 PG 14 WC Psychology, Multidisciplinary SC Psychology GA DA5IR UT WOS:000367837300003 ER PT J AU Lee, VR Pilliod, RA Frias, AE Rasanen, JP Shaffer, BL Caughey, AB AF Lee, Vanessa R. Pilliod, Rachel A. Frias, Antonio E. Rasanen, Juha P. Shaffer, Brian L. Caughey, Aaron B. TI When is the optimal time to deliver late preterm IUGR fetuses with abnormal umbilical artery Dopplers? SO JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE LA English DT Article DE Decision analysis; delivery timing; Doppler assessment; intrauterine growth restriction ID INTRAUTERINE GROWTH RESTRICTION; FOR-GESTATIONAL-AGE; END-DIASTOLIC VELOCITY; PRENATAL-DIAGNOSIS; DOWN-SYNDROME; FLOW; ABSENT; PARAMETERS; MORBIDITY; MORTALITY AB Objective: To determine the optimal timing of delivery in late preterm intrauterine growth restriction (IUGR) fetuses with abnormal umbilical artery Doppler (UAD) indices.Methods: A decision-analytic model was built to determine the optimal gestational age (GA) of delivery in a theoretic cohort of 10000 IUGR fetuses with elevated UAD systolic/diastolic ratios diagnosed at 34 weeks. All inputs were derived from the literature. Strategies involving expectant management accounted for the probabilities of stillbirth, spontaneous delivery and induction of labor for UAD absent or reversed end-diastolic flow (AREDF) at each successive week. Outcomes included short- and long-term neonatal morbidity and mortality with quality-adjusted life years (QALYs) generated based on these outcomes. Base case, sensitivity analyses and a Monte Carlo simulation were performed.Results: The optimal GA for delivery is 35 weeks, which minimized perinatal deaths and maximized total QALYs. Earlier delivery became optimal once the risk of stillbirth was threefold our baseline assumption; our model was also robust until the risk of AREDF at 35 weeks was half our baseline assumption, after which delivery at 36 weeks was preferred. Delivery at 35 weeks was the optimal strategy in 77% of trials in Monte Carlo multivariable sensitivity analysis.Conclusions: Weighing the risks of iatrogenic prematurity against the poor outcomes associated with AREDF, the ideal GA to deliver late preterm IUGR fetuses with elevated UAD indices is 35 weeks. C1 [Lee, Vanessa R.; Frias, Antonio E.; Rasanen, Juha P.; Shaffer, Brian L.; Caughey, Aaron B.] Oregon Hlth & Sci Univ, Dept Obstet & Gynecol, Portland, OR 97239 USA. [Pilliod, Rachel A.] Brigham & Womens Hosp, Dept Obstet & Gynecol, Boston, MA 02115 USA. [Pilliod, Rachel A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Lee, VR (reprint author), Oregon Hlth & Sci Univ, Dept Obstet & Gynecol, Mail Code L-466,3181 SW Sam Jackson Pk Rd, Portland, OR 97239 USA. EM leev@ohsu.edu NR 30 TC 1 Z9 1 U1 0 U2 8 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1476-7058 EI 1476-4954 J9 J MATERN-FETAL NEO M JI J. Matern.-Fetal Neonatal Med. PD MAR 3 PY 2016 VL 29 IS 5 BP 690 EP 695 DI 10.3109/14767058.2015.1018170 PG 6 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA CY3PX UT WOS:000366323100002 PM 25754212 ER PT J AU Yetisen, AK Coskun, AF England, G Cho, SY Butt, H Hurwitz, J Kolle, M Khademhosseini, A Hart, AJ Folch, A Yun, SH AF Yetisen, Ali K. Coskun, Ahmet F. England, Grant Cho, Sangyeon Butt, Haider Hurwitz, Jonty Kolle, Mathias Khademhosseini, Ali Hart, A. John Folch, Albert Yun, Seok Hyun TI Art on the Nanoscale and Beyond SO ADVANCED MATERIALS LA English DT Review ID ATOMIC-FORCE MICROSCOPE; ELECTRON-MICROSCOPE; FLUORESCENCE MICROSCOPY; MULTIPHOTON LITHOGRAPHY; 2-PHOTON POLYMERIZATION; DEVELOPMENTAL BIOLOGY; PHOTONIC NANOSENSOR; HOLOGRAPHIC SENSORS; MAGNETIC ELECTRON; MAYA-BLUE AB Methods of forming and patterning materials at the nano-and microscales are finding increased use as a medium of artistic expression, and as a vehicle for communicating scientific advances to a broader audience. While sharing many attributes of other art forms, miniaturized art enables the direct engagement of sensory aspects such as sight and touch for materials and structures that are otherwise invisible to the eye. The historical uses of nano-/microscale materials and imaging techniques in arts and sciences are presented. The motivations to create artwork at small scales are discussed, and representations in scientific literature and exhibitions are explored. Examples are presented using semiconductors, microfluidics, and nanomaterials as the artistic media; these utilized techniques including micromachining, focused ion beam milling, two-photon polymerization, and bottom-up nanostructure growth. Finally, the technological factors that limit the implementation of artwork at miniature scales are identified, and potential future directions are discussed. As research marches toward even smaller length scales, innovative and engaging visualizations and artistic endeavors will have growing implications on education, communication, policy making, media activism, and public perception of science and technology. C1 [Yetisen, Ali K.; Cho, Sangyeon; Yun, Seok Hyun] Harvard Univ, Sch Med, 65 Landsdowne St, Cambridge, MA 02139 USA. [Yetisen, Ali K.; Cho, Sangyeon; Yun, Seok Hyun] Massachusetts Gen Hosp, Wellman Ctr Photomed, 65 Landsdowne St, Cambridge, MA 02139 USA. [Coskun, Ahmet F.] CALTECH, Div Chem & Chem Engn, 1200 East Calif Blvd, Pasadena, CA 91125 USA. [England, Grant] Harvard Univ, Sch Engn & Appl Sci, 9 Oxford St, Cambridge, MA 02138 USA. [Butt, Haider] Univ Birmingham, Sch Mech Engn, Birmingham B15 2TT, W Midlands, England. [Hurwitz, Jonty] Royal British Soc Sculptors, 108 Old Brompton Rd, London SW7 3RA, England. [Kolle, Mathias; Hart, A. John] MIT, Dept Mech Engn, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Khademhosseini, Ali] Harvard Univ, Brigham & Womens Hosp, Biomat Innovat Res Ctr, Sch Med,Div Biomed Engn, Cambridge, MA 02139 USA. [Khademhosseini, Ali] Harvard Univ, Wyss Inst Biol Inspired Engn, Boston, MA 02115 USA. [Khademhosseini, Ali] King Abdulaziz Univ, Dept Phys, Jeddah 21413, Saudi Arabia. [Folch, Albert] Univ Washington, Dept Bioengn, William Foege Bldg 15th Ave NE, Seattle, WA 98195 USA. RP Yetisen, AK; Yun, SH (reprint author), Harvard Univ, Sch Med, 65 Landsdowne St, Cambridge, MA 02139 USA.; Yetisen, AK; Yun, SH (reprint author), Massachusetts Gen Hosp, Wellman Ctr Photomed, 65 Landsdowne St, Cambridge, MA 02139 USA. EM ayetisen@mgh.harvard.edu; syun@mgh.harvard.edu RI Kolle, Mathias/E-3313-2013; Hart, A. John/A-9027-2010; OI Kolle, Mathias/0000-0001-7395-8824; Hart, A. John/0000-0002-7372-3512; Khademhosseini, Ali/0000-0001-6322-8852; Butt, Haider/0000-0003-2434-9525 NR 199 TC 3 Z9 3 U1 51 U2 130 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA POSTFACH 101161, 69451 WEINHEIM, GERMANY SN 0935-9648 EI 1521-4095 J9 ADV MATER JI Adv. Mater. PD MAR 2 PY 2016 VL 28 IS 9 BP 1724 EP 1742 DI 10.1002/adma.201502382 PG 19 WC Chemistry, Multidisciplinary; Chemistry, Physical; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary; Physics, Applied; Physics, Condensed Matter SC Chemistry; Science & Technology - Other Topics; Materials Science; Physics GA DG6EV UT WOS:000372176200001 PM 26671704 ER PT J AU Singh, JA Yu, SH AF Singh, Jasvinder A. Yu, Shaohua TI Gout-related inpatient utilization: a study of predictors of outcomes and time trends SO ARTHRITIS RESEARCH & THERAPY LA English DT Article DE Gout; Inpatient utilization; Hospitalization; Comorbidity; Predictors; Length of stay; Hospital discharge; Resource utilization; Charges ID HEALTH-CARE UTILIZATION; HEART-FAILURE; MANAGEMENT; COMORBIDITIES; PREVALENCE; HOSPITALIZATION; HYPERURICEMIA; POPULATION; COSTS AB Background: To assess inpatient healthcare burden of gout n the USA after an Emergency Department (ED) visit and the predictors of gout-related hospitalizations. Method: We used the 2009, 2010 and 2012 US National ED Sample (NEDS) data to examine the time trends in inpatient visits with gout as the primary diagnosis. We used the 2012 NEDS data to assess multivariable-adjusted predictors of length of hospital stay, discharge to home (versus other) and total charges for gout-related inpatient visits. Results: Of the 205,152 ED visits for gout as the primary diagnosis in 2012, 77 % resulted in hospitalization. In 2009, 2010 and 2012, 63 36, 63 % and 64.5 36 of hospitalized patients were discharged home; respective durations of hospital stay were 4.15, 4.00 and 3.86 days. Older age 50 to <65 years (ref <50), renal failure, heart failure, osteoarthritis and diabetes were associated with a longer hospital stay and self-pay/uninsured status, hospital location in the Midwest or Western USA with a shorter hospital stay for gout. Similar factors were associated with total charges for gout-related admissions. Older age (65 to <80 and >= 80, relative to <50 years), diabetes, self-pay/no charge insurance status, metropolitan area residence, and a longer length of hospital stay were associated with lower odds of discharge to home; and self-pay/no charge (uninsured) status was associated with higher odds of discharge to borne, compared to Medicare coverage. Conclusions: Using a national sample, we noted declining duration of hospital stay and identified factors associated with the length of hospital stay, discharge to borne and charges for gout hospitalization following an ED visit. Future studies should examine whether better management of comorbidities in patients with gout can further reduce utilization and cost of gout-related hospitalizations. C1 [Singh, Jasvinder A.] Birmingham VA Med Ctr, Med Serv, 700 South 19th St, Birmingham, AL 35233 USA. [Singh, Jasvinder A.; Yu, Shaohua] Univ Alabama Birmingham, Sch Med, Dept Med, 1705 Univ Blvd, Birmingham, AL 35233 USA. [Singh, Jasvinder A.; Yu, Shaohua] Univ Alabama Birmingham, Sch Publ Hlth, Div Epidemiol, 1705 Univ Blvd, Birmingham, AL 35233 USA. [Singh, Jasvinder A.] Mayo Clin, Dept Orthoped Surg, Coll Med, 200 1st St SW, Rochester, MN 55905 USA. RP Singh, JA (reprint author), Birmingham VA Med Ctr, Med Serv, 700 South 19th St, Birmingham, AL 35233 USA.; Singh, JA (reprint author), Univ Alabama Birmingham, Sch Med, Dept Med, 1705 Univ Blvd, Birmingham, AL 35233 USA.; Singh, JA (reprint author), Univ Alabama Birmingham, Sch Publ Hlth, Div Epidemiol, 1705 Univ Blvd, Birmingham, AL 35233 USA.; Singh, JA (reprint author), Mayo Clin, Dept Orthoped Surg, Coll Med, 200 1st St SW, Rochester, MN 55905 USA. EM jassingh@uab.edu FU Univetsity of Alabama at Birmingham (JAB) Division of Rheumatology; National Institute of Arthritis, Musculoskeletal and skin Diseases (NIAMS) [P50 AR060772] FX This material is the resuIt of work supported by research funds from the Univetsity of Alabama at Birmingham (JAB) Division of Rheumatology and the resources and use of facilities at the Birmingham VA Medical Center. JAS is also suppoqed it grant from the National Institute of Arthritis, Musculoskeletal and skin Diseases (NIAMS) P50 AR060772. NR 32 TC 0 Z9 0 U1 2 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1478-6354 EI 1478-6362 J9 ARTHRITIS RES THER JI Arthritis Res. Ther. PD MAR 2 PY 2016 VL 18 DI 10.1186/s13075-016-0936-y PG 10 WC Rheumatology SC Rheumatology GA DF3YU UT WOS:000371285300001 PM 26935737 ER PT J AU Eyler, CE Zietman, AL AF Eyler, Christine E. Zietman, Anthony L. TI A (relatively) risky business: the link between prostatic radiotherapy and second malignancies SO BMJ-BRITISH MEDICAL JOURNAL LA English DT Editorial Material ID ATOMIC-BOMB SURVIVORS; CANCER INCIDENCE; BREAST-CANCER; RADIATION; MORTALITY; LYMPHOMA; DISEASE; MEN C1 [Eyler, Christine E.] Harvard Radiat Oncol Program, Boston, MA USA. [Zietman, Anthony L.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Zietman, AL (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. EM azietman@partners.org NR 15 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 1756-1833 J9 BMJ-BRIT MED J JI BMJ-British Medical Journal PD MAR 2 PY 2016 VL 352 AR i1073 DI 10.1136/bmj.i1073 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA DG0LN UT WOS:000371756500006 PM 26935234 ER PT J AU Gray, NE Harris, CJ Quinn, JF Soumyanath, A AF Gray, Nora E. Harris, Christopher J. Quinn, Joseph F. Soumyanath, Amala TI Centella asiatica modulates antioxidant and mitochondrial pathways and improves cognitive function in mice SO JOURNAL OF ETHNOPHARMACOLOGY LA English DT Article DE Aging; Cognition; Centella asiatica; Mitochondrial dysfunction; Reactive oxygen species ID AMYLOID-BETA TOXICITY; OXIDATIVE STRESS; ALZHEIMERS-DISEASE; NEURODEGENERATIVE DISEASES; SYNAPTIC PLASTICITY; BRAIN-REGIONS; RATS; MEMORY; MOUSE; DYSFUNCTION AB Ethnopharmacological relevance: This study investigates the cognitive enhancing effects of the plant Centella asiatica which is widely used Ayurvedic and traditional Chinese medicine. Aim of the study: The goal of this study was to determine the effects of a water extract of the medicinal plant Centella asiatica (CAW) on cognitive ability as well as mitochondrial and antioxidant response pathways in vivo. Materials and methods: Old and young C57BL/6 mice were treated with CAW (2 mg/mL) in their drinking water. Learning and memory was assessed using Morris Water Maze (MWM) and then tissue was collected and gene expression analyzed. Results: CAW improved performance in the MWM in aged animals and had a modest effect on the performance of young animals. CAW also increased the expression of mitochondria] and antioxidant response genes in the brain and liver of both young and old animals. Expression of synaptic markers was also increased in the hippocampus and frontal cortex, but not in the cerebellum of CAW-treated animals. Conclusions: These data indicate a cognitive enhancing effect of CAW in healthy mice. The gene expression changes caused by CAW suggest a possible effect on mitochondrial biogenesis, which in conjunction with activation of antioxidant response genes could contribute to cognitive improvement. (C) 2016 Elsevier Ireland Ltd. All rights reserved. C1 [Gray, Nora E.; Harris, Christopher J.; Quinn, Joseph F.; Soumyanath, Amala] Oregon Hlth & Sci Univ, Dept Neurol, 3181 SW Sam Jackson Pk Rd, Portland, OR 97239 USA. [Quinn, Joseph F.] Portland VA Med Ctr, Dept Neurol, Portland, OR 97239 USA. [Quinn, Joseph F.] Portland VA Med Ctr, Parkinsons Dis Res Educ & Clin Care Ctr PADRECC, Portland, OR 97239 USA. RP Gray, NE (reprint author), Oregon Hlth & Sci Univ, Dept Neurol, 3181 SW Sam Jackson Pk Rd, Portland, OR 97239 USA. EM grayn@ohsu.edu FU NIH-NCCAM Grant [R01AT008099]; Oregon Alzheimer's Disease Center (OADC) [3P30-AG008017 24 S1]; NIH-NCCAM [AT002688]; Department of Veterans Affairs FX This work was funded by NIH-NCCAM Grant R01AT008099 (Soumyanath), an Oregon Alzheimer's Disease Center (OADC) Grant 3P30-AG008017 24 S1 (Soumyanath), a T32 grant on which N. Gray was a trainee from NIH-NCCAM AT002688, and by a Department of Veterans Affairs Merit Review grant (Quinn). NR 40 TC 1 Z9 1 U1 1 U2 5 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0378-8741 J9 J ETHNOPHARMACOL JI J. Ethnopharmacol. PD MAR 2 PY 2016 VL 180 BP 78 EP 86 DI 10.1016/j.jep.2016.01.013 PG 9 WC Plant Sciences; Chemistry, Medicinal; Integrative & Complementary Medicine; Pharmacology & Pharmacy SC Plant Sciences; Pharmacology & Pharmacy; Integrative & Complementary Medicine GA DF7TN UT WOS:000371560600010 PM 26785167 ER PT J AU Liu, SM Bartnikas, LM Volko, SM Ausubel, FM Tang, DZ AF Liu, Simu Bartnikas, Lisa M. Volko, Sigrid M. Ausubel, Frederick M. Tang, Dingzhong TI Mutation of the Glucosinolate Biosynthesis Enzyme Cytochrome P450 83A1 Monooxygenase Increases Camalexin Accumulation and Powdery Mildew Resistance SO FRONTIERS IN PLANT SCIENCE LA English DT Article DE camalexin; powdery mildew; CYP83A1; plant immunity; Arabidopsis thaliana ID PHYTOALEXIN-DEFICIENT MUTANTS; ETHYLENE-INDUCED SENESCENCE; ARABIDOPSIS-THALIANA; SALICYLIC-ACID; CELL-DEATH; TRANSCRIPTION FACTOR; DISEASE RESISTANCE; DEFENSE RESPONSES; PLANT DEFENSE; SECONDARY METABOLITES AB Small secondary metabolites, including glucosinolates and the major phytoalexin camalexin, play important roles in immunity in Arabidopsis thaliana. We isolated an Arabidopsis mutant with increased resistance to the powdery mildew fungus Golovinomyces cichoracearurn and identified a mutation in the gene encoding cytochrome P450 83A1 monooxygenase (CYP83A1), which functions in glucosinolate biosynthesis. The cyp83a1-3 mutant exhibited enhanced defense responses to G. cichoracearurn and double mutant analysis showed that this enhanced resistance requires NPR1, EDS1, and PAD4, but not SID2 or EDS5. In cyp83a1-3 mutants, the expression of genes related to camalexin synthesis increased upon G. cichoracearurn infection. Significantly, the cyp83a1-3 mutant also accumulated higher levels of camalexin. Decreasing camalexin levels by mutation of the camalexin synthetase gene PAD3 or the camalexin synthesis regulator AtWRKY33 compromised the powdery mildew resistance in these mutants. Consistent with these observations, overexpression of PAD3 increased camalexin levels and enhanced resistance to G. cichoracearum. Taken together, our data indicate that accumulation of higher levels of camalexin contributes to increased resistance to powdery mildew. C1 [Liu, Simu; Tang, Dingzhong] Chinese Acad Sci, Inst Genet & Dev Biol, State Key Lab Plant Cell & Chromosome Engn, Beijing, Peoples R China. [Liu, Simu] Univ Chinese Acad Sci, Beijing, Peoples R China. [Bartnikas, Lisa M.; Volko, Sigrid M.; Ausubel, Frederick M.] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Volko, Sigrid M.; Ausubel, Frederick M.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Bartnikas, Lisa M.] Boston Childrens Hosp, Boston, MA 02115 USA. [Bartnikas, Lisa M.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Liu, Simu] Shenzhen Univ, Coll Life Sci, Shenzhen 518060, Peoples R China. [Volko, Sigrid M.] Nilogen Oncosyst, 3802 Spectrum Blvd,Ste 142E, Tampa, FL 33647 USA. RP Tang, DZ (reprint author), Chinese Acad Sci, Inst Genet & Dev Biol, State Key Lab Plant Cell & Chromosome Engn, Beijing, Peoples R China. EM dztang@genetics.ac.cn FU Strategic Priority Research Program of the Chinese Academy of Sciences [XDB11020100]; National Science Fund for Distinguished Young Scholars of China [31525019]; Ministry of Science and Technology of China [2014DFA31540]; U.S. National Institutes of Health [R37 GM48707]; U.S. National Science Foundation [MCB-0519898, IOS 0929226] FX The work was supported by grants from the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB11020100), National Science Fund for Distinguished Young Scholars of China (31525019), the Ministry of Science and Technology of China (2014DFA31540) to DT, and by U.S. National Institutes of Health grant R37 GM48707 and U.S. National Science Foundation grants MCB-0519898 and IOS 0929226 to FA. NR 56 TC 0 Z9 0 U1 5 U2 20 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1664-462X J9 FRONT PLANT SCI JI Front. Plant Sci. PD MAR 2 PY 2016 VL 7 AR 277 DI 10.3389/fpls.2016.00227 PG 13 WC Plant Sciences SC Plant Sciences GA DF1SZ UT WOS:000371120800001 ER PT J AU Hao, C Yang, SH Xu, WH Shen, JK Ye, SN Liu, XZ Dong, Z Xiao, BJ Feng, Y AF Hao, Cheng Yang, Shuhua Xu, Weihua Shen, Jacson K. Ye, Shunan Liu, Xianzhe Dong, Zhe Xiao, Baojun Feng, Yong TI MiR-708 promotes steroid-induced osteonecrosis of femoral head, suppresses osteogenic differentiation by targeting SMAD3 SO SCIENTIFIC REPORTS LA English DT Article ID MESENCHYMAL STEM-CELLS; TGF-BETA; OSTEOBLAST DIFFERENTIATION; STROMAL CELLS; NONTRAUMATIC OSTEONECROSIS; GENE-EXPRESSION; BONE-FORMATION; PATHWAY; DEXAMETHASONE; CANCER AB Steroid-induced osteonecrosis of femoral head (ONFH) is a serious complication of glucocorticoid (GC) use. We investigated the differential expression of miRs in the mesenchymal stem cells (MSCs) of patients with ONFH, and aimed to explain the relationship between GC use and the development of MSC dysfunction in ONFH. Cells were collected from bone marrow of patients with ONFH. Samples were assigned to either GCs Group or Control Group at 1:1 matched with control. We then used miRNA microarray analysis and real-time PCR to identify the differentially expressed miRs. We also induced normal MSCs with GCs to verify the differential expression above. Subsequently, we selected some of the miRs for further studies, including miRNA target and pathway prediction, and functional analysis. We discovered that miR-708 was upregulated in ONFH patients and GC-treated MSCs. SMAD3 was identified as a direct target gene of miR-708, and functional analysis demonstrated that miR-708 could markedly suppress osteogenic differentiation and adipogenesis differentiation of MSCs. Inhibition of miR-708 rescued the suppressive effect of GC on osteonecrosis. Therefore, we determined that GC use resulted in overexpression of miR-708 in MSCs, and thus, targeting miR-708 may serve as a novel therapeutic biomarker for the prevention and treatment of ONFH. C1 [Hao, Cheng; Yang, Shuhua; Xu, Weihua; Ye, Shunan; Liu, Xianzhe; Dong, Zhe; Xiao, Baojun; Feng, Yong] Huazhong Univ Sci & Technol, Tongji Med Coll, Union Hosp, Orthoped Hosp, Wuhan 430074, Hubei, Peoples R China. [Shen, Jacson K.; Feng, Yong] Massachusetts Gen Hosp, Dept Orthopaed Surg, Sarcoma Biol Lab, 55 Fruit St,Jackson 1115, Boston, MA 02114 USA. [Shen, Jacson K.; Feng, Yong] Harvard Univ, Sch Med, 55 Fruit St,Jackson 1115, Boston, MA 02114 USA. RP Xiao, BJ; Feng, Y (reprint author), Huazhong Univ Sci & Technol, Tongji Med Coll, Union Hosp, Orthoped Hosp, Wuhan 430074, Hubei, Peoples R China.; Feng, Y (reprint author), Massachusetts Gen Hosp, Dept Orthopaed Surg, Sarcoma Biol Lab, 55 Fruit St,Jackson 1115, Boston, MA 02114 USA.; Feng, Y (reprint author), Harvard Univ, Sch Med, 55 Fruit St,Jackson 1115, Boston, MA 02114 USA. EM drxiao999@sohu.com; fengyong1980@gmail.com FU Nature Science Foundation of China [8157090650, 81101375, 81271969, 30973044]; Nature Science Foundation of Hubei [2013CFB104] FX This work was supported by grants from the Nature Science Foundation of China (No. 8157090650, 81101375, 81271969 and 30973044) and Nature Science Foundation of Hubei (2013CFB104). NR 55 TC 2 Z9 2 U1 0 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 MAR 2 PY 2016 VL 6 AR 22599 DI 10.1038/srep22599 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DF2OA UT WOS:000371182000001 PM 26932538 ER PT J AU Hirano, AA Liu, X Boulter, J Grove, J Muller, LPD Barnes, S Brecha, NC AF Hirano, Arlene A. Liu, Xue Boulter, Jim Grove, James Mueller, Luis Perez de Sevilla Barnes, Steven Brecha, Nicholas C. TI Targeted Deletion of Vesicular GABA Transporter from Retinal Horizontal Cells Eliminates Feedback Modulation of Photoreceptor Calcium Channels SO ENEURO LA English DT Article DE Ca channels; Cx57-iCre; GABA receptors; inhibitory feedback; retinal horizontal cells; synaptic vesicles ID GAMMA-AMINOBUTYRIC-ACID; MOUSE RETINA; MAMMALIAN RETINA; GUINEA-PIG; INTRACELLULAR CALCIUM; CONE PHOTORECEPTORS; TRANSMITTER RELEASE; ROD PHOTORECEPTORS; VERTEBRATE RETINA; RABBIT RETINA AB The cellular mechanisms underlying feedback signaling from horizontal cells to photoreceptors, which are important for the formation of receptive field surrounds of early visual neurons, remain unsettled. Mammalian horizontal cells express a complement of synaptic proteins that are necessary and sufficient for calcium-dependent exocytosis of inhibitory neurotransmitters at their contacts with photoreceptor terminals, suggesting that they are capable of releasing GABA via vesicular release. To test whether horizontal cell vesicular release is involved in feedback signaling, we perturbed inhibitory neurotransmission in these cells by targeted deletion of the vesicular GABA transporter (VGAT), the protein responsible for the uptake of inhibitory transmitter by synaptic vesicles. To manipulate horizontal cells selectively, an iCre mouse line with Cre recombinase expression controlled by connexin57 (Cx57) regulatory elements was generated. In Cx57-iCre mouse retina, only horizontal cells expressed Cre protein, and its expression occurred in all retinal regions. After crossing with a VGAT(flox/flox) mouse line, VGAT was selectively eliminated from horizontal cells, which was confirmed immunohistochemically. Voltage-gated ion channel currents in horizontal cells of Cx57-VGAT(-/-) mice were the same as Cx57-VGAT(+/+) controls, as were the cell responses to the ionotropic glutamate receptor agonist kainate, but the response to the GABA(A) receptor agonist muscimol in Cx57-VGAT(-/-) mice was larger. In contrast, the feedback inhibition of photoreceptor calcium channels, which in control animals is induced by horizontal cell depolarization, was completely absent in Cx57-VGAT(-/-) mice. The results suggest that vesicular release of GABA from horizontal cells is required for feedback inhibition of photoreceptors. C1 [Hirano, Arlene A.; Liu, Xue; Grove, James; Mueller, Luis Perez de Sevilla; Barnes, Steven; Brecha, Nicholas C.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurobiol, Los Angeles, CA 90095 USA. [Hirano, Arlene A.; Barnes, Steven; Brecha, Nicholas C.] Vet Adm Greater Los Angeles Healthcare Syst, Los Angeles, CA 90073 USA. [Boulter, Jim] Univ Calif Los Angeles, Semel Inst Neurosci & Human Behav, Dept Psychiat & Biobehav Sci, Hatos Res Ctr Neuropharmacol,David Geffen Sch Med, Los Angeles, CA 90095 USA. [Barnes, Steven] Dalhousie Univ, Dept Physiol & Biophys, Halifax, NS B3H 4R2, Canada. [Barnes, Steven] Dalhousie Univ, Dept Ophthalmol & Visual Sci, Halifax, NS B3H 4R2, Canada. [Brecha, Nicholas C.] Univ Calif Los Angeles, David Geffen Sch Med, Jules Stein Eye Inst, Los Angeles, CA 90095 USA. [Brecha, Nicholas C.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA. [Liu, Xue] Chongqing Univ Sci & Technol, Biomat & Live Cell Imaging Inst, Chongqing 400044, Peoples R China. RP Hirano, AA (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurobiol, Los Angeles, CA 90095 USA. EM ahirano@mednet.ucla.edu FU National Institutes of Health [EY-15573]; UCLA Oppenheimer Seed Grant; Plum Foundation; Veterans Administration Career Scientist Award; Canadian Institutes of Health Research-Nova Scotia Health Research Foundation Regional Partnership Program Grant [MOP10968]; Natural Sciences and Engineering Research Council of Canada Discovery Award [194640] FX This research was supported by National Institutes of Health Grant EY-15573 (N.C.B.), UCLA Oppenheimer Seed Grant (A.A.H., J.B., N.C.B.), the Plum Foundation (S.B., N.C.B.), a Veterans Administration Career Scientist Award (N.C.B.), Canadian Institutes of Health Research-Nova Scotia Health Research Foundation Regional Partnership Program Grant MOP10968 (S.B.), and Natural Sciences and Engineering Research Council of Canada Discovery Award 194640 (S.B.). NR 61 TC 2 Z9 2 U1 0 U2 0 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 2373-2822 J9 ENEURO JI eNeuro PD MAR-APR PY 2016 VL 3 IS 2 AR UNSP e0148-15.2016 DI 10.1523/ENEURO.0148-15.2016 PG 13 WC Neurosciences SC Neurosciences & Neurology GA EH7AY UT WOS:000391926400031 ER PT J AU Schwartz, MD Nguyen, AT Warrier, DR Palmerston, JB Thomas, AM Morairty, SR Neylan, TC Kilduff, TS AF Schwartz, Michael D. Nguyen, Alexander T. Warrier, Deepti R. Palmerston, Jeremiah B. Thomas, Alexia M. Morairty, Stephen R. Neylan, Thomas C. Kilduff, Thomas S. TI Locus Coeruleus and Tuberomammillary Nuclei Ablations Attenuate Hypocretin/Orexin Antagonist-Mediated REM Sleep SO ENEURO LA English DT Article DE arousal; hypnotics; insomnia; monoamine; orexin; paradoxical sleep ID EYE-MOVEMENT SLEEP; ALMOREXANT PROMOTES SLEEP; WAKING CYCLE; HISTAMINERGIC NEURONS; LATERAL HYPOTHALAMUS; RECEPTOR ANTAGONISTS; PONTINE CARBACHOL; OREXIN RECEPTOR-1; PARADOXICAL SLEEP; FOS EXPRESSION AB Hypocretin 1 and 2 (Hcrts; also known as orexin A and B), excitatory neuropeptides synthesized in cells located in the tuberal hypothalamus, play a central role in the control of arousal. Hcrt inputs to the locus coeruleus norepinephrine (LC NE) system and the posterior hypothalamic histaminergic tuberomammillary nuclei (TMN HA) are important efferent pathways for Hcrt-induced wakefulness. The LC expresses Hcrt receptor 1 (HcrtR1), whereas HcrtR2 is found in the TMN. Although the dual Hcrt/orexin receptor antagonist almorexant (ALM) decreases wakefulness and increases NREM and REM sleep time, the neural circuitry that mediates these effects is currently unknown. To test the hypothesis that ALM induces sleep by selectively disfacilitating subcortical wake-promoting populations, we ablated LC NE neurons (LCx) or TMN HA neurons (TMNx) in rats using cell-type-specific saporin conjugates and evaluated sleep/wake following treatment with ALM and the GABAA receptor modulator zolpidem (ZOL). Both LCx and TMNx attenuated the promotion of REM sleep by ALM without affecting ALM-mediated increases in NREM sleep. Thus, eliminating either HcrtR1 signaling in the LC or HcrtR2 signaling in the TMN yields similar effects on ALM-induced REM sleep without affecting NREM sleep time. In contrast, neither lesion altered ZOL efficacy on any measure of sleep-wake regulation. These results contrast with those of a previous study in which ablation of basal forebrain cholinergic neurons attenuated ALM-induced increases in NREM sleep time without affecting REM sleep, indicating that Hcrt neurotransmission influences distinct aspects of NREM and REM sleep at different locations in the sleep-wake regulatory network. C1 [Schwartz, Michael D.; Nguyen, Alexander T.; Warrier, Deepti R.; Palmerston, Jeremiah B.; Thomas, Alexia M.; Morairty, Stephen R.; Kilduff, Thomas S.] SRI Int, Biosci Div, Ctr Neurosci, 333 Ravenswood Ave, Menlo Pk, CA 94025 USA. [Neylan, Thomas C.] Univ Calif San Francisco, San Francisco VA Med Ctr, NCIRE, San Francisco, CA 94121 USA. RP Kilduff, TS (reprint author), SRI Int, 333 Ravenswood Ave, Menlo Pk, CA 94025 USA. EM thomas.kilduff@sri.com OI Kilduff, Thomas/0000-0002-6823-0094 FU U.S. Army Medical Research Acquisition Activity [W81XWH-09-2-0081]; NIH [R01 NS077408] FX This work was supported by the U.S. Army Medical Research Acquisition Activity award number W81XWH-09-2-0081 and NIH R01 NS077408 to T.S.K. We thank Drs Priyattam J. Shiromani and Carlos Blanco-Centurion for providing Hcrt2-SAP; Tsui-Ming Chen, Alan Wilk, and Dr Simon Fisher for technical assistance; Dr Ling Jong for synthesis of almorexant; and Drs Sarah Black and Gregory Parks for helpful comments on data analysis and the paper. NR 77 TC 0 Z9 0 U1 0 U2 0 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 2373-2822 J9 ENEURO JI eNeuro PD MAR-APR PY 2016 VL 3 IS 2 AR UNSP e0018-16.2016 DI 10.1523/ENEURO.0018-16.2016 PG 16 WC Neurosciences SC Neurosciences & Neurology GA EH7AY UT WOS:000391926400007 ER PT J AU Ellis, C Hoffman, W Jaehnert, S Plagge, J Loftis, JM Schwartz, D Huckans, M AF Ellis, Carilyn Hoffman, William Jaehnert, Sarah Plagge, Jane Loftis, Jennifer M. Schwartz, Daniel Huckans, Marilyn TI Everyday Problems With Executive Dysfunction and Impulsivity in Adults Recovering From Methamphetamine Addiction SO ADDICTIVE DISORDERS & THEIR TREATMENT LA English DT Article DE methamphetamine; impulsivity; executive function ID DEPENDENT INDIVIDUALS; ABUSE; USERS; SYMPTOMS; THERAPY AB Objectives: Compared with nonaddicted controls (CTLs), adults in remission from methamphetamine addiction (MAREM) evidence impairments on objective measures of executive functioning and impulsivity. Methods: To evaluate the impact of these impairments in MA-REM adults, demographically matched groups (MA-REM, n=30; CTLs, n=24) completed objective and self-report measures of executive functioning and impulsivity. Results: MA-REMadults demonstrated significantly (P < 0.050) greater objective and subjective problems with executive functioning and impulsivity. Conclusions: These results suggest that adults in MA-REM are aware of their deficits and that these deficits have significant impact in everyday life. C1 [Ellis, Carilyn; Hoffman, William; Jaehnert, Sarah; Loftis, Jennifer M.; Schwartz, Daniel; Huckans, Marilyn] Portland VA Med Ctr, Res & Dev Serv, Portland, OR 97239 USA. [Ellis, Carilyn; Hoffman, William; Jaehnert, Sarah; Plagge, Jane; Huckans, Marilyn] Portland VA Med Ctr, Behav Hlth & Clin Neurosci Div, Portland, OR 97239 USA. [Ellis, Carilyn; Hoffman, William; Jaehnert, Sarah; Loftis, Jennifer M.; Schwartz, Daniel; Huckans, Marilyn] Oregon Hlth & Sci Univ, Sch Med, Methamphetamine Abuse Res Ctr, Portland, OR 97201 USA. [Hoffman, William; Loftis, Jennifer M.; Schwartz, Daniel; Huckans, Marilyn] Oregon Hlth & Sci Univ, Sch Med, Dept Psychiat, Portland, OR 97201 USA. [Hoffman, William; Huckans, Marilyn] Oregon Hlth & Sci Univ, Sch Med, Dept Behav Neurosci, Portland, OR 97201 USA. [Ellis, Carilyn] George Fox Univ, Grad Dept Clin Psychol, Newberg, OR USA. [Jaehnert, Sarah] Univ Pacific, Sch Profess Psychol, Hillsboro, OR USA. RP Huckans, M (reprint author), Portland VA Med Ctr, P3MHN,3710 SW US Vet Hosp Rd, Portland, OR 97239 USA. EM marilyn.huckans@va.gov FU BLRD VA [I01 BX002061]; NIDA NIH HHS [P50 DA018165] NR 28 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 1531-5754 EI 1535-1122 J9 ADDICT DISORD TREAT JI Addict. Disord. Treat. PD MAR PY 2016 VL 15 IS 1 BP 1 EP 5 DI 10.1097/ADT.0000000000000059 PG 5 WC Substance Abuse SC Substance Abuse GA EE5QZ UT WOS:000389664100001 PM 27034621 ER PT J AU Bakhshaie, J Ditre, JW Langdon, KJ Zvolensky, MJ AF Bakhshaie, Jafar Ditre, Joseph W. Langdon, Kirsten J. Zvolensky, Michael J. TI Past-month Pain and Cognitive-affective Smoking Processes Among Daily Smokers SO ADDICTIVE DISORDERS & THEIR TREATMENT LA English DT Article DE pain; tobacco; smoking; abstinence; cognition; affect ID FAGERSTROM TOLERANCE QUESTIONNAIRE; ABSTINENCE-RELATED EXPECTANCIES; LOW-BACK-PAIN; NICOTINE DEPENDENCE; CIGARETTE-SMOKING; ANXIETY SENSITIVITY; REPRESENTATIVE SAMPLE; MUSCULOSKELETAL PAIN; CESSATION; POPULATION AB Objectives: Initial evidence suggests that pain may motivate smoking, impede quitting, precipitate relapse, and play an important role in the maintenance of tobacco addiction. Despite this emerging literature, little is known about how cognitive-affective smoking processes may differ as a function of comorbid pain status. The goal of the current study was to test cross-sectional relations between past-month pain and reasons for quitting smoking, somatic symptom-related abstinence expectancies, and symptoms experienced during the most recent quit attempt, among a sample of daily tobacco smokers who were willing to engage in an unaided quit attempt. Methods: Participants included 109 adult smokers (34.9% female; M-age = 32.9, SD = 13.6) who were recruited to participate in an unaided quit attempt. Results: Smokers who endorsed past-month pain reported more reasons for quitting smoking, higher levels of somatic symptoms-related abstinence expectancies, and greater number of problems experienced during their most recent quit attempt. Conclusions: The present study serves as an initial investigation into the nature of current levels of pain in relation to a variety of cognitive-affective aspects of smoking. Clinical strategies that modify the pain experience may enhance motivation to quit and facilitate success in quitting. C1 [Bakhshaie, Jafar; Zvolensky, Michael J.] Univ Houston, Dept Psychol, Houston, TX 77024 USA. [Zvolensky, Michael J.] Univ Texas MD Anderson Canc Ctr, Dept Behav Sci, Houston, TX 77030 USA. [Ditre, Joseph W.] Syracuse Univ, Dept Psychol, Syracuse, NY USA. [Langdon, Kirsten J.] VA Boston Healthcare Syst, Natl Ctr PTSD, Womens Hlth Sci Div, Jamaica Plain, MA USA. [Langdon, Kirsten J.] Boston Univ, Sch Med, Dept Psychiat, Boston, MA 02118 USA. RP Bakhshaie, J (reprint author), Univ Houston, AHRL, 126 Heyne Bldg, Houston, TX 77024 USA.; Bakhshaie, J (reprint author), Univ Houston, SUTC, 126 Heyne Bldg, Houston, TX 77024 USA. EM jbakhshaie@uh.edu NR 54 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 1531-5754 EI 1535-1122 J9 ADDICT DISORD TREAT JI Addict. Disord. Treat. PD MAR PY 2016 VL 15 IS 1 BP 34 EP 41 DI 10.1097/ADT.0000000000000073 PG 8 WC Substance Abuse SC Substance Abuse GA EE5QZ UT WOS:000389664100005 ER PT J AU Miller, JW AF Miller, Joan W. TI VEGF: From Discovery to Therapy: The Champalimaud Award Lecture SO TRANSLATIONAL VISION SCIENCE & TECHNOLOGY LA English DT Article DE age-related macular degeneration (AMD); angiogenesis; Antonio Champalimaud Vision Award; Factor X; vascular endothelial growth factor (VEGF) ID ENDOTHELIAL GROWTH-FACTOR; VASCULAR-PERMEABILITY FACTOR; DIABETIC MACULAR EDEMA; RETINAL VEIN OCCLUSION; EXPERIMENTAL CHOROIDAL NEOVASCULARIZATION; RANIBIZUMAB PLUS PROMPT; NONHUMAN PRIMATE; INTRAVITREAL AFLIBERCEPT; IRIS NEOVASCULARIZATION; ANGIOGENIC ACTIVITY AB Purpose: Intraocular vascular diseases are leading causes of adult vision loss, and in the mid-1900s, I. C. Michaelson postulated that the retina releases a soluble, diffusible factor that causes abnormal vascular growth and leakage. What became known as "Factor X'' eluded investigators for decades. Methods: The field of cancer research, where Judah Folkman pioneered the concept of angiogenesis, provided the inspiration for the work honored by the 2014 Champalimaud Vision Award. Recognizing that tumors recruit their own blood supply to achieve critical mass, Dr Folkman proposed that angiogenic factors could be therapeutic targets in cancer. Napoleone Ferrara identified vascular endothelial growth factor (VEGF) as such an angiogenic agent: stimulated by hypoxic tumor tissue, secreted, and able to induce neovascularization. VEGF also was a candidate for Factor X, and the 2014 Champalimaud Laureates and colleagues worked individually and collaboratively to identify the role of VEGF in ocular disease. Results: The Champalimaud Laureates correlated VEGF with ocular neovascularization in animal models and in patients. Moreover, they showed that VEGF not only was sufficient, but it also was required to induce neovascularization in normal animal eyes, as VEGF inhibition abolished ocular neovascularization in key animal models. Conclusions: The identification of VEGF as Factor X altered the therapeutic paradigms for age-related macular degeneration (AMD), diabetic retinopathy, retinal vein occlusion, and other retinal disorders. Translational Relevance: The translation of VEGF from discovery to therapy resulted in the most successful applications of antiangiogenic therapy to date. Annually, over one million patients with eye disease are treated with anti-VEGF agents. C1 [Miller, Joan W.] Harvard Med Sch, Dept Ophthalmol, Massachusetts Eye & Ear, Massachusetts Gen Hosp, 243 Charles St, Boston, MA 02114 USA. RP Miller, JW (reprint author), Harvard Med Sch, Dept Ophthalmol, Massachusetts Eye & Ear, Massachusetts Gen Hosp, 243 Charles St, Boston, MA 02114 USA. EM Joan_Miller@meei.harvard.edu NR 47 TC 5 Z9 5 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 2164-2591 J9 TRANSL VIS SCI TECHN JI Transl. Vis. Sci. Technol. PD MAR PY 2016 VL 5 IS 2 AR 9 DI 10.1167/tvst.5.2.9 PG 13 WC Ophthalmology SC Ophthalmology GA ED2JD UT WOS:000388669300009 ER PT J AU Robert, MC Frenette, M Zhou, C Yan, Y Chodosh, J Jakobiec, FA Stagner, AM Vavvas, D Dohlman, CH Paschalis, EI AF Robert, Marie-Claude Frenette, Mathieu Zhou, Chengxin Yan, Yueran Chodosh, James Jakobiec, Frederick A. Stagner, Anna M. Vavvas, Demetrios Dohlman, Claes H. Paschalis, Eleftherios I. TI A Drug Delivery System for Administration of Anti-TNF-alpha Antibody SO TRANSLATIONAL VISION SCIENCE & TECHNOLOGY LA English DT Article DE polydimethylsiloxane; tumor necrosis factor alpha; drug delivery system; biologics; sustained-release; burn ID PERIPHERAL ULCERATIVE KERATITIS; DIABETIC MACULAR EDEMA; NECROSIS-FACTOR-ALPHA; CONTACT-LENSES; CORNEAL NEOVASCULARIZATION; TOPICAL INFLIXIMAB; BEVACIZUMAB; INHIBITORS AB Purpose: To describe the fabrication, evaluation, and preliminary in vivo safety of a new drug delivery system (DDS) for topical anti-TNF-alpha antibody administration. Methods: A DDS was fabricated using inverse template fabrication of a hydrophobic three-dimensional porous scaffold (100-300 mu m in diameter porosity) loaded with 10% polyvinyl alcohol hydrogel carrying 5 mg/ml (weight/volume) of anti-TNF-alpha antibody. Drug-loaded DDS was sterilized with 25 kGy of gamma irradiation. Long-term in vitro antibody affinity and release was evaluated at room temperature or 37 degrees C using enzyme-linked immunosorbent assay (ELISA) and protein fluorescence. In vivo clinical and histolopathological assessment was performed by subcutaneous implantation in BALB/c mice for 3 months. Results: Gamma irradiation, repeated dry/wet cycles, and storage at room temperature for 1 year or 37 degrees C for 1 month had no deleterious effects on antibody affinity. Anti-TNF-alpha release was high during the first minutes of aqueous exposure, followed by stabilization and gradual, low-dose, antibody release over the next 30 days. Histopathologic evaluation of explanted DDS showed a fibrous pseudocapsule and a myxoid acute/chronic inflammation without granuloma formation surrounding the implants. Conclusions: Sustained local delivery of anti-TNF-alpha antibody is feasible using the described DDS, which provides stability of the enclosed antibody for up to 1 year of storage. Preliminary results show good in vivo tolerance following subcutaneous placement for 3 months. The proposed fabrication and sterilization process opens new possibilities for the delivery of biologic agents to the anterior surface of the eye. Translational Relevance: The described DDS will facilitate the treatment of ocular surface diseases amenable to biologic therapy. C1 [Robert, Marie-Claude; Zhou, Chengxin; Chodosh, James; Jakobiec, Frederick A.; Stagner, Anna M.; Dohlman, Claes H.; Paschalis, Eleftherios I.] Harvard Med Sch, Dept Ophthalmol, Massachusetts Eye & Ear Infirm, Boston, MA USA. [Robert, Marie-Claude; Dohlman, Claes H.; Paschalis, Eleftherios I.] Harvard Med Sch, Boston Keratoprosthesis Lab, Schepens Eye Res Inst, Massachusetts Eye & Ear Infirm, Boston, MA USA. [Frenette, Mathieu] Univ Quebec, Dept Chem, Montreal, PQ, Canada. [Yan, Yueran; Vavvas, Demetrios] Harvard Med Sch, Angiogenesis Lab, Dept Ophthalmol, Massachusetts Eye & Ear Infirm, Boston, MA USA. [Jakobiec, Frederick A.; Stagner, Anna M.] Harvard Med Sch, David G Cogan Lab Ophthalm Pathol, Massachusetts Eye & Ear Infirm, Boston, MA USA. RP Paschalis, EI (reprint author), Harvard Med Sch, Boston Keratoprosthesis Lab, Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Boston, MA 02114 USA.; Paschalis, EI (reprint author), Harvard Med Sch, Schepens Eye Res Inst, Boston, MA 02114 USA. EM eleftherios_paschalis@meei.harvard.edu FU Boston Keratoprosthesis Research Fund; Massachusetts Eye and Ear; Eleanor and Miles Shore Fund FX Supported by grants from the Boston Keratoprosthesis Research Fund, Massachusetts Eye and Ear, and the Eleanor and Miles Shore Fund. NR 46 TC 2 Z9 2 U1 1 U2 1 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 2164-2591 J9 TRANSL VIS SCI TECHN JI Transl. Vis. Sci. Technol. PD MAR PY 2016 VL 5 IS 2 AR 11 DI 10.1167/tvst.5.2.11 PG 11 WC Ophthalmology SC Ophthalmology GA ED2JD UT WOS:000388669300011 PM 26981333 ER PT J AU Salvador-Culla, B Jeong, KJ Kolovou, PE Chiang, HH Chodosh, J Dohlman, CH Kohane, DS AF Salvador-Culla, Borja Jeong, Kyung Jae Kolovou, Paraskevi Evi Chiang, Homer H. Chodosh, James Dohlman, Claes H. Kohane, Daniel S. TI Titanium Coating of the Boston Keratoprosthesis SO TRANSLATIONAL VISION SCIENCE & TECHNOLOGY LA English DT Article DE keratoprosthesis; Boston Keratoprosthesis; artificial cornea; titanium coating; titanium oxide; titanium skirt; biointegration; corneal adhesion; titanium adhesion ID OSTEOBLAST-LIKE CELLS; TYPE-1 KERATOPROSTHESIS; SURFACE-ROUGHNESS; HYDROXYAPATITE; MULTICENTER; ENDOPHTHALMITIS; IMPLANTATION; TOMOGRAPHY; RETENTION; EFFICACY AB Purpose: We tested the feasibility of using titanium to enhance adhesion of the Boston Keratoprosthesis (B-KPro), ultimately to decrease the risk of implant-associated complications. Methods: Cylindrical rods were made of poly(methyl methacrylate) (PMMA), PMMA coated with titanium dioxide (TiO2) over a layer of polydopamine (PMMA(TiO2)), smooth (Ti) and sandblasted (Ti-SB) titanium, and titanium treated with oxygen plasma (Ti-ox and Ti-SBox). Topography and surface chemistry were analyzed by scanning electron microscopy (SEM), atomic force microscopy (AFM), and X-ray photoelectron spectroscopy (XPS). Adhesion force between rods and porcine corneas was measured ex vivo. Titanium sleeves, smooth and sandblasted, were inserted around the stem of the B-KPro and implanted in rabbits. Tissue adhesion to the stem was assessed and compared to an unmodified B-Kpro after 1 month. Results: X-ray photoelectron spectroscopy demonstrated successful deposition of TiO2 on polydopamine-coated PMMA. Oxygen plasma treatment did not change the XPS spectra of titanium rods (Ti and Ti-SB), although it increased their hydrophilicity. The materials did not show cell toxicity. After 14 days of incubation, PMMA(TiO2), smooth titanium treated with oxygen plasma (Ti-ox), and sandblasted titanium rods (Ti-SB, Ti-SBox) showed significantly higher adhesion forces than PMMA ex vivo. In vivo, the use of a Ti-SB sleeve around the stem of the B-KPro induced a significant increase in tissue adhesion compared to a Ti sleeve or bare PMMA. Conclusions: Sandblasted titanium sleeves greatly enhanced adherence of the B-KPro to the rabbit cornea. This approach may improve adhesion with the donor cornea in humans as well. Translational Relevance: This approach may improve adhesion with donor corneas in humans. C1 [Salvador-Culla, Borja; Kolovou, Paraskevi Evi; Chodosh, James; Dohlman, Claes H.] Harvard Med Sch, Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Boston, MA USA. [Salvador-Culla, Borja; Chiang, Homer H.; Kohane, Daniel S.] Harvard Med Sch, Lab Biomat & Drug Delivery, Dept Anesthesiol, Div Crit Care Med,Childrens Hosp Boston, Boston, MA USA. [Salvador-Culla, Borja; Chiang, Homer H.] MIT, David H Koch Inst Integrat Canc Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Jeong, Kyung Jae] Univ New Hampshire, Dept Chem Engn, Durham, NH 03824 USA. RP Kohane, DS (reprint author), Boston Childrens Hosp, 300 Longwood Ave,Enders 361, Boston, MA 02115 USA. EM Daniel.Kohane@childrens.harvard.edu FU Keratoprosthesis Fund, Massachusetts Eye and Ear Infirmary, Boston, MA, USA [R01 GM073626] FX Supported by the Keratoprosthesis Fund, Massachusetts Eye and Ear Infirmary, Boston, MA, USA, and R01 GM073626; DSK. The authors alone are responsible for the content and writing of this paper. NR 40 TC 1 Z9 1 U1 2 U2 2 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 2164-2591 J9 TRANSL VIS SCI TECHN JI Transl. Vis. Sci. Technol. PD MAR PY 2016 VL 5 IS 2 AR 17 DI 10.1167/tvst.5.2.17 PG 12 WC Ophthalmology SC Ophthalmology GA ED2JD UT WOS:000388669300017 PM 27152247 ER PT J AU Waks, AG King, TA Winer, EP AF Waks, Adrienne G. King, Tari A. Winer, Eric P. TI Timeliness in Breast Cancer Treatment-The Sooner, the Better SO JAMA ONCOLOGY LA English DT Editorial Material ID ADJUVANT CHEMOTHERAPY; INITIATION; SURVIVAL; IMPACT; TUMORS; TIME C1 [Waks, Adrienne G.; Winer, Eric P.] Brigham & Womens Canc Ctr, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA USA. [King, Tari A.] Brigham & Womens Hosp, Dana Farber Canc Inst, Dept Surg Oncol, 75 Francis St, Boston, MA 02115 USA. RP Winer, EP (reprint author), Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave, Boston, MA 02215 USA. EM eric_winer@dfci.harvard.edu NR 14 TC 2 Z9 2 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 MAR PY 2016 VL 2 IS 3 BP 302 EP 304 DI 10.1001/jamaoncol.2015.4506 PG 3 WC Oncology SC Oncology GA DW5JX UT WOS:000383681700006 PM 26658500 ER PT J AU Sacher, AG Dahlberg, SE Heng, J Mach, S Janne, PA Oxnard, GR AF Sacher, Adrian G. Dahlberg, Suzanne E. Heng, Jennifer Mach, Stacy Janne, Pasi A. Oxnard, Geoffrey R. TI Association Between Younger Age and Targetable Genomic Alterations and Prognosis in Non-Small-Cell Lung Cancer SO JAMA ONCOLOGY LA English DT Article ID ACUTE LYMPHOBLASTIC-LEUKEMIA; COLORECTAL-CANCER; BREAST-CANCER; EGFR MUTATIONS; BRAF MUTATIONS; NEVER-SMOKERS; GROUP-B; WOMEN; ADENOCARCINOMAS; ADOLESCENTS AB IMPORTANCE Non-small-cell lung cancer (NSCLC) diagnosed in young patients is rare, and the genomics and clinical characteristics of this disease are poorly understood. In contrast, the diagnosis of other cancers at a young age has been demonstrated to define unique disease biology. Herein, we report on the association of young age with targetable genomic alterations and prognosis in a cohort of 2237 patients with NSCLC. OBJECTIVE To determine the relationship between young age at diagnosis and the presence of a potentially targetable genomic alteration, disease prognosis, and natural history. DESIGN, SETTING, AND PARTICIPANTS A cohort of all 2237 patients with NSCLC who were genotyped at the Dana-Farber Cancer Institute between January 2002 and December 2014 were identified. Tumor genotype, patient characteristics, and clinical outcomes were collected and studied at a National Cancer Institute-designated comprehensive cancer center. Multivariate logistic regression was used to analyze the relationship between age and mutation status, and multivariate Cox proportional hazard models were fitted for survival analysis. MAIN OUTCOMES AND MEASURES The frequency of targetable genomic alterations by defined age categories as well as the association of these age groups with survival. Age categories used in this analysis were younger than 40, 40 to 49, 50 to 59, 60 to 69, and 70 years or older. RESULTS A cohort of 2237 patients with NSCLC was studied. Of the 2237 participants, 1939 (87%) had histologically confirmed adenocarcinoma, 269 (12%) had NSCLC not otherwise specified, and 29 (1%) had squamous histologic findings; 1396 (63%) had either stage IIIB or IV cancers; and median (range) age was 62 (20-95) years. We found that gene mutations for EGFR (P=.02) and ALK (P <.001) were associated with cancer diagnosis at a younger age, and a similar trend existed for ERBB2 (P =.15) and ROS1 (P=.10) but not BRAF V600E (P=.43). Among patients tested for all 5 targetable genomic alterations (n = 1325), younger age was associated with an increased frequency of a targetable genotype (P <.001). Those diagnosed at 50 years or younger have a 59% increased likelihood of harboring a targetable genotype. While presence of a potentially targetable genomic alteration treated with a targeted agent was associated with improved survival, the youngest and oldest age groups had similarly poor outcomes even when a targetable genotype was present. CONCLUSIONS AND RELEVANCE Younger age is associated with an increased likelihood of harboring a targetable genotype and is an underappreciated clinical biomarker in NSCLC. The survival of young patients with NCSLC is unexpectedly poor compared with other age groups, suggesting more aggressive disease biology. These findings underscore the importance of comprehensive genotyping, including next-generation sequencing, in younger patients with lung cancer. C1 [Sacher, Adrian G.; Heng, Jennifer; Mach, Stacy; Janne, Pasi A.; Oxnard, Geoffrey R.] Dana Farber Canc Inst, Lowe Ctr Thorac Oncol, Boston, MA 02115 USA. [Sacher, Adrian G.; Janne, Pasi A.; Oxnard, Geoffrey R.] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. [Sacher, Adrian G.; Janne, Pasi A.; Oxnard, Geoffrey R.] Harvard Med Sch, Boston, MA USA. [Dahlberg, Suzanne E.] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Dahlberg, Suzanne E.] Harvard TH Chan Sch Publ Hlth, Boston, MA USA. [Janne, Pasi A.] Dana Farber Canc Inst, Belfer Inst Appl Canc Sci, Boston, MA 02115 USA. RP Oxnard, GR (reprint author), Dana Farber Canc Inst, 450 Brookline Ave,Dana 1234, Boston, MA 02215 USA. EM Geoffrey_oxnard@dfci.harvard.edu RI Sacher, Adrian/I-8080-2016 OI Sacher, Adrian/0000-0001-7865-2701 FU National Cancer Institute of the National Institutes of Health [R01CA114465, P50CA090578]; Conquer Cancer Foundation of the American Society of Clinical Oncology; Bonnie J. Addario Lung Cancer Foundation; Canadian Institutes of Health Research; Canadian Association of Medical Oncologists; Gallup Research Fund; Kaplan Research Fund FX This study was supported by the National Cancer Institute of the National Institutes of Health (grants R01CA114465 and P50CA090578), the Conquer Cancer Foundation of the American Society of Clinical Oncology, the Bonnie J. Addario Lung Cancer Foundation, the Canadian Institutes of Health Research, the Canadian Association of Medical Oncologists, the Gallup Research Fund, and the Kaplan Research Fund. NR 46 TC 6 Z9 6 U1 2 U2 3 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 MAR PY 2016 VL 2 IS 3 BP 313 EP 320 DI 10.1001/jamaoncol.2015.4482 PG 8 WC Oncology SC Oncology GA DW5JX UT WOS:000383681700008 PM 26720421 ER PT J AU Swisher, EM Harrell, MI Norquist, BM Walsh, T Brady, M Lee, M Hershberg, R Kalli, KR Lankes, H Konnick, EQ Pritchard, CC Monk, BJ Chan, JK Burger, R Kaufmann, SH Birrer, MJ AF Swisher, Elizabeth M. Harrell, Maria I. Norquist, Barbara M. Walsh, Tom Brady, Mark Lee, Ming Hershberg, Robert Kalli, Kimberly R. Lankes, Heather Konnick, Eric Q. Pritchard, Colin C. Monk, Bradley J. Chan, John K. Burger, Robert Kaufmann, Scott H. Birrer, Michael J. TI Somatic Mosaic Mutations in PPM1D and TP53 in the Blood of Women With Ovarian Carcinoma SO JAMA ONCOLOGY LA English DT Article ID FALLOPIAN-TUBE; CANCER; BREAST; GENES AB IMPORTANCE Somatic mosaic mutations in PPM1D have been reported in patients with breast cancer, lung cancer, and ovarian cancer (OC), but cause or effect has not been established. OBSERVATIONS To test the hypothesis that somatic mosaic mutations are associated with chemotherapy exposure, we used massively parallel sequencing to quantitate mutations in peripheral blood mononuclear cells (PBMCs) of 686 women with primary OC (n = 412) or relapsed OC (n = 274). The frequency of somatic mosaic PPM1D mutations in PBMCs was significantly associated with prior chemotherapy (P < .001), and, in patients exposed to chemotherapy, with older age at blood draw (recurrent OC odds ratio [OR], 17.24; 95% CI, 6.80-43.69; and primary OC postchemotherapy OR, 4.82; 95% CI, 1.43-16.18). In contrast, somatic mosaic mutations in TP53 were not significantly associated with chemotherapy or age. In sequential PBMC samples harvested from 13 patients with OC near diagnosis and after a median of 2 different chemotherapy regimens, somatic mosaic PPM1D mutations increased in 11 individuals (84.6%) and TP53 mutations appeared in 2 (15.4%). CONCLUSIONS AND RELEVANCE Chemotherapy exposure and age influence the accumulation of PPM1D-mutated PBMC clones. Care should be taken to control for chemotherapy exposure and age at blood draw when testing the association of somatic mosaic mutations in PBMCs with cancer risk. C1 [Swisher, Elizabeth M.; Harrell, Maria I.; Norquist, Barbara M.] Univ Washington, Dept Obstet & Gynecol, Seattle, WA 98195 USA. [Walsh, Tom; Lee, Ming] Univ Washington, Dept Med, Seattle, WA USA. [Brady, Mark; Lankes, Heather] NRG Oncol, Stat Off, Buffalo, NY USA. [Hershberg, Robert] VentiRx Pharmaceut, Seattle, WA USA. [Kalli, Kimberly R.; Kaufmann, Scott H.] Mayo Clin, Dept Oncol, Rochester, MN USA. [Konnick, Eric Q.; Pritchard, Colin C.] Univ Washington, Dept Lab Med, Seattle, WA 98195 USA. [Monk, Bradley J.] St Josephs Hosp, Div Gynecol Oncol, Phoenix, AZ USA. [Chan, John K.] Palo Alto Sutter Hlth, Calif Pacific Med Ctr, Div Gynecol Oncol, San Francisco, CA USA. [Burger, Robert] Univ Penn, Dept Obstet & Gynecol, Philadelphia, PA 19104 USA. [Birrer, Michael J.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. RP Swisher, EM (reprint author), Univ Washington, Med Ctr, Dept Obstet & Gynecol, Box 356460, Seattle, WA 98195 USA. EM swishere@uw.edu OI Kaufmann, Scott/0000-0002-4900-7145 FU National Cancer Institute [U10 CA27469, U24 CA114793, U10 CA180868]; Mayo Clinic SPORE in Ovarian Cancer [P50 CA136393]; Ovarian Cancer Research Fund; Wendy Feuer Fund for the Prevention and Treatment of Ovarian Cancer; Department of Defense CDMRP award [PC131820]; Prostate Cancer Foundation Young Investigator award and SU2C (Stand Up To Cancer), Ovarian Cancer Research Fund, Ovarian Cancer National Alliance, National Ovarian Cancer Coalition Dream Team Translational Research Grant [SU2C-AACR-DT16-15] FX This study was supported by National Cancer Institute grants to the Gynecologic Oncology Group Tissue Bank (grants U10 CA27469, U24 CA114793, and U10 CA180868) and Mayo Clinic SPORE in Ovarian Cancer (grant No. P50 CA136393), as well as the Ovarian Cancer Research Fund (ES, SK), the Wendy Feuer Fund for the Prevention and Treatment of Ovarian Cancer (ES, BN), The Department of Defense CDMRP award (PC131820, CP), and the Prostate Cancer Foundation Young Investigator award (CP) and SU2C (Stand Up To Cancer), Ovarian Cancer Research Fund, Ovarian Cancer National Alliance, National Ovarian Cancer Coalition Dream Team Translational Research Grant (grant No. SU2C-AACR-DT16-15). SU2C is a program of the Entertainment Industry Foundation. Research grants are administered by the American Association for Cancer Research, a scientific partner of SU2C (ES, SK, BN). NR 7 TC 8 Z9 8 U1 1 U2 2 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 MAR PY 2016 VL 2 IS 3 BP 370 EP 372 DI 10.1001/jamaoncol.2015.6053 PG 3 WC Oncology SC Oncology GA DW5JX UT WOS:000383681700019 PM 26847329 ER PT J AU Katz, MS Utengen, A Anderson, PF Thompson, MA Attai, DJ Johnston, C Dizon, DS AF Katz, Matthew S. Utengen, Audun Anderson, Patricia F. Thompson, Michael A. Attai, Deanna J. Johnston, Claire Dizon, Don S. TI Disease-Specific Hashtags for Online Communication About Cancer Care SO JAMA ONCOLOGY LA English DT Letter C1 [Katz, Matthew S.] Lowell Gen Hosp, Dept Radiat Med, Lowell, MA USA. [Utengen, Audun] Symplur LLC, Los Angeles, CA USA. [Anderson, Patricia F.] Univ Michigan, Taubman Hlth Sci Lib, Ann Arbor, MI 48109 USA. [Thompson, Michael A.] Aurora Hlth Care, Aurora Res Inst, Milwaukee, WI USA. [Attai, Deanna J.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Surg, Los Angeles, CA 90095 USA. [Johnston, Claire] Amer Soc Clin Oncol, Alexandria, VA USA. [Dizon, Don S.] Massachusetts Gen Hosp, Gillette Ctr Gynecol Oncol, Boston, MA 02114 USA. RP Katz, MS (reprint author), Lowell Gen Hosp, 295 Varnum Ave, Lowell, MA 01854 USA. EM Matthew.Katz@lowellgeneral.org OI Utengen, Audun/0000-0003-4851-269X NR 5 TC 8 Z9 8 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 MAR PY 2016 VL 2 IS 3 BP 392 EP 394 DI 10.1001/jamaoncol.2015.3960 PG 4 WC Oncology SC Oncology GA DW5JX UT WOS:000383681700027 PM 26539640 ER PT J AU Fox, AB Hamilton, AB Frayne, SM Wiltsey-Stirman, S Bean-Mayberry, B Carney, D Di Leone, BAL Gierisch, JM Goldstein, KM Romodan, Y Sadler, AG Yano, EM Yee, EF Vogt, D AF Fox, Annie B. Hamilton, Alison B. Frayne, Susan M. Wiltsey-Stirman, Shannon Bean-Mayberry, Bevanne Carney, Diane Di Leone, Brooke A. L. Gierisch, Jennifer M. Goldstein, Karen M. Romodan, Yasmin Sadler, Anne G. Yano, Elizabeth M. Yee, Ellen F. Vogt, Dawne TI Effectiveness of an Evidence-Based Quality Improvement Approach to Cultural Competence Training: The Veterans Affairs' "Caring for Women Veterans" Program SO JOURNAL OF CONTINUING EDUCATION IN THE HEALTH PROFESSIONS LA English DT Article DE evidence-based quality improvement; implementation science; mixed methods; culture/diversity/cultural competence; evaluation-educational intervention; workplace learning ID HEALTH-CARE; DISPARITIES; GENDER; IMPLEMENTATION; DEPRESSION; FRAMEWORK AB Introduction: Although providing culturally sensitive health care is vitally important, there is little consensus regarding the most effective strategy for implementing cultural competence trainings in the health care setting. Evidence-based quality improvement (EBQI), which involves adapting evidence-based practices to meet local needs, may improve uptake and effectiveness of a variety of health care innovations. Yet, to our knowledge, EBQI has not yet been applied to cultural competence training. To evaluate whether EBQI could enhance the impact of an evidence-based training intended to improve veterans affairs health care staff gender sensitivity and knowledge (Caring for Women Veterans; CWV), we compared the reach and effectiveness of EBQI delivery versus standard web-based implementation strategies of CWV and assessed barriers and facilitators to EBQI implementation. Methods: Workgroups at four diverse veterans affairs health care sites were randomized to either an EBQI or standard web-based implementation condition (SI). All EBQI sites selected a group-based implementation strategy. Employees (N = 84) completed pretraining and posttraining assessments of gender sensitivity and knowledge, and focus groups/interviews were conducted with leadership and staff before and after implementation. Results: Reach of CWV was greater in the EBQI condition versus the SI condition. Whereas both gender sensitivity and knowledge improved in the EBQI condition, only gender sensitivity improved in the SI condition. Qualitative analyses revealed that the EBQI approach was well received, although a number of barriers were identified. Discussion: Findings suggest that EBQI can enhance the uptake and effectiveness of employee trainings. However, the decision to pursue EBQI must be informed by a consideration of available resources. C1 [Fox, Annie B.; Wiltsey-Stirman, Shannon] VA Boston Healthcare Syst, Womens Hlth Sci Div, Natl Ctr Posttraumat Stress Disorder, Boston, MA USA. [Hamilton, Alison B.] VA Greater Los Angeles Healthcare Syst, HSR&D Ctr Study Healthcare Innovat Implementat &, Los Angeles, CA USA. [Hamilton, Alison B.] Univ Calif Los Angeles, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90024 USA. [Frayne, Susan M.] VA Palo Alto Healthcare Syst, VA HSR&D Ctr Innovat Implementat Ci2i, Med, Palo Alto, CA USA. [Frayne, Susan M.] Stanford Univ, Div Gen Med Disciplines, Stanford, CA 94305 USA. [Frayne, Susan M.] Stanford Univ, Ctr Primary Care & Outcomes Res, Stanford, CA 94305 USA. [Wiltsey-Stirman, Shannon; Vogt, Dawne] Boston Univ, Sch Med, Dept Psychiat, Boston, MA 02118 USA. [Bean-Mayberry, Bevanne; Yano, Elizabeth M.] VA Greater Los Angeles Healthcare Syst, VA HSR&D Ctr Study Healthcare Innovat Implementat, Los Angeles, CA USA. [Bean-Mayberry, Bevanne] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, West Los Angeles, CA USA. [Carney, Diane; Romodan, Yasmin] VA Palo Alto Hlth Care Syst, VA HSR&D Ctr Innovat Implementat Ci2i, Palo Alto, CA USA. [Di Leone, Brooke A. L.] Philadelphia VA Med Ctr, Ctr Hlth Equ Res & Promot, Philadelphia, PA USA. [Gierisch, Jennifer M.] Durham VA Med Ctr, Ctr Hlth Serv Res Primary Care, Durham, NC USA. [Gierisch, Jennifer M.] Duke Univ, Sch Med, Dept Med, Durham, NC 27706 USA. [Goldstein, Karen M.] Durham VA Med Ctr, Ctr Hlth Serv Res Primary Care, Durham, NC USA. [Goldstein, Karen M.] Duke Univ, Sch Med, Div Gen Internal Med, Durham, NC USA. [Sadler, Anne G.] Iowa City VA Healthcare Syst, Psychiat, Ctr Comprehens Access & Delivery Res & Evaluat CA, Iowa City, IA USA. [Sadler, Anne G.] Univ Iowa, Dept Psychiat, Carver Coll Med, Iowa City, IA 52242 USA. [Yano, Elizabeth M.] UCLA Fielding Sch Publ Hlth, Dept Hlth Policy & Management, Los Angeles, CA USA. [Yee, Ellen F.] New Mexico VA Hlth Care Syst, Med, Albuquerque, NM USA. [Yee, Ellen F.] Univ New Mexico, Sch Med, Dept Med, Albuquerque, NM 87131 USA. [Vogt, Dawne] VA Boston Healthcare Syst, Psychiat, Womens Hlth Sci Div, Natl Ctr Posttraumat Stress Disorder, Boston, MA USA. RP Fox, AB (reprint author), VA Boston Healthcare Syst, Natl Ctr PTSD 116B 3, 150 South Huntington Ave, Boston, MA 02130 USA. EM annie.fox-galalis@va.gov OI Wiltsey Stirman, Shannon/0000-0001-9917-5078 FU Department of Veterans Affairs, Veterans Health Administration, Health Services Research Development [SDR 10-012]; National Center for PTSD; National Institute of Mental Health [R25 MH080916-01A2]; VA HSRD QUERI; VA HSR&D Senior Research Career Scientist Award [RCS 05-195] FX This research was supported, in part, by Department of Veterans Affairs, Veterans Health Administration, Health Services Research & Development SDR 10-012 (PIs: E. M. Yano, S. M. Frayne, and A. B. Hamilton) and the National Center for PTSD. At the time of the study, A. B. Hamilton was an investigator with the Implementation Research Institute (IRI), at the George Warren Brown School of Social Work, Washington University, St. Louis, through an award from the National Institute of Mental Health (R25 MH080916-01A2) and VA HSR&D QUERI. E. M. Yano's effort was supported by a VA HSR&D Senior Research Career Scientist Award (Project #RCS 05-195). S. Wiltsey-Stirman is currently affiliated with the Dissemination and Training Division, National Center for PTSD, the Department of Psychiatry and Behavioral Sciences at Stanford University, and VA Palo Alto Healthcare System in Menlo Park, CA. NR 35 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 0894-1912 EI 1554-558X J9 J CONTIN EDUC HEALTH JI J. Contin. Educ. Health Prof. PD SPR PY 2016 VL 36 IS 2 BP 96 EP 103 DI 10.1097/CEH.0000000000000073 PG 8 WC Education, Scientific Disciplines; Health Care Sciences & Services SC Education & Educational Research; Health Care Sciences & Services GA EC7FD UT WOS:000388301000003 PM 27262152 ER PT J AU Barocas, JA Linas, BP Kim, AY Fangman, J Westergaard, RP AF Barocas, Joshua A. Linas, Benjamin P. Kim, Arthur Y. Fangman, John Westergaard, Ryan P. TI Acceptability of Rapid Point-of-Care Hepatitis C Tests Among People Who Inject Drugs and Utilize Syringe-Exchange Programs SO OPEN FORUM INFECTIOUS DISEASES LA English DT Article DE hepatitis C screening; people who inject drugs; rapid diagnostics; syringe exchange programs ID COST-EFFECTIVENESS; VIRUS-INFECTION; STRATEGIES; HCV AB People who inject drugs may benefit from point-of-care hepatitis C virus (HCV) testing offered at syringe exchanges. We sought to understand whether this population would be willing to undergo rapid HCV testing. We found that there was broad support for rapid HCV testing, especially among younger people who inject drugs with high perceived risk. C1 [Barocas, Joshua A.; Kim, Arthur Y.] Massachusetts Gen Hosp, Div Infect Dis, 55 Fruit St,GrJ 504, Boston, MA 02114 USA. [Linas, Benjamin P.] Boston Univ, Med Ctr, HIV Epidemiol & Outcomes Res Unit, Div Infect Dis, Boston, MA 02215 USA. [Fangman, John] Med Coll Wisconsin, Div Infect Dis, Milwaukee, WI 53226 USA. [Westergaard, Ryan P.] Univ Wisconsin, Sch Med & Publ Hlth, Dept Med, Madison, WI 53706 USA. [Westergaard, Ryan P.] Univ Wisconsin, Sch Med & Publ Hlth, Dept Populat Hlth Sci, Madison, WI 53706 USA. RP Barocas, JA (reprint author), Massachusetts Gen Hosp, Div Infect Dis, 55 Fruit St,GrJ 504, Boston, MA 02114 USA. EM jbarocas@mgh.harvard.edu NR 10 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 2328-8957 J9 OPEN FORUM INFECT DI JI Open Forum Infect. Dis. PD SPR PY 2016 VL 3 IS 2 DI 10.1093/ofid/ofw075 PG 3 WC Infectious Diseases SC Infectious Diseases GA EC3IR UT WOS:000388020200031 ER PT J AU Lo, J Lu, MT Kim, EA Nou, E Hallett, TR Park, J Hoffmann, U Grinspoon, SK AF Lo, Janet Lu, Michael T. Kim, Elli A. Nou, Eric Hallett, Travis R. Park, Jakob Hoffmann, Udo Grinspoon, Steven K. TI Statin Effects to Reduce Hepatosteatosis as Measured by Computed Tomography in Patients With Human Immunodeficiency Virus SO OPEN FORUM INFECTIOUS DISEASES LA English DT Article DE hepatosteatosis; human immunodeficiency virus; LDL cholesterol; statin ID FATTY LIVER-DISEASE; PLACEBO-CONTROLLED-TRIAL; NONALCOHOLIC STEATOHEPATITIS; METABOLIC SYNDROME; OPEN-LABEL; EFFICACY; RISK; ROSUVASTATIN; ATHEROSCLEROSIS; DYSLIPIDEMIA AB Hepatosteatosis is highly prevalent among patients living with human immunodeficiency virus. In a 1-year, randomized, double-blind trial of atorvastatin or placebo, atorvastatin increased liver/spleen ratio among patients with nonalcoholic fatty liver disease, indicating a reduction in hepatosteatosis. This reduction in hepatosteatosis is associated with reduction in low-density lipoprotein cholesterol with statin therapy. C1 [Lo, Janet; Kim, Elli A.; Nou, Eric; Grinspoon, Steven K.] Massachusetts Gen Hosp, Dept Med, Div Endocrine, Program Nutr Metab, Boston, MA 02114 USA. [Lo, Janet; Lu, Michael T.; Kim, Elli A.; Nou, Eric; Hallett, Travis R.; Park, Jakob; Hoffmann, Udo; Grinspoon, Steven K.] Harvard Med Sch, Boston, MA USA. [Lu, Michael T.; Hallett, Travis R.; Park, Jakob; Hoffmann, Udo] Massachusetts Gen Hosp, Dept Radiol, Cardiac PET MR CT Program, Boston, MA 02114 USA. RP Lo, J (reprint author), Massachusetts Gen Hosp, LON-203,55 Fruit St, Boston, MA 02114 USA. EM jlo@mgh.harvard.edu NR 30 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 2328-8957 J9 OPEN FORUM INFECT DI JI Open Forum Infect. Dis. PD SPR PY 2016 VL 3 IS 2 DI 10.1093/ofid/ofw062 PG 5 WC Infectious Diseases SC Infectious Diseases GA EC3IR UT WOS:000388020200018 ER PT J AU Stephenson, KE Neubauer, GH Bricault, CA Shields, J Bayne, M Reimer, U Pawlowski, N Knaute, T Zerweck, J Seaman, MS Rosenberg, ES Barouch, DH AF Stephenson, Kathryn E. Neubauer, George H. Bricault, Christine A. Shields, Jennifer Bayne, Madeleine Reimer, Ulf Pawlowski, Nikolaus Knaute, Tobias Zerweck, Johannes Seaman, Michael S. Rosenberg, Eric S. Barouch, Dan H. TI Antibody Responses After Analytic Treatment Interruption in Human Immunodeficiency Virus-1-Infected Individuals on Early Initiated Antiretroviral Therapy SO OPEN FORUM INFECTIOUS DISEASES LA English DT Article DE antibody; HIV eradication; HIV vaccine; microarray; treatment interruption ID PRIMARY HIV-1 INFECTION; B-CELL RESPONSES; NEUTRALIZING ANTIBODIES; BREADTH; 447-52D AB The examination of antibody responses in human immunodeficiency virus (HIV)-1-infected individuals in the setting of antiretroviral treatment (ART) interruption can provide insight into the evolution of antibody responses during viral rebound. In this study, we assessed antibody responses in 20 subjects in AIDS Clinical Trials Group A5187, wherein subjects were treated with antiretroviral therapy during acute/early HIV-1 infection, underwent analytic treatment interruption, and subsequently demonstrated viral rebound. Our data suggest that early initiation of ART arrests the maturation of HIV-1-specific antibody responses, preventing epitope diversification of antibody binding and the development of functional neutralizing capacity. Antibody responses do not appear permanently blunted, however, because viral rebound triggered the resumption of antibody maturation in our study. We also found that antibody responses measured by these assays did not predict imminent viral rebound. These data have important implications for the HIV-1 vaccine and eradication fields. C1 [Stephenson, Kathryn E.; Neubauer, George H.; Bricault, Christine A.; Shields, Jennifer; Bayne, Madeleine; Seaman, Michael S.; Barouch, Dan H.] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Ctr Virol & Vaccine Res, Boston, MA USA. [Stephenson, Kathryn E.; Barouch, Dan H.] Ragon Inst MGH MIT & Harvard, Boston, MA USA. [Reimer, Ulf; Pawlowski, Nikolaus; Knaute, Tobias; Zerweck, Johannes] JPT Peptide Technol, Berlin, Germany. [Rosenberg, Eric S.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Barouch, DH (reprint author), Beth Israel Deaconess Med Ctr, Ctr Virol & Vaccine Res, 330 Brookline Ave,E-CLS 1045, Boston, MA 02215 USA. EM dbarouch@bidmc.harvard.edu NR 17 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 2328-8957 J9 OPEN FORUM INFECT DI JI Open Forum Infect. Dis. PD SPR PY 2016 VL 3 IS 2 DI 10.1093/ofid/ofw100 PG 9 WC Infectious Diseases SC Infectious Diseases GA EC3IR UT WOS:000388020200053 ER PT J AU Mafi, JN Rothberg, MB Sepucha, KR Barry, MJ AF Mafi, John N. Rothberg, Michael B. Sepucha, Karen R. Barry, Michael J. TI Time for Quality Measures to Get Personal SO JOINT COMMISSION JOURNAL ON QUALITY AND PATIENT SAFETY LA English DT Editorial Material ID PATIENT-REPORTED OUTCOMES; HEALTH-CARE; CLINICAL-PRACTICE; INFORMATION; MANAGEMENT; TRENDS; MAMMOGRAPHY; EXPERIENCE; PHYSICIANS; DECISIONS C1 [Mafi, John N.] Beth Israel Deaconess Med Ctr, Gen Internal Med, Boston, MA 02215 USA. [Mafi, John N.] Harvard Med Sch, Boston, MA 02115 USA. [Mafi, John N.] Univ Calif Los Angeles, David Geffen Sch Med, Div Gen Internal Med & Hlth Serv Res, Med, Los Angeles, CA 90095 USA. [Mafi, John N.] RAND Corp, Hlth Policy, Santa Monica, CA 90401 USA. [Rothberg, Michael B.] Cleveland Clin, Inst Med, Res, Cleveland, OH 44106 USA. [Rothberg, Michael B.] Cleveland Clin, Ctr Value Based Care Res, Cleveland, OH 44106 USA. [Rothberg, Michael B.] Case Western Reserve Univ, Cleveland Clin, Lerner Coll Med, Ctr Value Based Care, Cleveland, OH 44106 USA. [Sepucha, Karen R.] Massachusetts Gen Hosp, Div Gen Internal Med, Hlth Decis Sci Ctr, Boston, MA 02114 USA. [Sepucha, Karen R.; Barry, Michael J.] Harvard Med Sch, Med, Boston, MA USA. [Barry, Michael J.] Informed Med Decis Fdn, Boston, MA USA. [Barry, Michael J.] Healthwise, Boston, MA USA. [Barry, Michael J.] Massachusetts Gen Hosp, John D Stoeckle Ctr Primary Care Innovat, Boston, MA 02114 USA. RP Mafi, JN (reprint author), Beth Israel Deaconess Med Ctr, Gen Internal Med, Boston, MA 02215 USA.; Mafi, JN (reprint author), Harvard Med Sch, Boston, MA 02115 USA.; Mafi, JN (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Div Gen Internal Med & Hlth Serv Res, Med, Los Angeles, CA 90095 USA.; Mafi, JN (reprint author), RAND Corp, Hlth Policy, Santa Monica, CA 90401 USA. EM jmafi@mednet.ucla.edu NR 48 TC 1 Z9 1 U1 2 U2 3 PU JOINT COMMISSION RESOURCES INC PI OAK BROOK PA 1515 W 22 ST, STE 1300W, OAK BROOK, IL 60523 USA SN 1553-7250 EI 1938-131X J9 JT COMM J QUAL PATIE JI Jt. Comm. J. Qual. Patient Saf. PD MAR PY 2016 VL 42 IS 3 BP 132 EP 136 PG 5 WC Health Care Sciences & Services SC Health Care Sciences & Services GA EB7FO UT WOS:000387552100005 PM 26892702 ER PT J AU VanEpps, EM Roberto, CA Park, S Economos, CD Bleich, SN AF VanEpps, Eric M. Roberto, Christina A. Park, Sara Economos, Christina D. Bleich, Sara N. TI Restaurant Menu Labeling Policy: Review of Evidence and Controversies SO CURRENT OBESITY REPORTS LA English DT Review DE Menu labeling; Calorie labeling; Obesity prevention; Food policy ID FAST-FOOD RESTAURANTS; OF-THE-LITERATURE; AMERICAN-HEART-ASSOCIATION; FULL-SERVICE RESTAURANTS; CHAIN RESTAURANTS; SCIENTIFIC STATEMENT; PHYSICAL-ACTIVITY; CALORIE LABELS; ENERGY-INTAKE; PORTION SIZE AB In response to high rates of obesity in the USA, several American cities, counties, and states have passed laws requiring restaurant chains to post labels identifying the energy content of items on menus, and nationwide implementation of menu labeling is expected in late 2016. In this review, we identify and summarize the results of 16 studies that have assessed the impact of real-world numeric calorie posting. We also discuss several controversies surrounding the US Food and Drug Administration's implementation of federally mandated menu labeling. Overall, the evidence regarding menu labeling is mixed, showing that labels may reduce the energy content of food purchased in some contexts, but have little effect in other contexts. However, more data on a range of ong-term consumption habits and restaurant responses is needed to fully understand the impact menu labeling laws will have on the US population's diet. C1 [VanEpps, Eric M.] VA Ctr Hlth Equ Res & Promot, Philadelphia, PA USA. [Roberto, Christina A.; Park, Sara] Perelman Sch Med, Dept Med Eth & Hlth Policy, 423 Guardian Dr,1105b Blockley Hall, Philadelphia, PA 19104 USA. [Economos, Christina D.] Tufts Univ, Friedman Sch Nutr Sci & Policy, ChildObesity180, Boston, MA 02111 USA. [Economos, Christina D.] Tufts Univ, Sch Med, Boston, MA 02111 USA. [Bleich, Sara N.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Hlth Policy & Management, Baltimore, MD USA. RP Roberto, CA (reprint author), Perelman Sch Med, Dept Med Eth & Hlth Policy, 423 Guardian Dr,1105b Blockley Hall, Philadelphia, PA 19104 USA. EM croberto@mail.med.upenn.edu FU NIA NIH HHS [P30 AG034546] NR 47 TC 1 Z9 1 U1 1 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 2162-4968 J9 CURR OBES REP JI Curr. Obes. Rep. PD MAR PY 2016 VL 5 IS 1 BP 72 EP 80 DI 10.1007/s13679-016-0193-z PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EB0SH UT WOS:000387055300009 PM 26877095 ER PT J AU Jurczyszyn, A Olszewska-Szopa, M Vesole, AS Vesole, DH Siegel, DS Richardson, PG Paba-Prada, C Callander, NS Huras, H Skotnicki, AB AF Jurczyszyn, Artur Olszewska-Szopa, Magdalena Vesole, Adam S. Vesole, David H. Siegel, David S. Richardson, Paul G. Paba-Prada, Claudia Callander, Natalie S. Huras, Hubert Skotnicki, Aleksander B. TI Multiple Myeloma in Pregnancy-A Review of the Literature and a Case Series SO CLINICAL LYMPHOMA MYELOMA & LEUKEMIA LA English DT Review DE Diagnosis; Management; Multiple myeloma; Pregnancy; Therapy ID COMPRESSION; MANAGEMENT; WOMAN AB Pregnancy in multiple myeloma is extremely rare because the average age of onset approaches 70 years. However, the fetal outcomes are comparable to those in pregnancy without multiple myeloma. We report 5 additional cases along with a review of the existing literature. We provide a review of potential treatment regimens and approaches to the management of pregnancy during multiple myeloma. Multiple myeloma (MM) typically affects older patients with a median age at diagnosis of 67 to 70 years and only 3% of cases are diagnosed before the age of 40. Moreover, MM is more common in men. Therefore, pregnancy rarely occurs in patients with MM and only 37 cases of MM in pregnancy have been reported in the literature. Herein we report an additional 5 cases. The diagnosis of MM might be problematic in this context because some of the symptoms and signs, such as back pain and anemia, can be attributed to pregnancy. Furthermore, if the patient wishes to continue her pregnancy, therapeutic options are currently limited. The list of agents that can be safely administered in pregnant women includes glucocorticoids. Moreover, any continuation of pregnancy has obvious long-term psychosocial repercussions for the patient and her family because of the currently incurable nature of MM. The reported cases of MM in pregnancy represent a spectrum of clinical manifestations. The selection of efficacious and safe treatments is challenging, especially if continuation of pregnancy is desired. Although some authors postulate that pregnancy might lead to progression of MM, data are limited and no consensus on this point has been reached. C1 [Jurczyszyn, Artur; Skotnicki, Aleksander B.] Jagiellonian Univ, Coll Med, Dept & Clin Haematol, 17 Kopernika St, PL-31501 Krakow, Poland. [Olszewska-Szopa, Magdalena] Med Univ, Dept Haematol Blood Neoplasms & Bone Marrow Trans, Wroclaw, Poland. [Vesole, Adam S.; Vesole, David H.; Siegel, David S.] UMC, John Theurer Canc Ctr Hackensack, Hackensack, NJ USA. [Vesole, David H.] Georgetown Univ, Dept Med, Washington, DC USA. [Richardson, Paul G.; Paba-Prada, Claudia] Dana Farber Canc Inst, Dept Med, Boston, MA 02115 USA. [Callander, Natalie S.] Univ Wisconsin, Dept Med, Carbone Canc Ctr, Madison, WI USA. [Huras, Hubert] Jagiellonian Univ, Coll Med, Dept & Clin Obstet & Perinatol, Krakow, Poland. RP Jurczyszyn, A (reprint author), Jagiellonian Univ, Coll Med, Dept & Clin Haematol, 17 Kopernika St, PL-31501 Krakow, Poland. EM mmjurczy@cyf-kr.edu.pl NR 38 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 2152-2650 EI 2152-2669 J9 CL LYMPH MYELOM LEUK JI Clin. Lymphoma Myeloma Leuk. PD MAR PY 2016 VL 16 IS 3 BP E39 EP E45 DI 10.1016/j.clml.2015.11.020 PG 7 WC Oncology; Hematology SC Oncology; Hematology GA EA0DS UT WOS:000386256300003 PM 26847816 ER PT J AU Kurtzman, D Vleugels, RA Callen, J AF Kurtzman, Drew Vleugels, Ruth Ann Callen, Jeffrey TI Approach to and Management of the Neutrophilic Dermatoses SO CURRENT DERMATOLOGY REPORTS LA English DT Article DE Neutrophilic dermatosis; Sweet's syndrome; Pyoderma gangrenosum; Neutrophil; Reactive dermatosis; Treatment ID SUBCORNEAL PUSTULAR DERMATOSIS; ERYTHEMA-ELEVATUM-DIUTINUM; INDUCED SWEETS-SYNDROME; BOWEL-BYPASS SYNDROME; TUMOR-NECROSIS-FACTOR; PYODERMA-GANGRENOSUM; RHEUMATOID-ARTHRITIS; DORSAL HANDS; ECCRINE HIDRADENITIS; DIAGNOSTIC-CRITERIA AB The neutrophilic dermatoses are a related set of disorders that share common features. These disorders are not directly related to infection and are considered forms of "sterile" neutrophilic inflammation. They can occur with an associated systemic disease or as a primary cutaneous process. Subcorneal pustular dermatosis, Sweet's syndrome, erythema elevatum diutinum, bowel-associated dermatosis-arthritis syndrome, pyoderma gangrenosum, and neutrophilic eccrine hidradenitis represent the most common of these disorders. This review highlights the salient features of the neutrophilic dermatoses with an emphasis on clinical features, evaluation, and management. C1 [Kurtzman, Drew] VA Boston Healthcare Syst, Dept Dermatol, Boston, MA 02130 USA. [Kurtzman, Drew; Vleugels, Ruth Ann] Harvard Med Sch, Brigham & Womens Hosp, Dept Dermatol, Boston, MA 02115 USA. [Callen, Jeffrey] Univ Louisville, Div Dermatol, Louisville, KY 40292 USA. RP Kurtzman, D (reprint author), VA Boston Healthcare Syst, Dept Dermatol, Boston, MA 02130 USA.; Kurtzman, D (reprint author), Harvard Med Sch, Brigham & Womens Hosp, Dept Dermatol, Boston, MA 02115 USA. EM dkurtzman@partners.org NR 101 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA EI 2162-4933 J9 CURR DERMATOL REP JI Curr. Dermatol. Rep. PD MAR PY 2016 VL 5 IS 1 BP 18 EP 29 DI 10.1007/s13671-016-0129-6 PG 12 WC Dermatology SC Dermatology GA EA0VS UT WOS:000386306700004 ER PT J AU Dehlendorf, C Fox, E Sobel, L Borrero, S AF Dehlendorf, Christine Fox, Edith Sobel, Lauren Borrero, Sonya TI Patient-Centered Contraceptive Counseling: Evidence to Inform Practice SO CURRENT OBSTETRICS AND GYNECOLOGY REPORTS LA English DT Article DE Contraception; Contraceptive counseling; Patient-centered; Decision making ID RANDOMIZED CONTROLLED-TRIAL; DECISION-MAKING; UNINTENDED PREGNANCY; QUALITATIVE-ANALYSIS; WOMENS PERSPECTIVES; REPRODUCTIVE AGE; HEALTH-CARE; KNOWLEDGE; ATTITUDES; SERVICES AB Patient centeredness is an increasingly recognized aspect of quality health care. The application of this framework to contraceptive counseling and care has not been well described. We propose a definition of patient-centered contraceptive counseling that focuses on and prioritizes each patient's individual needs and preferences regarding contraceptive methods and the counseling experience. Guided by this definition, we review recent research that has advanced our understanding of how patient-centered contraceptive counseling can be delivered in practice, focusing on how women decide on a contraceptive method, their preferences for counseling, and their experiences with counseling. This research provides evidence that women have diverse preferences around attributes of their contraceptive methods and value personal, supportive relationships with their family planning providers that focus on their individual preferences. We discuss the implications of this research for practice and review recent interventions that incorporate patient centeredness to varying degrees. C1 [Dehlendorf, Christine; Fox, Edith] Univ Calif San Francisco, Dept Family & Community Med, San Francisco, CA 94143 USA. [Dehlendorf, Christine] Univ Calif San Francisco, Dept Obstet Gynecol & Reprod Sci, San Francisco, CA USA. [Dehlendorf, Christine] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Sobel, Lauren] Touro Univ Calif Vallejo, Coll Osteopath Med, Vallejo, CA USA. [Borrero, Sonya] Univ Pittsburgh, Sch Med, Pittsburgh, PA USA. [Borrero, Sonya] VA Pittsburgh Healthcare Syst, VA Ctr Hlth Equ Res & Promot, Pittsburgh, PA USA. RP Fox, E (reprint author), Univ Calif San Francisco, Dept Family & Community Med, San Francisco, CA 94143 USA. EM christine.dehlendorf@ucsf.edu; edith.fox@ucsf.edu; lauren.sobel@tu.edu; borrsp@upmc.edu NR 62 TC 2 Z9 2 U1 5 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 2161-3303 J9 CURR OBSTET GYNECOL JI CURR. OBSTET. GYNECOL. REP. PD MAR PY 2016 VL 5 IS 1 BP 55 EP 63 DI 10.1007/s13669-016-0139-1 PG 9 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA EA0DA UT WOS:000386254400007 ER PT J AU Adams, MJ Ng, AK Mauch, P Lipsitz, SR Winters, P Lipshultz, SE AF Adams, Michael Jacob Ng, Andrea K. Mauch, Peter Lipsitz, Stuart R. Winters, Paul Lipshultz, Steven E. TI Peak oxygen consumption in Hodgkin's lymphoma survivors treated with mediastinal radiotherapy as a predictor of quality of life 5 years later (vol 39, pg 93, 2015) SO PROGRESS IN PEDIATRIC CARDIOLOGY LA English DT Correction C1 [Adams, Michael Jacob; Winters, Paul] Univ Rochester, Sch Med & Dent, Dept Publ Hlth Sci, Rochester, NY USA. [Ng, Andrea K.; Mauch, Peter] Brigham & Womens Hosp, Dept Radiat Oncol, 75 Francis St, Boston, MA 02115 USA. [Ng, Andrea K.; Mauch, Peter] Dana Farber Canc Inst, Boston, MA 02115 USA. [Lipsitz, Stuart R.] Brigham & Womens Hosp, Dept Med, Div Gen Internal Med, 75 Francis St, Boston, MA 02115 USA. [Lipsitz, Stuart R.] Brigham & Womens Hosp, Ctr Surg & Publ Hlth, 75 Francis St, Boston, MA 02115 USA. [Ng, Andrea K.; Mauch, Peter; Lipsitz, Stuart R.] Harvard Med Sch, Boston, MA USA. [Lipsitz, Stuart R.] Harvard Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Lipshultz, Steven E.] Wayne State Univ, Childrens Hosp Michigan, Sch Med, Dept Pediat, 3901 Beaubien Blvd,1K40, Detroit, MI 48201 USA. RP Lipshultz, SE (reprint author), Wayne State Univ, Childrens Hosp Michigan, Sch Med, Dept Pediat, 3901 Beaubien Blvd,1K40, Detroit, MI 48201 USA. EM slipshultz@med.wayne.edu OI Adams, Michael Jacob/0000-0002-3245-5793 NR 1 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 1058-9813 EI 1558-1519 J9 PROG PEDIATR CARDIOL JI Prog. Pediatr. Cardiol. PD MAR PY 2016 VL 40 BP 47 EP 47 DI 10.1016/j.ppedcard.2016.01.001 PN 3 PG 1 WC Cardiac & Cardiovascular Systems; Pediatrics SC Cardiovascular System & Cardiology; Pediatrics GA EA1ZL UT WOS:000386390700011 ER PT J AU Gaffney, AW Hang, JQ Lee, MS Su, L Zhang, FY Christiani, DC AF Gaffney, Adam W. Hang, Jing-qing Lee, Mi-Sun Su, Li Zhang, Feng-ying Christiani, David C. TI Commuting mode and pulmonary function in Shanghai, China SO EUROPEAN RESPIRATORY JOURNAL LA English DT Article ID RECOMBINANT HUMAN DEOXYRIBONUCLEASE; PUBLIC TRANSPORTATION MODES; PARTICULATE AIR-POLLUTION; SOLID-FUEL USE; CARBON-MONOXIDE; LUNG-FUNCTION; PERSONAL EXPOSURE; CYSTIC-FIBROSIS; FINE PARTICLES; HONG-KONG AB Exposure to air pollution can be particularly high during commuting and may depend on the mode of transportation. We investigated the impact of commuting mode on pulmonary function in Shanghai, China. The Shanghai Putuo Study is a cross-sectional, population-based study. Our primary outcomes were forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) % predicted, and the secondary outcome was spirometric airflow obstruction. We tested the association between mode of transportation and these outcomes after adjusting for confounders. The study population consisted of 20102 subjects. After adjusting for confounders, the change (95% CI) in FEV1 was -2.15% pred (-2.88- -1.42% pred) among pedestrians, -1.32% pred (-2.05- -0.59% pred) among those taking buses without air conditioning, -1.33% pred (-2.05- -0.61% pred) among those taking buses with air conditioning and -2.83% pred (-5.56- -0.10% pred) among those using underground railways, as compared to cyclists (the reference group). The effects of mode on FVC % predicted were in the same direction. Private car use had a significant protective effect on FVC % predicted and the risk of airflow obstruction (defined by Global Initiative for Chronic Obstructive Lung Disease but not by lower limit of normal criteria). Mode of transportation is associated with differences in lung function, which may reflect pollution levels in different transportation microenvironments. C1 [Gaffney, Adam W.; Christiani, David C.] Massachusetts Gen Hosp, 55 Fruit St, Boston, MA 02114 USA. [Hang, Jing-qing; Zhang, Feng-ying] Shanghai Putuo Dist Peoples Hosp, Shanghai, Peoples R China. [Lee, Mi-Sun; Su, Li; Christiani, David C.] Harvard TH Chan Sch Publ Hlth, Dept Environm Hlth, Environm & Occupat Med & Epidemiol Program, Boston, MA USA. [Christiani, David C.] Harvard Med Sch, Boston, MA USA. RP Gaffney, AW (reprint author), Massachusetts Gen Hosp, 55 Fruit St, Boston, MA 02114 USA. EM agaffney@partners.org FU US National Institutes of Health [T32 HL116275, NIEHS ES00002]; Shanghai Putuo District People's Hospital FX This study was supported by the US National Institutes of Health (grants T32 HL116275 and NIEHS ES00002) and the Shanghai Putuo District People's Hospital. The study sponsors had no role in the study design, analysis or manuscript preparation. Funding information for this article has been deposited with FundRef. NR 39 TC 1 Z9 1 U1 1 U2 2 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 MAR PY 2016 VL 47 IS 3 BP 733 EP 741 DI 10.1183/13993003.00637-2015 PG 9 WC Respiratory System SC Respiratory System GA DZ6DB UT WOS:000385950700010 PM 26541519 ER PT J AU van den Blink, B Dillingh, MR Ginns, LC Morrison, LD Moerland, M Wijsenbeek, M Trehu, EG Bartholmai, BJ Burggraaf, J AF van den Blink, Bernt Dillingh, Marlous R. Ginns, Leo C. Morrison, Lake D. Moerland, Matthijs Wijsenbeek, Marlies Trehu, Elizabeth G. Bartholmai, Brian J. Burggraaf, Jacobus TI Recombinant human pentraxin-2 therapy in patients with idiopathic pulmonary fibrosis: safety, pharmacokinetics and exploratory efficacy SO EUROPEAN RESPIRATORY JOURNAL LA English DT Article ID SERUM AMYLOID-P; LUNG FIBROSIS; QUANTIFICATION; DIAGNOSIS; SURVIVAL; DISEASE; TRIAL AB Abnormal fibrogenic repair response upon alveolar injury is believed to play an important role in the pathogenesis of idiopathic pulmonary fibrosis (IPF). PRM-151 (recombinant human pentraxin-2, also known as serum amyloid P), has been shown to reduce fibrosis in preclinical lung fibrosis models, and was well tolerated with a favourable pharmacokinetic profile in an earlier single-dose phase I study. A randomised, double-blind, placebo-controlled, multiple ascending dose trial was performed to assess the tolerability and pharmacokinetic and pharmacodynamic characteristics of multiple doses of PRM-151 in IPF patients. Subjects in three successive cohorts (1, 5, or 10 mg.kg-(1) versus placebo) received intravenous study drug on days 1, 3, 5, 8 and 15, and were followed-up to day 57. PRM-151 was well tolerated at all dose levels, with no serious adverse reactions. Administration of PRM-151 resulted in two-to eight-fold dose-dependent increases in circulating pentraxin-2 levels. Forced vital capacity and 6-min walk test showed trends towards improvement in the combined PRM-151 dose groups. On high-resolution computed tomography scans, stable or improved lung volume unoccupied by interstitial lung abnormality was noted in some PRM-151 subjects compared to placebo subjects on day 57. The efficacy of PRM-151 in IPF remains to be investigated in dedicated future trials. C1 [van den Blink, Bernt; Wijsenbeek, Marlies] Erasmus MC, Dept Pulm Med, S Gravendijkwal 230, NL-3015 CE Rotterdam, Netherlands. [Dillingh, Marlous R.; Moerland, Matthijs; Burggraaf, Jacobus] Ctr Human Drug Res, Leiden, Netherlands. [Ginns, Leo C.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Morrison, Lake D.] Duke Univ, Dept Med, Durham, NC USA. [Trehu, Elizabeth G.] Promedior Inc, Lexington, MA USA. [Bartholmai, Brian J.] Mayo Clin, Div Thorac Radiol, Rochester, MI USA. RP van den Blink, B (reprint author), Erasmus MC, Dept Pulm Med, S Gravendijkwal 230, NL-3015 CE Rotterdam, Netherlands. EM B.vandenBlink@erasmusmc.nl FU Promedior, Inc. FX This study was funded by Promedior, Inc. All authors received clinical trial support from Promedior, Inc. E.G. Trehu is an employee of Promedior, Inc. Funding information for this article has been deposited with FundRef. NR 23 TC 3 Z9 3 U1 2 U2 4 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 MAR PY 2016 VL 47 IS 3 BP 889 EP 897 DI 10.1183/13993003.00850-2015 PG 9 WC Respiratory System SC Respiratory System GA DZ6DB UT WOS:000385950700025 PM 26869678 ER PT J AU Walker, HE Rosenberg, SM Stanton, AL Petrie, KJ Partridge, AH AF Walker, Hayley E. Rosenberg, Shoshana M. Stanton, Annette L. Petrie, Keith J. Partridge, Ann H. TI Perceptions, Attributions, and Emotions Toward Endocrine Therapy in Young Women with Breast Cancer SO JOURNAL OF ADOLESCENT AND YOUNG ADULT ONCOLOGY LA English DT Article DE breast cancer; survivorship; psychosocial ID ADJUVANT HORMONAL-THERAPY; EARLY DISCONTINUATION; OLDER WOMEN; ADHERENCE; TAMOXIFEN; NONADHERENCE; PREDICTORS; BELIEFS; COHORT; MEDICATION AB Purpose: The aims of this study were to describe symptoms attributed to endocrine therapy (ET) and perceptions of ET in a sample of young women with breast cancer and to explore whether these factors are associated with adherence to ET. Methods: An online questionnaire was completed by 106 young women taking ET for hormone receptor-positive breast cancer. In addition to demographic and medical characteristics, the survey assessed symptom attribution, emotions, and perceptions related to ET. A supplemental survey measuring adherence to ET was completed by 82/106 women. Means, medians, and frequency distributions were calculated for continuous and categorical covariates, respectively. An exploratory analysis evaluated whether adherence was associated with patient characteristics and views. Results: The mean age of respondents was 39 years (range 22-45 years). Two-thirds of women had stage 1 or 2 breast cancer. Women attributed an average of nine symptoms to ET; hot flashes, night sweats, and decreased libido were the most frequently attributed symptoms. Positive emotions toward ET were more common than negative emotions were, although only 48% of respondents believed that ET was essential. Women of higher financial status and those who reported more positive emotions toward ET reported greater adherence with ET. A significant difference in symptom attribution was not detected between less and more adherent respondents. Conclusions: Young women's views regarding ET may play an important role in determining adherence behavior. Given that young women have a higher risk of recurrence, some of which may be attributable to ET non-adherence, further work is needed to confirm these findings and determine whether interventions designed to modify young women's perceptions of ET could promote adherence. C1 [Walker, Hayley E.; Rosenberg, Shoshana M.; Partridge, Ann H.] Harvard Med Sch, Boston, MA USA. [Rosenberg, Shoshana M.; Partridge, Ann H.] Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. [Stanton, Annette L.] Univ Calif Los Angeles, Dept Psychol, Los Angeles, CA USA. [Stanton, Annette L.] Univ Calif Los Angeles, Dept Psychiat Biobehav Sci, Los Angeles, CA USA. [Stanton, Annette L.] Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr, Los Angeles, CA 90024 USA. [Petrie, Keith J.] Univ Auckland, Auckland, New Zealand. RP Partridge, AH (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. EM ahpartridge@partners.org FU NIH [5 R25 CA057711]; Breast Cancer Research Foundation; Susan G. Komen FX Research support was provided by the following: NIH 5 R25 CA057711 (to S.M.R.), Breast Cancer Research Foundation (to A.L.S.), and Susan G. Komen (to A.H.P.). NR 31 TC 1 Z9 1 U1 3 U2 4 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 2156-5333 EI 2156-535X J9 J ADOLESC YOUNG ADUL JI J. Adolesc. Young Adult Oncol. PD MAR PY 2016 VL 5 IS 1 BP 16 EP 23 DI 10.1089/jayao.2015.0051 PG 8 WC Oncology SC Oncology GA DY7XR UT WOS:000385343100004 PM 26812461 ER PT J AU Elmariah, S Farrell, LA Daher, M Shi, X Keyes, MJ Cain, CH Pomerantsev, E Vlahakes, GJ Inglessis, I Passeri, JJ Palacios, IF Fox, CS Rhee, EP Gerszten, RE AF Elmariah, Sammy Farrell, Laurie A. Daher, Maureen Shi, Xu Keyes, Michelle J. Cain, Carolyn H. Pomerantsev, Eugene Vlahakes, Gus J. Inglessis, Ignacio Passeri, Jonathan J. Palacios, Igor F. Fox, Caroline S. Rhee, Eugene P. Gerszten, Robert E. TI Metabolite Profiles Predict Acute Kidney Injury and Mortality in Patients Undergoing Transcatheter Aortic Valve Replacement SO JOURNAL OF THE AMERICAN HEART ASSOCIATION LA English DT Article DE aortic stenosis; kidney; metabolomics; mortality; transcatheter aortic valve implantation ID CARDIAC-SURGERY; S-ADENOSYLHOMOCYSTEINE; IMPLANTATION INCIDENCE; SERUM CREATININE; RENAL-FUNCTION; RISK; DISEASE; ATHEROSCLEROSIS; BIOMARKER; STENOSIS AB Background-Acute kidney injury (AKI) occurs commonly after transcatheter aortic valve replacement (TAVR) and is associated with markedly increased postoperative mortality. We previously identified plasma metabolites predictive of incident chronic kidney disease, but whether metabolite profiles can identify those at risk of AKI is unknown. Methods and Results-We performed liquid chromatography-mass spectrometry-based metabolite profiling on plasma from patients undergoing TAVR and subjects from the community-based Framingham Heart Study (N=2164). AKI was defined by using the Valve Academic Research Consortium-2 criteria. Of 44 patients (mean age 82 +/- 9 years, 52% female) undergoing TAVR, 22 (50%) had chronic kidney disease and 9 (20%) developed AKI. Of 85 metabolites profiled, we detected markedly concordant cross-sectional metabolic changes associated with chronic kidney disease in the hospital-based TAVR and Framingham Heart Study cohorts. Baseline levels of 5-adenosylhomocysteine predicted AKI after TAVR, despite adjustment for baseline glomerular filtration rate (odds ratio per 1-SD increase 5.97, 95% CI 1.62-22.0; P=0.007). Of the patients who had AKI, 6 (66.7%) subsequently died, compared with 3 (8.6%) deaths among those patients who did not develop AKI (P=0.0008) over a median follow-up of 7.8 months. 5-adenosylhomocysteine was predictive of all-cause mortality after TAVR (hazard ratio per 1-SD increase 2.96, 95% CI 1.33-6.58; P=0.008), independent of baseline glomerular filtration rate. Conclusions-In an elderly population with severe aortic stenosis undergoing TAVR, metabolite profiling improves the prediction of AKI. Given the multifactorial nature of AKI after TAVR, metabolite profiles may identify those patients with reduced renal reserve. C1 [Elmariah, Sammy; Farrell, Laurie A.; Daher, Maureen; Shi, Xu; Keyes, Michelle J.; Cain, Carolyn H.; Pomerantsev, Eugene; Inglessis, Ignacio; Passeri, Jonathan J.; Palacios, Igor F.; Gerszten, Robert E.] Harvard Med Sch, Massachusetts Gen Hosp, Div Cardiol, Boston, MA USA. [Elmariah, Sammy; Farrell, Laurie A.; Shi, Xu; Keyes, Michelle J.; Rhee, Eugene P.; Gerszten, Robert E.] Harvard Med Sch, Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA USA. [Vlahakes, Gus J.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Cardiac Surg, Boston, MA USA. [Rhee, Eugene P.] Harvard Med Sch, Massachusetts Gen Hosp, Div Nephrol, Boston, MA USA. [Elmariah, Sammy] Harvard Clin Res Inst, Boston, MA USA. [Fox, Caroline S.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Fox, Caroline S.] Boston Univ, Sch Med, Framingham, MA USA. [Fox, Caroline S.] Brigham & Womens Hosp, Div Endocrinol, 75 Francis St, Boston, MA 02115 USA. [Fox, Caroline S.] NHLBI, Div Intramural Res, Bldg 10, Bethesda, MD 20892 USA. RP Gerszten, RE (reprint author), Massachusetts Gen Hosp, Cardiovasc Res Ctr, Simches Res Bldg,185 Cambridge St,3208, Boston, MA 02114 USA. EM gerszten.robert@mgh.harvard.edu FU American Heart Association [14 FTF20440012]; National Institutes of Health [R01DK081572, R01HL098280, N01HC25195]; MGH Heart Center Hassenfeld Cardiovascular Research Scholar Program FX We are appreciative of support from the American Heart Association (14 FTF20440012 to Elmariah), the National Institutes of Health (R01DK081572 and R01HL098280 to Gerszten and N01HC25195 to the Framingham Heart Study), and the MGH Heart Center Hassenfeld Cardiovascular Research Scholar Program (to Elmariah). NR 33 TC 1 Z9 1 U1 3 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2047-9980 J9 J AM HEART ASSOC JI J. Am. Heart Assoc. PD MAR PY 2016 VL 5 IS 3 AR e002712 DI 10.1161/JAHA.115.002712 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DY7MA UT WOS:000385312200018 PM 27068627 ER PT J AU Lee, JJ Pedley, A Hoffmann, U Massaro, JM Keaney, JF Vasan, RS Fox, CS AF Lee, Jane J. Pedley, Alison Hoffmann, Udo Massaro, Joseph M. Keaney, John F., Jr. Vasan, Ramachandran S. Fox, Caroline S. TI Cross-Sectional Associations of Computed Tomography (CT)-Derived Adipose Tissue Density and Adipokines: The Framingham Heart Study SO JOURNAL OF THE AMERICAN HEART ASSOCIATION LA English DT Article DE adipokine; adipose tissue; computed tomography; epidemiology ID METABOLIC RISK-FACTORS; BODY-FAT DISTRIBUTION; II DIABETES-MELLITUS; INSULIN-RESISTANCE; ADIPOCYTE SIZE; CELL-SIZE; CARDIOMETABOLIC RISK; ABDOMINAL OBESITY; ECTOPIC FAT; ADIPONECTIN AB Background-Excess accumulation of abdominal subcutaneous (SAT) and visceral adipose tissue (VAT) is associated with adverse levels of adipokines and cardiovascular disease risk. Whether fat quality is associated with adipokines has not been firmly established. This study examined the association between abdominal SAT and VAT density, an indirect measure of fat quality, with a panel of metabolic regulatory biomarkers secreted by adipose tissue or the liver independently of absolute fat volumes. Methods and Results-We evaluated 1829 Framingham Heart Study participants (44.9% women). Abdominal SAT and VAT density was estimated indirectly by adipose tissue attenuation using computed tomography. Adipokines included adiponectin, leptin receptor, leptin, fatty acid-binding protein 4 (FABP-4), retinol-binding protein 4 (RBP-4), and fetuin-A. Fat density was associated with all the biomarkers evaluated, except fetuin-A. Lower fat density (ie, more-negative fat attenuation) was associated with lower adiponectin and leptin receptor, but higher leptin and FABP-4 levels (all P<0.0001). SAT density was inversely associated with RPB-4 in both sexes, whereas the association between VAT density and RPB-4 was only observed in men (P<0.0001). In women, after additional adjustment for respective fat volume, SAT density retained the significant associations with adiponectin, leptin, FABP-4, and RBP-4; and VAT density with adiponectin only (all P<0.0001). In men, significant associations were maintained upon additional adjustment for respective fat volume (P<0.005). Conclusions-Lower abdominal fat density was associated with a profile of biomarkers suggestive of greater cardiometabolic risk. These observations support that fat density may be a valid biomarker of cardiometabolic risk. C1 [Lee, Jane J.; Pedley, Alison; Vasan, Ramachandran S.; Fox, Caroline S.] NHLBI, Div Intramural Res, Framingham Heart Study, Framingham, MA USA. [Lee, Jane J.; Pedley, Alison; Vasan, Ramachandran S.; Fox, Caroline S.] NHLBI, Populat Studies Branch, Framingham, MA USA. [Hoffmann, Udo] Massachusetts Gen Hosp, Dept Radiol, Boston, MA USA. [Massaro, Joseph M.] Boston Univ, Dept Biostat, Boston, MA 02215 USA. [Keaney, John F., Jr.] Univ Massachusetts, Sch Med, Div Cardiovasc Med, Worcester, MA USA. [Vasan, Ramachandran S.] Boston Univ, Sch Med, Whitaker Cardiovasc Inst, Evans Dept Med, Boston, MA 02118 USA. [Vasan, Ramachandran S.] Boston Univ, Sch Med, Cardiol Sect, Boston, MA 02118 USA. [Vasan, Ramachandran S.] Boston Univ, Sch Med, Sect Prevent Med, Boston, MA 02118 USA. [Vasan, Ramachandran S.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02118 USA. [Fox, Caroline S.] Brigham & Womens Hosp, Div Endocrinol, 75 Francis St, Boston, MA 02115 USA. [Fox, Caroline S.] Harvard Med Sch, Boston, MA USA. RP Fox, CS (reprint author), NHLBI, Framingham Heart Study, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. EM foxca@nhlbi.nih.gov FU National Heart, Lung and Blood Institute [N01-HC-25195, R01DK080739] FX This work was supported by the National Heart, Lung and Blood Institute's Framingham Heart Study (contract N01-HC-25195) and by R01DK080739 (Vasan). NR 52 TC 3 Z9 3 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2047-9980 J9 J AM HEART ASSOC JI J. Am. Heart Assoc. PD MAR PY 2016 VL 5 IS 3 AR e002545 DI 10.1161/JAHA.115.002545 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DY7MA UT WOS:000385312200009 PM 26927600 ER PT J AU Pokorney, SD Piccini, JP Stevens, SR Patel, MR Pieper, KS Halperin, JL Breithardt, G Singer, DE Hankey, GJ Hacke, W Becker, RC Berkowitz, SD Nessel, CC Mahaffey, KW Fox, KAA Califf, RM AF Pokorney, Sean D. Piccini, Jonathan P. Stevens, Susanna R. Patel, Manesh R. Pieper, Karen S. Halperin, Jonathan L. Breithardt, Gunter Singer, Daniel E. Hankey, Graeme J. Hacke, Werner Becker, Richard C. Berkowitz, Scott D. Nessel, Christopher C. Mahaffey, Kenneth W. Fox, Keith A. A. Califf, Robert M. CA ROCKET AF Steering Comm TI Cause of Death and Predictors of All-Cause Mortality in Anticoagulated Patients With Nonvalvular Atrial Fibrillation: Data From ROCKET AF SO JOURNAL OF THE AMERICAN HEART ASSOCIATION LA English DT Article DE atrial fibrillation; mortality; rivaroxaban; stroke; warfarin ID CONGESTIVE-HEART-FAILURE; CATHETER ABLATION; RISK-FACTOR; FOLLOW-UP; WARFARIN; THERAPY; DABIGATRAN; STROKE; METAANALYSIS; EFFICACY AB Background-Atrial fibrillation is associated with higher mortality. Identification of causes of death and contemporary risk factors for all-cause mortality may guide interventions. Methods and Results-In the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) study, patients with nonvalvular atrial fibrillation were randomized to rivaroxaban or dose-adjusted warfarin. Cox proportional hazards regression with backward elimination identified factors at randomization that were independently associated with all-cause mortality in the 14 171 participants in the intention-to-treat population. The median age was 73 years, and the mean CHADS(2) score was 3.5. Over 1.9 years of median follow-up, 1214 (8.6%) patients died. Kaplan-Meier mortality rates were 4.2% at 1 year and 8.9% at 2 years. The majority of classified deaths (1081) were cardiovascular (72%), whereas only 6% were nonhemorrhagic stroke or systemic embolism. No significant difference in all-cause mortality was observed between the rivaroxaban and warfarin arms (P=0.15). Heart failure (hazard ratio 1.51, 95% CI 1.33-1.70, P<0.0001) and age >= 75 years (hazard ratio 1.69, 95% CI 1.51-1.90, P<0.0001) were associated with higher all-cause mortality. Multiple additional characteristics were independently associated with higher mortality, with decreasing creatinine clearance, chronic obstructive pulmonary disease, male sex, peripheral vascular disease, and diabetes being among the most strongly associated (model C-index 0.677). Conclusions-In a large population of patients anticoagulated for nonvalvular atrial fibrillation, approximate to 7 in 10 deaths were cardiovascular, whereas <1 in 10 deaths were caused by nonhemorrhagic stroke or systemic embolism. Optimal prevention and treatment of heart failure, renal impairment, chronic obstructive pulmonary disease, and diabetes may improve survival. C1 [Pokorney, Sean D.; Piccini, Jonathan P.; Stevens, Susanna R.; Patel, Manesh R.; Pieper, Karen S.; Becker, Richard C.] Duke Univ, Med Ctr, Duke Clin Res Inst, Durham, NC USA. [Califf, Robert M.] Duke Univ, Med Ctr, Duke Translat Med Inst, Durham, NC USA. [Halperin, Jonathan L.] Mt Sinai Med Ctr, Cardiovasc Inst, New York, NY 10029 USA. [Breithardt, Gunter] Hosp Univ Munster, Dept Cardiovasc Med, Div Electrophysiol, Munster, Germany. [Singer, Daniel E.] Massachusetts Gen Hosp, Div Gen Med, Clin Epidemiol Unit, Boston, MA 02114 USA. [Singer, Daniel E.] Harvard Med Sch, Boston, MA 02114 USA. [Hankey, Graeme J.] Royal Perth Hosp, Dept Neurol, Perth, WA, Australia. [Hacke, Werner] Heidelberg Univ, Heidelberg, Germany. [Berkowitz, Scott D.] Bayer HealthCare Pharmaceut Inc, Global Clin Dev, Whippany, NJ USA. [Nessel, Christopher C.] Janssen Res & Dev, Raritan, NJ USA. [Mahaffey, Kenneth W.] Stanford Univ, Med, Stanford, CA USA. [Fox, Keith A. A.] Univ Edinburgh, Edinburgh EH8 9YL, Midlothian, Scotland. [Fox, Keith A. A.] Royal Infirm Edinburgh NHS Trust, Edinburgh, Midlothian, Scotland. RP Pokorney, SD (reprint author), Duke Univ, Med Ctr, Div Cardiol, 2301 Erwin Rd,DUMC 3845, Durham, NC 27710 USA. EM sean.pokorney@duke.edu RI De Caterina, Raffaele/K-3857-2016; Hankey, Graeme /H-4968-2014; OI De Caterina, Raffaele/0000-0003-1637-574X; Hankey, Graeme /0000-0002-6044-7328; Urina, Miguel/0000-0001-6003-4622; Macleod, Malcolm Robert/0000-0001-9187-9839 FU Johnson & Johnson Pharmaceutical Research & Development (Raritan, NJ); Bayer HealthCare AG (Leverkusen, Germany) FX The ROCKET AF trial was sponsored by Johnson & Johnson Pharmaceutical Research & Development (Raritan, NJ) and Bayer HealthCare AG (Leverkusen, Germany). NR 26 TC 2 Z9 2 U1 3 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2047-9980 J9 J AM HEART ASSOC JI J. Am. Heart Assoc. PD MAR PY 2016 VL 5 IS 3 AR e002197 DI 10.1161/JAHA.115.002197 PG 13 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DY7MA UT WOS:000385312200002 PM 26955859 ER PT J AU Santhanakrishnan, R Wang, N Larson, MG Magnani, JM Vasan, RS Wang, TJ Yap, J Feng, L Yap, KB Ong, HY Ng, TP Richards, AM Lam, CSP Ho, JE AF Santhanakrishnan, Rajalakshmi Wang, Na Larson, Martin G. Magnani, Jared M. Vasan, Ramachandran S. Wang, Thomas J. Yap, Jonathan Feng, Liang Yap, Keng B. Ong, Hean Y. Ng, Tze P. Richards, Arthur Mark Lam, Carolyn S. P. Ho, Jennifer E. TI Racial Differences in Electrocardiographic Characteristics and Prognostic Significance in Whites Versus Asians SO JOURNAL OF THE AMERICAN HEART ASSOCIATION LA English DT Article DE electrocardiography; epidemiology; left ventricular hypertrophy; mortality; race ID LEFT-VENTRICULAR HYPERTROPHY; AMERICAN-HEART-ASSOCIATION; QT INTERVAL; MYOCARDIAL-INFARCTION; CHINESE SUBJECTS; NORMAL LIMITS; POPULATION; AGE; COMMITTEE; CRITERIA AB Background-Racial differences in electrocardiographic (ECG) characteristics and prognostic significance among Whites and Asians are not well described. Methods and Results-We studied 2677 White Framingham Heart Study participants (57% women) and 2972 Asian (64% women) Singapore Longitudinal Aging Study participants (mean age 66 years in both) free of myocardial infarction or heart failure. Racial differences in ECG characteristics and effect on mortality were assessed. In linear regression models, PR interval was longer in Asians compared with Whites (multivariable-adjusted beta +/- SE 5.0 +/- 1.4 ms in men and 6.6 +/- 0.9 ms in women, both P<0.0006). QT interval was shorter in Asian men (beta +/- SE -6.2 +/- 1.2 ms, P<0.0001) and longer in Asian women (beta +/- SE 3.6 +/- 0.9 ms, P=0.02) compared to White men and women, respectively. Asians had greater odds of having ECG left ventricular hypertrophy (LVH) compared with Whites (odds ratio [OR] 3.56, 95% confidence interval [CI] 1.36-9.35 for men, OR 1.93, 95% CI 1.35-2.76 for women, both P<0.02). Over a mean follow-up of 11 +/- 3 years in Framingham and 8 +/- 3 years in Singapore, mortality rates were 24.5 and 13.4 per 1000 person-years among Whites and Asians, respectively. In Cox models, the presence of LVH had a greater effect on all-cause mortality in Asians compared with Whites (hazard ratio [HR] 2.66, 95% CI 1.83-3.88 vs HR 1.30, 95% CI 0.90-1.89, P for interaction=0.02). Conclusion-Our findings from two large community-based cohorts show prominent race differences in ECG characteristics between Whites and Asians, and also suggest a differential association with mortality. These differences may carry implications for race-specific ECG reference ranges and cardiovascular risk. C1 [Santhanakrishnan, Rajalakshmi; Magnani, Jared M.; Vasan, Ramachandran S.] Boston Univ, Sch Med, Dept Med, Cardiovasc Med Sect, Boston, MA 02118 USA. [Vasan, Ramachandran S.] Boston Univ, Sch Med, Sect Prevent Med & Epidemiol, Boston, MA 02118 USA. [Wang, Na] Boston Univ, Sch Publ Hlth, Data Coordinating Ctr, Boston, MA USA. [Larson, Martin G.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [Larson, Martin G.; Magnani, Jared M.; Vasan, Ramachandran S.; Ho, Jennifer E.] NHLBI, Framingham, MA USA. [Larson, Martin G.; Magnani, Jared M.; Vasan, Ramachandran S.; Ho, Jennifer E.] Boston Univ Framingham Heart Study, Framingham, MA USA. [Wang, Thomas J.] Vanderbilt Univ, Dept Med, Div Cardiovasc Med, Nashville, TN USA. [Yap, Jonathan; Lam, Carolyn S. P.] Natl Heart Ctr Singapore, Dept Cardiol, Singapore, Singapore. [Feng, Liang; Lam, Carolyn S. P.] Duke NUS Grad Med Sch, Singapore, Singapore. [Yap, Keng B.] Ng Teng Fong Hosp, Geriatr Med, Singapore, Singapore. [Ong, Hean Y.] Khoo Teck Puat Hosp, Dept Cardiol, Singapore, Singapore. [Ng, Tze P.] Yong Loo Lin Sch Med, Singapore, Singapore. [Richards, Arthur Mark] Natl Univ Hlth Syst, Cardiovasc Res Inst, Singapore, Singapore. [Richards, Arthur Mark] Univ Otago, Christchurch Heart Inst, Christchurch, New Zealand. [Ho, Jennifer E.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Ho, Jennifer E.] Massachusetts Gen Hosp, Dept Med, Div Cardiol, Boston, MA 02114 USA. RP Ho, JE (reprint author), Massachusetts Gen Hosp, CPZN 185 Cambridge St,3224, Boston, MA 02114 USA. EM jho1@partners.org FU National Heart, Lung, and Blood Institute's Framingham Heart Study [N01-HC-25195, HHSN268201500001I]; National Institutes of Health [K23-HL116780]; Boston University School of Medicine, Department of Medicine Career Investment award (Boston, MA) FX This work was partially supported by the National Heart, Lung, and Blood Institute's Framingham Heart Study (Contract No. N01-HC-25195 and HHSN268201500001I). This work was supported by the National Institutes of Health-K23-HL116780 (Dr Ho). Dr Ho is supported by a Boston University School of Medicine, Department of Medicine Career Investment award (Boston, MA). NR 35 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2047-9980 J9 J AM HEART ASSOC JI J. Am. Heart Assoc. PD MAR PY 2016 VL 5 IS 3 AR e002956 DI 10.1161/JAHA.115.002956 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DY7MA UT WOS:000385312200040 PM 27016575 ER PT J AU Truong, QA Schulman-Marcus, J Zakroysky, P Chou, ET Nagurney, JT Fleg, JL Schoenfeld, DA Udelson, JE Hoffmann, U Woodard, PK AF Truong, Quynh A. Schulman-Marcus, Joshua Zakroysky, Pearl Chou, Eric T. Nagurney, John T. Fleg, Jerome L. Schoenfeld, David A. Udelson, James E. Hoffmann, Udo Woodard, Pamela K. TI Coronary CT Angiography Versus Standard Emergency Department Evaluation for Acute Chest Pain and Diabetic Patients: Is There Benefit With Early Coronary CT Angiography? SO JOURNAL OF THE AMERICAN HEART ASSOCIATION LA English DT Article DE acute coronary syndrome; cardiac computed tomography; chest pain diagnosis; diabetes mellitus; emergency department ID COMPUTED TOMOGRAPHIC ANGIOGRAPHY; ACUTE CARDIAC ISCHEMIA; MYOCARDIAL-INFARCTION; ASSISTED TOMOGRAPHY; ARTERY-DISEASE; RISK-FACTORS; TRIAL; MULTICENTER; MELLITUS; ACQUISITION AB Background-Cardiac computed tomography angiography (CCTA) reduces emergency department length of stay compared with standard evaluation in patients with low-and intermediate-risk acute chest pain. Whether diabetic patients have similar benefits is unknown. Methods and Results-In this prespecified analysis of the Rule Out Myocardial Ischemia/Infarction by Computer Assisted Tomography (ROMICAT II) multicenter trial, we randomized 1000 patients (17% diabetic) with symptoms suggestive of acute coronary syndrome to CCTA or standard evaluation. The rate of acute coronary syndrome was 8% in both diabetic and nondiabetic patients (P=1.0). Length of stay was unaffected by the CCTA strategy for diabetic patients (23.9 versus 27.2 hours, P=0.86) but was reduced for nondiabetic patients compared with standard evaluation (8.4 versus 26.5 hours, P<0.0001; P interaction=0.004). CCTA resulted in 3-fold more direct emergency department discharge in both groups (each P=0.0001, P interaction=0.27). No difference in hospital admissions was seen between the 2 strategies in diabetic and nondiabetic patients (P interaction=0.09). Both groups had more downstream testing and higher radiation doses with CCTA, but these were highest in diabetic patients (all P interaction=0.04). Diabetic patients had fewer normal CCTAs than nondiabetic patients (32% versus 50%, P=0.003) and similar normalcy rates with standard evaluation (P=0.70). Notably, 66% of diabetic patients had no or mild stenosis by CCTA with short length of stay comparable to that of nondiabetic patients (P=0.34), whereas those with > 50% stenosis had a high prevalence of acute coronary syndrome, invasive coronary angiography, and revascularization. Conclusions-Knowledge of coronary anatomy with CCTA is beneficial for diabetic patients and can discriminate between lower risk patients with no or little coronary artery disease who can be discharged immediately and higher risk patients with moderate to severe disease who warrant further workup. C1 [Truong, Quynh A.; Schulman-Marcus, Joshua] New York Presbyterian Hosp, Dalio Inst Cardiovasc Imaging, New York, NY USA. [Truong, Quynh A.; Schulman-Marcus, Joshua] Weill Cornell Med Coll, New York, NY USA. [Nagurney, John T.] Massachusetts Gen Hosp, Emergency Dept, Boston, MA 02114 USA. [Hoffmann, Udo] Massachusetts Gen Hosp, Cardiac MR PET CT Program, Dept Radiol, Boston, MA 02114 USA. [Zakroysky, Pearl; Schoenfeld, David A.] Harvard Med Sch, Massachusetts Gen Hosp, Ctr Biostat, Boston, MA USA. [Chou, Eric T.] Kaiser Permanente, Fontana Med Ctr, Fontana, CA USA. [Fleg, Jerome L.] NHLBI, Div Cardiovasc Sci, Bldg 10, Bethesda, MD 20892 USA. [Udelson, James E.] Tufts Med Ctr, Div Cardiol, Boston, MA USA. [Udelson, James E.] Tufts Med Ctr, Ctr Cardiovasc, Boston, MA USA. [Woodard, Pamela K.] Washington Univ, Sch Med, Mallinckrodt Inst Radiol, St Louis, MO USA. RP Woodard, PK (reprint author), 510 South Kingshighway Blvd 8131, St Louis, MO 63110 USA. EM woodardp@mir.wustl.edu FU NIH/NHLBI [U01HL092040, U01HL092022]; NIH [K23HL098370, L30HL093896] FX The study was supported by the NIH/NHLBI (U01HL092040 and U01HL092022). Dr Truong was supported by the NIH (K23HL098370 and L30HL093896). NR 19 TC 1 Z9 1 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2047-9980 J9 J AM HEART ASSOC JI J. Am. Heart Assoc. PD MAR PY 2016 VL 5 IS 3 AR e003137 DI 10.1161/JAHA.115.003137 PG 11 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DY7MA UT WOS:000385312200053 PM 27006119 ER PT J AU Hu, LS Zhang, HB Bergholz, J Sun, SN Xiao, ZXJ AF Hu, Linshan Zhang, Haibo Bergholz, Johann Sun, Shengnan Xiao, Zhi-Xiong Jim TI MDM2/MDMX: Master negative regulators for p53 and RB SO MOLECULAR & CELLULAR ONCOLOGY LA English DT Editorial Material DE MDM2; MDMX; p53; RB ID RETINOBLASTOMA PROTEIN; MDM2; INACTIVATION; SUPPRESSION; PATHWAY AB MDM2 (mouse double minute 2 homolog) and MDMX (double minute X human homolog, also known as MDM4) are critical negative regulators of tumor protein p53. Our recent work shows that MDMX binds to and promotes degradation of retinoblastoma protein (RB) in an MDM2-dependent manner. In a xenograft tumor growth mouse model, silencing of MDMX results in inhibition of p53-deficient tumor growth, which can be effectively reversed by concomitant RB silencing. Thus, MDMX exerts its oncogenic activity via suppression of RB. C1 [Hu, Linshan; Zhang, Haibo; Bergholz, Johann; Sun, Shengnan; Xiao, Zhi-Xiong Jim] Sichuan Univ, Coll Life Sci, Ctr Growth Metab & Aging, Key Lab Bioresource & Ecoenvironm,Minist Educ, Chengdu, Peoples R China. [Zhang, Haibo] NCI, LCBG, Bethesda, MD 20892 USA. [Bergholz, Johann] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. RP Xiao, ZXJ (reprint author), Sichuan Univ, Coll Life Sci, Ctr Growth Metab & Aging, Key Lab Bioresource & Ecoenvironm,Minist Educ, Chengdu, Peoples R China. EM jimzx@scu.edu.cn NR 10 TC 1 Z9 1 U1 2 U2 2 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 2372-3556 EI 2372-3548 J9 MOL CELL ONCOL JI MOL. CELL ONCOL. PD MAR PY 2016 VL 3 IS 2 AR UNSP e1106635 DI 10.1080/23723556.2015.1106635 PG 3 WC Oncology SC Oncology GA DY6OR UT WOS:000385247100052 PM 27308631 ER PT J AU Johnsen, JI Wickstrom, M Baryawno, N AF Johnsen, John Inge Wickstrom, Malin Baryawno, Ninib TI Wingless/beta-catenin signaling as a modulator of chemoresistance in cancer SO MOLECULAR & CELLULAR ONCOLOGY LA English DT Article DE beta-catenin; chemoresistance; MGMT; temozolomide ID DRUG-RESISTANCE; MGMT; METHYLTRANSFERASE; PATHWAY AB O6-methylguanine-DNA methyltransferase (MGMT) is a DNA repair enzyme involved in chemoresistance. We have shown that MGMT abundance is regulated by canonical Wingless (Wnt) signaling and that inhibition of Wnt signaling restores chemosensitivity in preclinical cancer models. These findings have direct therapeutic implications for the treatment of cancers with high MGMT expression. C1 [Johnsen, John Inge; Wickstrom, Malin] Karolinska Inst, Dept Womens & Childrens Hlth, Childhood Canc Res Unit, S-17176 Stockholm, Sweden. [Baryawno, Ninib] Harvard Univ, Dept Stem & Regenerat Biol, Cambridge, MA 02138 USA. [Baryawno, Ninib] Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA. [Baryawno, Ninib] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Baryawno, Ninib] Harvard Stem Cell Inst, Cambridge, MA USA. RP Johnsen, JI (reprint author), Karolinska Inst, Dept Womens & Childrens Hlth, Childhood Canc Res Unit, S-17176 Stockholm, Sweden. EM john.inge.johnsen@ki.se NR 10 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 2372-3556 EI 2372-3548 J9 MOL CELL ONCOL JI MOL. CELL ONCOL. PD MAR PY 2016 VL 3 IS 2 AR UNSP e1131356 DI 10.1080/23723556.2015.1131356 PG 3 WC Oncology SC Oncology GA DY6OR UT WOS:000385247100062 PM 27308637 ER PT J AU Bingham, D Scheich, B Byfield, R Wilson, B Bateman, BT AF Bingham, Debra Scheich, Benjamin Byfield, Renee Wilson, Barbara Bateman, Brian T. TI Postpartum Hemorrhage Preparedness Elements Vary Among Hospitals in New Jersey and Georgia SO JOGNN-JOURNAL OF OBSTETRIC GYNECOLOGIC AND NEONATAL NURSING LA English DT Article DE hemorrhage preparedness; hemorrhage protocol; obstetric hemorrhage; quality improvement ID PREGNANCY-RELATED MORTALITY; UNITED-STATES; OBSTETRIC HEMORRHAGE; EPIDEMIOLOGY; MORBIDITY; DISPARITY; PROTOCOLS; DELIVERY; SAFETY; RATES AB Objective: To identify the presence or absence of 38 postpartum hemorrhage preparedness elements in hospitals in New Jersey and Georgia as a component of the Postpartum Hemorrhage Project of the Association of Women's Health, Obstetric and Neonatal Nurses. Design: Quality improvement baseline assessment survey. Setting: Hospitals (N = 95) in New Jersey and Georgia. Participants: Key informants were clinicians who were members of their hospitals' obstetric teams and were recognized as knowledgeable about their hospitals' postpartum hemorrhage policies. Methods: An electronic survey was sent by e-mail to each identified hospital's key informant. Results: The mean number of elements present was 23.1 (SD = 5.2; range = 12-34). Volume of births, students, magnet status, and other hospital characteristics did not predict preparedness. None of the hospitals had all of the 38 preparedness elements available. Less than 50% of the hospitals had massive hemorrhage protocols, performed risk assessments and drills, or measured blood loss. For every 10% increase in the total percentage of African American women who gave birth, there was a decrease of one preparedness element. Conclusion: Objective measures of preparedness are needed, because perceptions of preparedness were inconsistent with the number of preparedness elements reported. C1 [Bingham, Debra] Assoc Womens Hlth Obstet & Neonatal Nurses, Nursing Res Educ & Practice, 1800 M St NW,Suite 740 South, Washington, DC 20036 USA. [Scheich, Benjamin] Assoc Womens Hlth Obstet & Neonatal Nurses, Data Analyt, Washington, DC USA. [Byfield, Renee] Assoc Womens Hlth Obstet & Neonatal Nurses, Washington, DC USA. [Wilson, Barbara] Univ Utah, Coll Nursing, Acad Programs, Salt Lake City, UT 84112 USA. [Bateman, Brian T.] Massachusetts Gen Hosp, Dept Anesthesiol Crit Care & Pain Med, Anesthesia, Boston, MA 02114 USA. [Bateman, Brian T.] Harvard Med Sch, Boston, MA USA. RP Bingham, D (reprint author), Assoc Womens Hlth Obstet & Neonatal Nurses, Nursing Res Educ & Practice, 1800 M St NW,Suite 740 South, Washington, DC 20036 USA. EM dbingham@awhonn.org FU Merck, through its Merck for Mothers program FX The research in this publication was supported by funding from Merck, through its Merck for Mothers program, and is the sole responsibility of the authors. Merck for Mothers is known as MSD for Mothers outside the United States and Canada. The authors acknowledge the contributions of the other members of the AWHONN Postpartum Hemorrhage Project Quality Improvement Expert Panel and Regional Project Leaders for their help in developing the survey: NR 36 TC 1 Z9 1 U1 2 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0884-2175 EI 1552-6909 J9 JOGNN-J OBST GYN NEO JI JOGNN PD MAR-APR PY 2016 VL 45 IS 2 BP 227 EP 238 DI 10.1016/j.jogn.2015.12.003 PG 12 WC Nursing; Obstetrics & Gynecology SC Nursing; Obstetrics & Gynecology GA DY3MS UT WOS:000384998000008 PM 26852254 ER PT J AU Manchikanti, L Candido, KD Singh, V Hirsch, JA AF Manchikanti, Laxmaiah Candido, Kenneth D. Singh, Vijay Hirsch, Joshua A. TI Evidence-based review of epidural adhesiolysis is misleading SO JOURNAL OF NEUROSURGICAL SCIENCES LA English DT Letter ID DOUBLE-BLIND; INJECTIONS; TRIAL C1 [Manchikanti, Laxmaiah] Univ Louisville, Louisville, KY 40292 USA. [Candido, Kenneth D.] Advocate Illinois Mason Med Ctr, Dept Anesthesiol, Chicago, IL USA. [Singh, Vijay] Spine Pain Diagnost Associates, Niagara, WI USA. [Singh, Vijay] Massachusetts Gen Hosp, Dept Minimally Invas Spine Surg, Boston, MA 02114 USA. [Singh, Vijay] Harvard Med Sch, Radiol, Boston, MA USA. RP Manchikanti, L (reprint author), Pain Management Ctr Paducah, Paducah, KY USA. EM drlm@thepainmd.com NR 5 TC 0 Z9 0 U1 0 U2 0 PU EDIZIONI MINERVA MEDICA PI TURIN PA CORSO BRAMANTE 83-85 INT JOURNALS DEPT., 10126 TURIN, ITALY SN 0390-5616 EI 1827-1855 J9 J NEUROSURG SCI JI J. Neurosurg. Sci. PD MAR PY 2016 VL 60 IS 1 BP 136 EP 137 PG 2 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA DY2UF UT WOS:000384946900017 PM 26947785 ER PT J AU Worsley, R Santoro, N Miller, KK Parish, SJ Davis, SR AF Worsley, Roisin Santoro, Nanette Miller, Karen K. Parish, Sharon J. Davis, Susan R. TI Hormones and Female Sexual Dysfunction: Beyond Estrogens and Androgens-Findings From the Fourth International Consultation on Sexual Medicine SO JOURNAL OF SEXUAL MEDICINE LA English DT Article DE Oxytocin; Progesterone; Endocrine Disorder ID POLYCYSTIC-OVARY-SYNDROME; QUALITY-OF-LIFE; METABOLIC SYNDROME; PROGESTERONE-RECEPTOR; POSTMENOPAUSAL WOMEN; INTRANASAL OXYTOCIN; EMOTIONAL DISTRESS; PLASMA OXYTOCIN; DEFICIENT WOMEN; OBESITY AB Introduction: In recent years, multiple hormones have been investigated in relation to female sexual function. Because consumers can easily purchase products claiming to contain these hormones, a clear statement regarding the current state of knowledge is required. Aim: To review the contribution of hormones, other than estrogens and androgens, to female sexual functioning and the evidence that specific endocrinopathies in women are associated with female sexual dysfunction (FSD) and to update the previously published International Society of Sexual Medicine Consensus on this topic. Methods: The literature was searched using several online databases with an emphasis on studies examining the physiologic role of oxytocin, prolactin, and progesterone in female sexual function and any potential therapeutic effect of these hormones. The association between common endocrine disorders, such as polycystic ovary syndrome, pituitary disorders, and obesity, and FSD also was examined. Main Outcome Measures: Quality of data published in the literature and recommendations were based on the Grading of Recommendations Assessment, Development and Education system. Results: There is no evidence to support the use of oxytocin or progesterone for FSD. Treating hyperprolactinemia might lessen FSD. Polycystic ovary syndrome, obesity, and metabolic syndrome could be associated with FSD, but data are limited. There is a strong association between diabetes mellitus and FSD. Conclusion: Further research is required; in particular, high-quality, large-scale studies of women with common endocrinopathies are needed to determine the impact of these prevalent disorders on female sexual function. Copyright (C) 2016, International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved. C1 [Worsley, Roisin; Davis, Susan R.] Sch Publ Hlth & Prevent Med, Womens Hlth Res Program, Melbourne, Vic, Australia. [Santoro, Nanette] Univ Colorado, Sch Med, Dept Obstet & Gynecol, Aurora, CO USA. [Miller, Karen K.] Massachusetts Gen Hosp, Neuroendocrine Res Program Womens Hlth, Boston, MA 02114 USA. [Miller, Karen K.] Massachusetts Gen Hosp, Neuroendocrine & Pituitary Clin Ctr, Boston, MA 02114 USA. [Miller, Karen K.] Harvard Med Sch, Boston, MA USA. [Parish, Sharon J.] Weill Cornell Med Coll, Dept Clin Psychiat Clin Med, New York, NY USA. RP Davis, SR (reprint author), Monash Univ, Womens Hlth Res Program, Sch Publ Hlth & Prevent Med, Level 6,99 Commercial Rd, Melbourne, Vic 3004, Australia. EM Susan.Davis@monash.edu OI Worsley, Roisin/0000-0001-9201-1222 FU National Health and Medical Research Council [1041853] FX S.R.D. is a National Health and Medical Research Council Research Fellow (grant 1041853). NR 65 TC 2 Z9 2 U1 3 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1743-6095 EI 1743-6109 J9 J SEX MED JI J. Sex. Med. PD MAR PY 2016 VL 13 IS 3 BP 283 EP 290 DI 10.1016/j.jsxm.2015.12.014 PG 8 WC Urology & Nephrology SC Urology & Nephrology GA DX9PB UT WOS:000384726500001 PM 26944460 ER PT J AU Santoro, N Worsley, R Miller, KK Parish, SJ Davis, SR AF Santoro, Nanette Worsley, Roisin Miller, Karen K. Parish, Sharon J. Davis, Susan R. TI Role of Estrogens and Estrogen-Like Compounds in Female Sexual Function and Dysfunction SO JOURNAL OF SEXUAL MEDICINE LA English DT Article DE Hormones; Female Sexual Dysfunction; Estrogen ID PREMATURE OVARIAN FAILURE; OLDER POSTMENOPAUSAL WOMEN; BREAST-CANCER SURVIVORS; VAGINAL ATROPHY; TURNER-SYNDROME; MENOPAUSAL TRANSITION; REPLACEMENT THERAPY; STEROID-HORMONES; ANDROGEN LEVELS; MIDLIFE WOMEN AB Introduction: Sex steroids are important in female sexual function and dysfunction. Aim: To review the role of estrogens in the physiology and pathophysiology of female sexual functioning and the evidence for efficacy of estrogen therapy for female sexual dysfunction to update the previously published International Society of Sexual Medicine Consensus on this topic. Methods: Panel members reviewed the published literature using online databases for studies pertaining to estrogen in female sexual function and dysfunction. Attention was specifically given to clinical trials that had reported on sexual function outcomes in women treated with estrogen. Main Outcome Measures: Quality of data published in the literature and recommendations were based on the GRADES system. Results: Observational studies that have considered relationship factors and physical or mental health have reported that these factors contribute more to sexual functioning than menopausal status or estrogen levels. Few clinical trials have investigated estrogen therapy with sexual function as a primary outcome. The available data do not support systemic estrogen therapy for the treatment of female sexual dysfunction. Topical vaginal estrogen therapy improves sexual function in postmenopausal women with vulvovaginal atrophy (VVA) and is considered first-line treatment of VVA. Oral ospemifene, a selective estrogen receptor modulator, is effective for the treatment of VVA and might have independent systemic effects on female sexual function. Conclusion: For sexual problems, the treatment of VVA remains the most pertinent indication for estrogen therapy. When systemic symptoms are absent, estrogen therapy ideally can be administered by a vaginal preparation alone. Systemic estrogen therapy with combined estrogen and progestin in non-hysterectomized women is indicated for women who require treatment for vasomotor and/or other systemic estrogen deficiency symptoms. The improvement in well-being achieved by relief of vasomotor and other symptoms might improve libido in some women and abrogate further intervention. Copyright (C) 2016, International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved. C1 [Santoro, Nanette] Univ Colorado, Sch Med, Aurora, CO USA. [Worsley, Roisin; Davis, Susan R.] Sch Publ Hlth & Prevent Med, Womens Hlth Res Program, Melbourne, Vic, Australia. [Miller, Karen K.] Massachusetts Gen Hosp, Neuroendocrine Res Program Womens Hlth, Boston, MA 02114 USA. [Miller, Karen K.] Massachusetts Gen Hosp, Neuroendocrine & Pituitary Clin Ctr, Boston, MA 02114 USA. [Miller, Karen K.] Harvard Med Sch, Boston, MA USA. [Parish, Sharon J.] Weill Cornell Med Coll, New York, NY USA. RP Davis, SR (reprint author), Monash Univ, Womens Hlth Res Program, Sch Publ Hlth & Prevent Med, Level 6,99 Commercial Rd, Melbourne, Vic 3004, Australia. EM Susan.Davis@monash.edu OI Worsley, Roisin/0000-0001-9201-1222 FU National Health and Medical Research Council [1041853] FX S.R.D. is an National Health and Medical Research Council Research Fellow (grant 1041853). NR 96 TC 3 Z9 3 U1 2 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1743-6095 EI 1743-6109 J9 J SEX MED JI J. Sex. Med. PD MAR PY 2016 VL 13 IS 3 BP 305 EP 316 DI 10.1016/j.jsxm.2015.11.015 PG 12 WC Urology & Nephrology SC Urology & Nephrology GA DX9PB UT WOS:000384726500003 PM 26944462 ER PT J AU Chitilian, HV AF Chitilian, Hovig V. TI Preface SO INTERNATIONAL ANESTHESIOLOGY CLINICS LA English DT Editorial Material C1 [Chitilian, Hovig V.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Chitilian, HV (reprint author), Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02139 USA. EM HCHITILIAN@MGH.HARVARD.EDU NR 0 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 0020-5907 J9 INT ANESTHESIOL CLIN JI Int. Anesthesiol. Clin. PD SPR PY 2016 VL 54 IS 2 BP VII EP VIII DI 10.1097/AIA.0000000000000092 PG 2 WC Anesthesiology SC Anesthesiology GA DV9MT UT WOS:000383265400001 PM 26967807 ER PT J AU Vazquez, R Chitilian, HV AF Vazquez, Rafael Chitilian, Hovig V. TI Anesthesia for the Endovascular Management of Aortic Disease SO INTERNATIONAL ANESTHESIOLOGY CLINICS LA English DT Review ID CEREBROSPINAL-FLUID DRAINAGE; SPINAL-CORD ISCHEMIA; LEFT SUBCLAVIAN ARTERY; ABDOMINAL COMPARTMENT SYNDROME; RANDOMIZED-CONTROLLED-TRIAL; OPEN SURGICAL REPAIR; INTRAOPERATIVE TRANSESOPHAGEAL ECHOCARDIOGRAPHY; CONTRAST-INDUCED NEPHROPATHY; LONG-TERM OUTCOMES; ANEURYSM REPAIR C1 [Vazquez, Rafael; Chitilian, Hovig V.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Gray Bigelow 444,55 Fruit St, Boston, MA 02114 USA. RP Chitilian, HV (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Gray Bigelow 444,55 Fruit St, Boston, MA 02114 USA. EM HCHITILIAN@MGH.HARVARD.EDU NR 126 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 0020-5907 J9 INT ANESTHESIOL CLIN JI Int. Anesthesiol. Clin. PD SPR PY 2016 VL 54 IS 2 BP 52 EP 75 DI 10.1097/AIA.0000000000000093 PG 24 WC Anesthesiology SC Anesthesiology GA DV9MT UT WOS:000383265400004 PM 26967802 ER PT J AU Luo, Y Anderson, TA AF Luo, Yong Anderson, Thomas A. TI Phantom Limb Pain: A Review SO INTERNATIONAL ANESTHESIOLOGY CLINICS LA English DT Review ID SPINAL-CORD STIMULATION; POST-AMPUTATION PAIN; DORSAL-ROOT GANGLION; TIME-SERIES ANALYSIS; POSTAMPUTATION PAIN; LOWER-EXTREMITY; CORTICAL REORGANIZATION; CONTROLLED-TRIAL; DOUBLE-BLIND; STUMP PAIN C1 [Luo, Yong; Anderson, Thomas A.] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. [Anderson, Thomas A.] Harvard Med Sch, Boston, MA USA. RP Anderson, TA (reprint author), Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. EM TANDERSON9@MGH.HARVARD.EDU NR 87 TC 1 Z9 1 U1 18 U2 20 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0020-5907 J9 INT ANESTHESIOL CLIN JI Int. Anesthesiol. Clin. PD SPR PY 2016 VL 54 IS 2 BP 121 EP 139 DI 10.1097/AIA.0000000000000095 PG 19 WC Anesthesiology SC Anesthesiology GA DV9MT UT WOS:000383265400007 PM 26967805 ER PT J AU Obedin-Maliver, J Makadon, HJ AF Obedin-Maliver, Juno Makadon, Harvey J. TI Transgender men and pregnancy SO OBSTETRIC MEDICINE LA English DT Review DE Transgender pregnancy; gender identity; counseling; sexual orientation; primary care transgender people; obstetrical care of transgender people; behavioral aspects of transgender pregnancy; testosterone in pregnancy ID TESTOSTERONE LEVELS; BIRTH AB Transgender people have experienced significant advances in societal acceptance despite experiencing continued stigma and discrimination. While it can still be difficult to access quality health care, and there is a great deal to be done to create affirming health care organizations, there is growing interest around the United States in advancing transgender health. The focus of this commentary is to provide guidance to clinicians caring for transgender men or other gender nonconforming people who are contemplating, carrying, or have completed a pregnancy. Terms transgender and gender nonconforming specifically refer to those whose gender identity (e.g., being a man) differs from their female sex assigned at birth. Many, if not most transgender men retain their female reproductive organs and retain the capacity to have children. Review of their experience demonstrates the need for preconception counseling that includes discussion of stopping testosterone while trying to conceive and during pregnancy, and anticipating increasing experiences of gender dysphoria during and after pregnancy. The clinical aspects of delivery itself fall within the realm of routine obstetrical care, although further research is needed into how mode and environment of delivery may affect gender dysphoria. Postpartum considerations include discussion of options for chest (breast) feeding, and how and when to reinitiate testosterone. A positive perinatal experience begins from the moment transgender men first present for care and depends on comprehensive affirmation of gender diversity. C1 [Obedin-Maliver, Juno] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Obedin-Maliver, Juno] San Francisco VA Med Ctr, Dept Gynecol, San Francisco, CA USA. [Makadon, Harvey J.] Fenway Inst, Natl LGBT Hlth Educ Ctr, 1340 Boylston St, Boston, MA 02215 USA. [Makadon, Harvey J.] Harvard Med Sch, Boston, MA USA. RP Makadon, HJ (reprint author), Fenway Inst, Natl LGBT Hlth Educ Ctr, 1340 Boylston St, Boston, MA 02215 USA. EM hmakadon@fenwayhealth.org NR 41 TC 0 Z9 0 U1 4 U2 4 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1753-495X EI 1753-4968 J9 OBSTET MED JI Obstet. Med. PD MAR PY 2016 VL 9 IS 1 BP 4 EP 8 DI 10.1177/1753495X15612658 PG 5 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA DV7LR UT WOS:000383118000002 ER PT J AU Goto, T Gibo, K Hagiwara, Y Okubo, M Brown, DFM Brown, CA Hasegawa, K AF Goto, Tadahiro Gibo, Koichiro Hagiwara, Yusuke Okubo, Masashi Brown, David F. M. Brown, Calvin A., III Hasegawa, Kohei TI Factors Associated with First-Pass Success in Pediatric Intubation in the Emergency Department SO WESTERN JOURNAL OF EMERGENCY MEDICINE LA English DT Article DE Intubation; Pediatric; Children; Emergency Medicine ID AIRWAY MANAGEMENT; ENDOTRACHEAL INTUBATION; TRACHEAL INTUBATION; VIDEO LARYNGOSCOPE; 1ST ATTEMPT AB Introduction: The objective of this study was to investigate the factors associated with first-pass success in pediatric intubation in the emergency department (ED). Methods: We analyzed the data from two multicenter prospective studies of ED intubation in 17 EDs between April 2010 and September 2014. The studies prospectively measured patient's age, sex, principal indication for intubation, methods (e.g., rapid sequence intubation [RSI]), devices, and intubator's level of training and specialty. To evaluate independent predictors of first-pass success, we fit logistic regression model with generalized estimating equations. In the sensitivity analysis, we repeated the analysis in children < 10 years. Results: A total of 293 children aged = 18 years who underwent ED intubation were eligible for the analysis. The overall first-pass success rate was 60% (95% CI [54%-66%]). In the multivariable model, age = 10 years (adjusted odds ratio [aOR], 2.45; 95% CI [1.23-4.87]), use of RSI (aOR, 2.17; 95% CI [1.31-3.57]), and intubation attempt by an emergency physician (aOR, 3.21; 95% CI [1.78-5.83]) were significantly associated with a higher chance of first-pass success. Likewise, in the sensitivity analysis, the use of RSI (aOR, 3.05; 95% CI [1.63-5.70]), and intubation attempt by an emergency physician (aOR, 4.08; 95% CI [1.92-8.63]) were significantly associated with a higher chance of first-pass success. Conclusion: Based on two large multicenter prospective studies of ED airway management, we found that older age, use of RSI, and intubation by emergency physicians were the independent predictors of a higher chance of first-pass success in children. Our findings should facilitate investigations to develop optimal airway management strategies in critically-ill children in the ED. C1 [Goto, Tadahiro; Brown, David F. M.; Hasegawa, Kohei] Massachusetts Gen Hosp, Dept Emergency Med, 125 Nashua St,Suite 125, Boston, MA 02114 USA. [Gibo, Koichiro] Okinawa Prefectural Chubu Hosp, Dept Emergency Med, Uruma, Okinawa, Japan. [Hagiwara, Yusuke] Tokyo Metropolitan Childrens Med Ctr, Dept Paediat Emergency & Crit Care Med, Div Paediat Emergency Med, Tokyo, Japan. [Okubo, Masashi] Mayo Clin, Dept Emergency Med, Rochester, MN USA. [Brown, Calvin A., III] Brigham & Womens Hosp, Dept Emergency Med, Boston, MA 02115 USA. RP Goto, T (reprint author), Massachusetts Gen Hosp, Dept Emergency Med, 125 Nashua St,Suite 125, Boston, MA 02114 USA. EM tgoto1@mgh.harvard.edu NR 23 TC 0 Z9 0 U1 0 U2 0 PU WESTJEM PI ORANGE PA C/O SHAHRAM LOTFIPOUR, MD, MPH, 333 CITY BLVD W STE 640, RT 128-01, ORANGE, CA 92868 USA SN 1936-900X EI 1936-9018 J9 WEST J EMERG MED JI West. J. Emerg. Med. PD MAR PY 2016 VL 17 IS 4 BP 129 EP 134 DI 10.5811/westjem.2016.1.28685 PG 6 WC Emergency Medicine SC Emergency Medicine GA DV3QE UT WOS:000382837100003 PM 26973736 ER PT J AU Akindele, RN Svoboda, LA Martins, Y Freedman, RA Elfiky, A Berlin, ST Lathan, CS AF Akindele, Ruth N. Svoboda, Ludmila A. Martins, Yolanda Freedman, Rachel A. Elfiky, Aymen Berlin, Suzanne T. Lathan, Christopher S. TI Closing the disparity gap: Attributes of patients referred to a community cancer program SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Meeting Abstract CT 8th AACR Conference on the Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved CY NOV 13-16, 2015 CL Atlanta, GA SP Amer Assoc Canc Res C1 [Akindele, Ruth N.; Svoboda, Ludmila A.; Martins, Yolanda; Freedman, Rachel A.; Elfiky, Aymen; Berlin, Suzanne T.; Lathan, Christopher S.] Dana Farber Canc Inst, Boston, MA 02115 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 1055-9965 EI 1538-7755 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD MAR PY 2016 VL 25 IS 3 SU S MA A28 DI 10.1158/1538-7755.DISP16-A28 PG 2 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA DR8PH UT WOS:000380159300042 ER PT J AU Hudson, A Zeigler-Johnson, C Glanz, K Spangler, E Rebbeck, TR Morales, KH AF Hudson, Aaron Zeigler-Johnson, Charnita Glanz, Karen Spangler, Elaine Rebbeck, Timothy R. Morales, Knashawn H. TI An analysis of the interaction between obesity and measures predicting prostate cancer-free survival SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Meeting Abstract CT 8th AACR Conference on the Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved CY NOV 13-16, 2015 CL Atlanta, GA SP Amer Assoc Canc Res C1 [Hudson, Aaron] Univ Illinois, Champaign, IL USA. [Zeigler-Johnson, Charnita] Thomas Jefferson Univ, Philadelphia, PA 19107 USA. [Glanz, Karen; Spangler, Elaine; Morales, Knashawn H.] Univ Penn, Philadelphia, PA 19104 USA. [Rebbeck, Timothy R.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Rebbeck, Timothy R.] Harvard TH Chan Sch Publ Hlth, 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 1055-9965 EI 1538-7755 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD MAR PY 2016 VL 25 IS 3 SU S MA A75 DI 10.1158/1538-7755.DISP15-A75 PG 1 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA DR8PH UT WOS:000380159300201 ER PT J AU San Miguel, SL Ayala-Marin, A Briant, KJ Desai, N Gatus, L Gomez-Aristizabal, D Gonzalez, E Gonzalez, ME Heredia, NI Lazo, N Ortiz, R Rangel, L Rivera, Y Sanchez, J Serrano, M Whitaker, RAT AF San Miguel, Sandra L. Ayala-Marin, Aleli Briant, Katherine J. Desai, Niyati Gatus, Leticia Gomez-Aristizabal, Diego Gonzalez, Evelyn Gonzalez, Martha E. Heredia, Natalia I. Lazo, Nadia Ortiz, Rosa Rangel, Lizette Rivera, Yonaira Sanchez, Janet Serrano, Mayra Whitaker, Rose A. Trevino TI National Outreach Network Community Health Educators: An effective framework to reduce cancer health disparities among Latinos SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Meeting Abstract CT 8th AACR Conference on the Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved CY NOV 13-16, 2015 CL Atlanta, GA SP Amer Assoc Canc Res C1 [San Miguel, Sandra L.; Whitaker, Rose A. Trevino] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Ayala-Marin, Aleli] Univ Puerto Rico, San Juan, PR 00936 USA. [Briant, Katherine J.] Fred Hutchinson Canc Res Ctr, 1124 Columbia St, Seattle, WA 98104 USA. [Desai, Niyati] Oregon Hlth & Sci Univ, Knight Canc Inst, Gresham, OR USA. [Gatus, Leticia] Baylor Coll Med, Houston, TX 77030 USA. [Gomez-Aristizabal, Diego] Dana Farber Canc Inst, Boston, MA 02115 USA. [Gonzalez, Evelyn; Ortiz, Rosa] Fox Chase Canc Ctr, 7701 Burholme Ave, Philadelphia, PA 19111 USA. [Gonzalez, Martha E.] Univ Miami, Miami, FL USA. [Heredia, Natalia I.; Rangel, Lizette] Univ Texas Hlth Sci Ctr Houston, Houston, TX 77030 USA. [Lazo, Nadia] Boston Med Ctr, Boston, MA USA. [Rivera, Yonaira] H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL USA. [Sanchez, Janet] New Mexico State Univ, Las Cruces, NM 88003 USA. [Serrano, Mayra] City Hope Natl Med Ctr, Duarte, CA USA. NR 0 TC 0 Z9 0 U1 2 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 EI 1538-7755 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD MAR PY 2016 VL 25 IS 3 SU S MA A31 DI 10.1158/1538-7755.DISP15-A31 PG 2 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA DR8PH UT WOS:000380159300040 ER PT J AU Kakumanu, S Jaffee, K Visness, CM Dresen, A Burger, M Witter, FR O'Connor, GT Cruikshank, WW Shreffler, WG Bacharier, LB Gern, JE AF Kakumanu, Sujani Jaffee, Katy Visness, Cynthia M. Dresen, Amy Burger, Melissa Witter, Frank R. O'Connor, George T. Cruikshank, William W. Shreffler, Wayne G. Bacharier, Leonard B. Gern, James E. TI The influence of atopy and asthma on immune responses in inner-city adults SO IMMUNITY INFLAMMATION AND DISEASE LA English DT Article DE Adults; atopy; asthma; cytokines; immune responses; immunology; inner-city; maternal ID BLOOD MONONUCLEAR-CELLS; IFN-GAMMA RESPONSES; CYTOKINE RESPONSES; EARLY-LIFE; RHINOVIRUS; PHENOTYPES; DEFICIENT; INNATE; CHILDREN; ALLERGEN AB Asthma in the inner-city population is usually atopic in nature, and is associated with significant morbidity and mortality. However, the underlying immune abnormalities that underlie asthma in urban adults have not been well defined. We investigated the influence of atopy and asthma on cytokine responses of inner-city adult women to define immune abnormalities associated with asthma and atopy. Blood samples were collected from 509 of 606 inner-city women enrolled in the Urban Environment and Childhood Asthma (URECA) study. We tested for associations between atopy and asthma status and cytokine responses in peripheral blood mononuclear cells incubated ex vivo with a panel of innate and adaptive immune stimulants. Atopic subjects had heightened Th2 cytokine responses (IL-4, IL-5, IL-13) to cockroach and dust mite antigens, tetanus toxoid, and phytohemagglutinin (P < 0.05 for all). Differences in cytokine responses were greatest in response to stimulation with cockroach and dust mite. In a multivariate analysis, atopy was broadly related to increased Th2-like responses to all antigens and PHA, while asthma was only weakly related to mitogen-induced IL-4 and IL-5 responses. There were few asthma or allergy-related differences in responses to innate stimuli, including IFN-alpha and IFN-gamma responses. In this inner-city adult female population, atopy is associated with enhanced Th2 responses to allergens and other stimuli, and there was little or no additional signal attributable to asthma. In particular, these data indicate that altered systemic interferon and innate immune responses are not associated with allergies and/or asthma in inner-city women. C1 [Kakumanu, Sujani; Dresen, Amy; Burger, Melissa; Gern, James E.] Univ Wisconsin, Sch Med & Publ Hlth, Madison, WI USA. [Jaffee, Katy; Visness, Cynthia M.] Rho Inc, Div Fed Syst, Chapel Hill, NC USA. [Witter, Frank R.] Johns Hopkins Univ, Sch Med, Dept Obstet & Gynecol, Baltimore, MD 21205 USA. [O'Connor, George T.; Cruikshank, William W.] Boston Univ, Sch Med, Dept Pulm Med, Boston, MA 02118 USA. [Shreffler, Wayne G.] Massachusetts Gen Hosp, Ctr Immunol & Inflammatory Dis, Boston, MA 02114 USA. [Shreffler, Wayne G.] Massachusetts Gen Hosp, Food Allergy Ctr, Boston, MA 02114 USA. [Shreffler, Wayne G.] Harvard Med Sch, Boston, MA USA. [Bacharier, Leonard B.] Washington Univ, Sch Med, Dept Pediat, Div Allergy & Pulm Med, St Louis, MO 63110 USA. [Bacharier, Leonard B.] St Louis Childrens Hosp, St Louis, MO 63178 USA. RP Kakumanu, S (reprint author), Univ Wisconsin, Middleton Vet Mem Hosp, Sch Med & Publ Hlth, 600 Highland Ave CSC9988, Madison, WI 53705 USA. EM ssk@medicine.wisc.edu FU NIAID NIH HHS [T32 AI007635, UM2 AI117870, UM1 AI114271]; NIDDK NIH HHS [P30 DK040561] NR 32 TC 1 Z9 1 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2050-4527 J9 IMMUN INFLAMM DIS JI IMMUN. INFLAMM. DIS. PD MAR PY 2016 VL 4 IS 1 BP 80 EP 90 DI 10.1002/iid3.96 PG 11 WC Immunology SC Immunology GA DT6BX UT WOS:000381569000008 PM 27042305 ER PT J AU Hill, EV Wake, M Carapinha, R Normand, SL Wolf, RE Norris, K Reede, JY AF Hill, Emorcia V. Wake, Michael Carapinha, Rene Normand, Sharon-Lise Wolf, Robert E. Norris, Keith Reede, Joan Y. TI RATIONALE AND DESIGN OF THE WOMEN AND INCLUSION IN ACADEMIC MEDICINE STUDY SO ETHNICITY & DISEASE LA English DT Article DE Women; Minority Groups; Academic Medical Centers; Career Development; Diversity Inclusion AB Background and Objective: Women of color (WOC) (African American, Hispanic, Native American/Alaskan Native, and Asian American) faculty remain disproportionately underrepresented among medical school faculty and especially at senior ranks compared with White female faculty. The barriers or facilitators to the career advancement of WOC are poorly understood. The Women and Inclusion in Academic Medicine (WIAM) study was developed to characterize individual, institutional and sociocultural factors that influence the entry, progression and persistence, and advancement of women faculty in academic medical careers with a focus on WOC. Methods: Using a purposive sample of 13 academic medical institutions, we collected qualitative interview data from 21 WOC junior faculty and quantitative data from 3,127 (38.9% of 8,053 eligible women) respondents via an online survey. To gather institutional data, we used an online survey and conducted 23 key administrative informant interviews from the 13 institutions. Grounded theory methodology will be used to analyze qualitative data. Multivariable analysis including hierarchical linear modeling will be used to investigate outcomes, such as the inclusiveness of organizational gender climate and women faculty's intent to stay. Conclusion: We describe the design, methods, rationale and limitations of one of the largest and most comprehensive studies of women faculty in academic medicine with a focus on WOC. This study will enhance our understanding of challenges that face women, and, especially WOC, faculty in academic medicine and will provide solutions at both the individual and institutional levels. C1 [Hill, Emorcia V.; Carapinha, Rene; Reede, Joan Y.] Harvard Med Sch, Off Divers Inclus & Community Partnership, Boston, MA USA. [Wake, Michael] Dana Farber Canc Inst, Clin Trials Off, Boston, MA 02115 USA. [Carapinha, Rene] Harvard Med Sch, Dept Global Hlth & Social Med, Boston, MA USA. [Normand, Sharon-Lise; Wolf, Robert E.] Harvard Med Sch, Dept Hlth Care Policy, Boston, MA USA. [Normand, Sharon-Lise] Harvard Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Norris, Keith] Univ Calif Los Angeles, Div Gen Internal Med & Hlth Serv Res, Los Angeles, CA 90024 USA. [Reede, Joan Y.] Harvard Sch Publ Hlth, Dept Social & Behav Sci, Boston, MA USA. RP Hill, EV (reprint author), 164 Longwood Ave,3rd Floor Room 306, Boston, MA 02115 USA. EM hill@hms.harvard.edu FU National Institutes of Health from the National Heart, Lung and Blood Institute [5 RO1 HL101996-02]; Josiah Macy Jr. Foundation [B07-07] FX This work was supported by a National Institutes of Health R01 award (5 RO1 HL101996-02) from the National Heart, Lung and Blood Institute and grant B07-07 from the Josiah Macy Jr. Foundation. NR 25 TC 1 Z9 1 U1 0 U2 0 PU INT SOC HYPERTENSION BLACKS-ISHIB PI ATLANTA PA 100 AUBURN AVE NE STE 401, ATLANTA, GA 30303-2527 USA SN 1049-510X EI 1945-0826 J9 ETHNIC DIS JI Ethn. Dis. PD SPR PY 2016 VL 26 IS 2 BP 245 EP 254 DI 10.18865/ed.26.2.245 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DS5DB UT WOS:000380799800014 PM 27103776 ER PT J AU McCloud, RF Okechukwu, CA Sorensen, G Viswanath, K AF McCloud, Rachel F. Okechukwu, Cassandra A. Sorensen, Glorian Viswanath, Kasisomayajula TI Entertainment or Health? Exploring the Internet Usage Patterns of the Urban Poor: A Secondary Analysis of a Randomized Controlled Trial SO JOURNAL OF MEDICAL INTERNET RESEARCH LA English DT Article DE health communication; socioeconomic factors; information-seeking behavior; Internet ID DIGITAL DIVIDE; INFORMATION; COMMUNICATION; INEQUALITIES; POPULATIONS; CHILDREN; SEEKING; GAPS AB Background: Important gaps remain in our knowledge of how individuals from low socioeconomic position (SEP) use the Internet for resources and in understanding the full range of activities they perform online. Although self-report data indicate that low SEP individuals use the Internet less than high SEP people for health information and for other beneficial capital-enhancing activities, these results may not provide an accurate overall view of online use. Objective: The aim of this study was to determine the ways in which low SEP individuals use the Internet, including for entertainment, social networking, and capital-enhancing functions, and how they are associated with health information seeking. Methods: Detailed Web tracking data were collected from 118 low SEP individuals who participated in the intervention group of a randomized controlled trial that provided Internet access. Websites were grouped by topic, including categories of capital-enhancing websites that provided access to resources and information. Different types of online activities were summed into an Internet use index. Single and multiple negative binomial regression models were fitted with the Internet use index as the predictor and health information seeking as the outcome. Next, models were fitted with low, medium, and high Web usage in capital-enhancing, entertainment, and social network categories to determine their associations with health information seeking. Results: Participants used the Web for diverse purposes, with 63.6% (75/118) accessing the Internet for all defined types of Internet use. Each additional category of Internet use was associated with 2.12 times the rate of health information seeking (95% CI 1.84-2.44, P<.001). Higher use of each type of capital-enhancing information was associated with higher rates of health information seeking, with high uses of government (incident rate ratio [IRR] 8.90, 95% CI 4.82-16.42, P<.001) and news (IRR 11.36, 95% CI 6.21-20.79, P<.001) websites associated with the highest rates of health information seeking compared to their lowest use categories. High entertainment website use (IRR 3.91, 95% CI 2.07-7.37, P<.001) and high social network use (IRR 2.06, 95% CI 1.08-3.92, P=.03) were also associated with higher health information seeking. Conclusions: These data clearly show that familiarity and skills in using the Internet enhance the capacity to use it for diverse purposes, including health and to increase capital, and that Internet usage for specific activities is not a zero sum game. Using it for one type of topic, such as entertainment, does not detract from using it for other purposes. Findings may inform ways to engage low SEP groups with Internet resources. C1 [McCloud, Rachel F.; Sorensen, Glorian; Viswanath, Kasisomayajula] Dana Farber Canc Inst, Ctr Community Based Res, 450 Brookline Ave,LW 601, Boston, MA 02115 USA. [Okechukwu, Cassandra A.; Sorensen, Glorian; Viswanath, Kasisomayajula] Harvard TH Chan Sch Publ Hlth, Dept Social & Behav Sci, Boston, MA USA. RP McCloud, RF (reprint author), Dana Farber Canc Inst, Ctr Community Based Res, 450 Brookline Ave,LW 601, Boston, MA 02115 USA. EM rachel_faulkenberry@dfci.harvard.edu OI okechukwu, cassandra/0000-0002-4429-7120 FU Click to Connect: Improving Health Literacy through Internet Literacy [RO1 CA122894, R25 CA057711] FX This project was supported by Click to Connect: Improving Health Literacy through Internet Literacy, grant number RO1 CA122894 and grant number R25 CA057711 (KV, PI). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. We would like to thank Sara Minsky, the Click to Connect team, and the Health Communication Core at the Viswanath Lab at the Dana-Farber Cancer Institute for their work on this project. NR 36 TC 0 Z9 0 U1 3 U2 3 PU JMIR PUBLICATIONS, INC PI TORONTO PA 59 WINNERS CIRCLE, TORONTO, ON M4L 3Y7, CANADA SN 1438-8871 J9 J MED INTERNET RES JI J. Med. Internet Res. PD MAR PY 2016 VL 18 IS 3 AR e46 DI 10.2196/jmir.4375 PG 12 WC Health Care Sciences & Services; Medical Informatics SC Health Care Sciences & Services; Medical Informatics GA DS4UR UT WOS:000380777600001 PM 26940637 ER PT J AU Mifflin, J AF Mifflin, Jeffrey TI ROBINSON JEFFERS: Poet and Prophet SO JOURNAL OF THE WEST 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. NR 1 TC 0 Z9 0 U1 0 U2 0 PU ABC-CLIO PI SANTA BARBARA PA 130 CREMONA DR, SANTA BARBARA, CA 93117 USA SN 0022-5169 EI 1930-0115 J9 J WEST JI J. West PD SPR PY 2016 VL 55 IS 2 BP 95 EP 95 PG 1 WC History SC History GA DR8YJ UT WOS:000380184000019 ER PT J AU Ling, MF Luster, AD AF Ling, Morris F. Luster, Andrew D. TI Allergen-Specific CD4(+) T Cells in Human Asthma SO ANNALS OF THE AMERICAN THORACIC SOCIETY LA English DT Article AB In allergic asthma, aeroallergen exposure of sensitized individuals mobilizes robust innate and adaptive airway immune responses, stimulating eosinophilic airway inflammation and the activation and infiltration of allergen-specific CD4(+) T cells into the airways. Allergen-specific CD4(+) T cells are thought to be central players in the asthmatic response as they specifically recognize the allergen and initiate and orchestrate the asthmatic inflammatory response. In this article, we briefly review the role of allergen-specific CD4(+) T cells in the pathogenesis of human allergic airway inflammation in allergic individuals, discuss the use of allergen-major histocompatibility complex class II tetramers to characterize allergen-specific CD4(+) T cells, and highlight current gaps in knowledge and directions for future research pertaining to the role of allergen-specific CD4(+) T cells in human asthma. C1 [Ling, Morris F.; Luster, Andrew D.] Harvard Med Sch, Massachusetts Gen Hosp, Div Rheumatol Allergy & Immunol, Ctr Immunol & Inflammatory Dis, Boston, MA USA. RP Luster, AD (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Boston, MA 02114 USA. EM aluster@mgh.harvard.edu FU National Institutes of Health [F32 AI108125, U19 AI095261, R37 AI040618] FX Supported by grants from the National Institutes of Health (F32 AI108125, U19 AI095261, and R37 AI040618). NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1546-3222 EI 2325-6621 J9 ANN AM THORAC SOC JI Ann. Am. Thoracic Society PD MAR PY 2016 VL 13 SU 1 BP S25 EP S30 DI 10.1513/AnnalsATS.201507-431MG PG 6 WC Respiratory System SC Respiratory System GA DR6BQ UT WOS:000379986500002 PM 27027948 ER PT J AU Holliday, E Fuller, CD Kalpathy-Cramer, J Gomez, D Rimner, A Li, Y Senan, S Wilson, LD Choi, J Komaki, R Thomas, CR AF Holliday, Emma Fuller, Clifton D. Kalpathy-Cramer, Jayashree Gomez, Daniel Rimner, Andreas Li, Ying Senan, Suresh Wilson, Lynn D. Choi, Jehee Komaki, Ritsuko Thomas, Charles R., Jr. TI Quantitative assessment of target delineation variability for thymic cancers: agreement evaluation of a prospective segmentation challenge SO JOURNAL OF RADIATION ONCOLOGY LA English DT Article DE Radiotherapy; Thymoma; Thymic carcinoma; Treatment planning; Target delineation; Consensus guidelines ID VOLUME DELINEATION; RADIATION-THERAPY; POSTOPERATIVE RADIOTHERAPY; SURGICAL RESECTION; COOPERATIVE GROUP; CONTOURING ATLAS; CATEGORICAL DATA; CERVICAL-CANCER; CT; GUIDELINES AB We sought to quantitatively determine the interobserver variability of expert radiotherapy target-volume delineation for thymic cancers, as part of a larger effort to develop an expert-consensus contouring atlas. A pilot dataset was created consisting of a standardized case presentation with pre- and post-operative DICOM CT image sets from a single patient with Masaoka-Koga Stage III thymoma. Expert thoracic radiation oncologists delineated tumor targets on the pre- and post-operative scans as they would for a definitive and adjuvant case, respectively. Respondents completed a survey including recommended dose prescription and target volume margins for definitive and post-operative scenarios. Interobserver variability was analyzed quantitatively with Warfield's simultaneous truth, performance level estimation (STAPLE) algorithm and Dice similarity coefficient (DSC). Seven users completed contouring for definitive and adjuvant cases; of these, five completed online surveys. Segmentation performance was assessed, with high mean +/- SD STAPLE-estimated segmentation sensitivity for definitive case GTV and CTV at 0.77 and 0.80, respectively, and post-operative CTV sensitivity of 0.55; all volumes had specificity of a parts per thousand yen0.99. Interobserver agreement was markedly higher for the definitive target volumes, with mean +/- SD DSC of 0.88 +/- 0.03 and 0.89 +/- 0.04 for GTV and CTV, respectively, compared to post-op CTV DSC of 0.69 +/- 0.06 (Kruskal-Wallis p < 0.01. Expert agreement for definitive case volumes was exceptionally high, though significantly lower agreement was noted post-operatively. Technique and dose prescription between experts was substantively consistent, and these preliminary results will be utilized to create an expert-consensus contouring atlas to aid the nonexpert radiation oncologist in the planning of these challenging, rare tumors. C1 [Holliday, Emma; Fuller, Clifton D.; Gomez, Daniel; Komaki, Ritsuko] Univ Texas MD Anderson Canc Ctr, Div Radiat Oncol, 1515 Holcombe Blvd,Unit 97, Houston, TX 77030 USA. [Kalpathy-Cramer, Jayashree] Massachusetts Gen Hosp, Dept Radiol, Boston, MA USA. [Rimner, Andreas] Mem Sloan Kettering Canc Ctr, Dept Radiat Oncol, 1275 York Ave, New York, NY 10021 USA. [Li, Ying] Univ Texas Hlth Sci Ctr San Antonio, Dept Radiat Oncol, San Antonio, TX 78229 USA. [Senan, Suresh] Univ Med Ctr, Dept Radiat Oncol, Amsterdam, Netherlands. [Wilson, Lynn D.] Yale Canc Ctr, Dept Therapeut Radiol, New Haven, CT USA. [Choi, Jehee] Kaiser Permanente Southern Calif, Dept Radiat Oncol, Los Angeles, CA USA. [Thomas, Charles R., Jr.] Oregon Hlth & Sci Univ, Knight Canc Ctr, Dept Radiat Med, Portland, OR 97201 USA. RP Fuller, CD (reprint author), Univ Texas MD Anderson Canc Ctr, Div Radiat Oncol, 1515 Holcombe Blvd,Unit 97, Houston, TX 77030 USA. EM cdfuller@mdanderson.org FU NCI NIH HHS [K12 CA088084, L30 CA136381, U01 CA154601] NR 49 TC 0 Z9 0 U1 1 U2 2 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1948-7894 EI 1948-7908 J9 J RADIOL ONCOL JI J. RADIOL. ONCOL. PD MAR PY 2016 VL 5 IS 1 BP 55 EP 61 DI 10.1007/s13566-015-0230-7 PG 7 WC Oncology SC Oncology GA DR1JX UT WOS:000379662900007 PM 27570583 ER PT J AU Borja, M Galan, JA Cantu, E Zugasti-Cruz, A Rodriguez-Acosta, A Lazcano, D Lucena, S Suntravat, M Sanchez, EE AF Borja, Miguel Anthony Galan, Jacob Cantu, Esteban, Jr. Zugasti-Cruz, Alejandro Rodriguez-Acosta, Alexis Lazcano, David Lucena, Sara Suntravat, Montamas Eliza Sanchez, Elda TI MORULUSTATIN, A DISINTEGRIN THAT INHIBITS ADP-INDUCED PLATELET AGGREGATION, ISOLATED FROM THE MEXICAN TAMAULIPAN ROCK RATTLESNAKE (Crotalus lepidus morulus) SO REVISTA CIENTIFICA-FACULTAD DE CIENCIAS VETERINARIAS LA English DT Article DE Crotalus lepidus morulus; disintegrin; hemostasis; morulustatin; platelets; venom ID SNAKE-VENOM DISINTEGRIN; MOHAVE RATTLESNAKE; HEMOSTASIS; EVOLUTION; TOXINS AB The Tamaulipan rock rattlesnake (Crotalus lepidus morulus) is a montane snake that occurs in the humid pine-oak forest and the upper cloud forest of the Sierra Madre Oriental in southwestern Tamaulipas, central Nuevo Leon, and southeastern Coahuila in Mexico. Venom from this rattlesnake was fractionated by High-Performance Liquid Chromatography for the purpose of discovering disintegrin molecules. Disintegrins are nonenzymatic, small molecular weight peptides that interfere with cell-cell and cell-matrix interactions by binding to various cell receptors. Eleven fractions were collected by anion exchange chromatography and pooled into six groups (I, II, III, IV, V, and VI). Proteins of the six groups were analyzed by SDS-PAGE and western blot using antibodies raised against a disintegrin. The antibodies recognized different protein bands in five (II, III, IV, V, and VI) of six groups in a molecular mass range of 7 to 105 kDa. Western blot analysis revealed fewer protein bands in the higher molecular mass range and two bands in the disintegrin weight range in group II compared with the other four groups. Proteins in group II were further separated into nine fractions using reverse phase C18 chromatography. Fraction 4 inhibited platelet aggregation and was named morulustatin, which exhibited a single band with a molecular mass of approximately 7 kDa. Mass spectrometry analysis of fraction 4 revealed the identification of disintegrin peptides LRPGAQCADGLCCDQCR (MH+ 2035.84) and AGEECDCGSPANCCDAATCK (MH+ 2328.82). Morulustatin inhibited ADP-induced platelet aggregation in human whole blood and was concentration-dependent with an IC50 of 89.5 nM +/- 12. C1 [Borja, Miguel] Univ Juarez Estado Durango, Fac Ciencias Biol, Gomez Palacio, Durango, Mexico. [Anthony Galan, Jacob] Harvard Med Sch, Massachusetts Gen Hosp, Dept Mol Biol, Simches Res Ctr, Boston, MA USA. [Cantu, Esteban, Jr.; Lucena, Sara; Suntravat, Montamas; Eliza Sanchez, Elda] Texas A&M Univ, Natl Nat Toxins Res Ctr, Kingsville, TX 78363 USA. [Zugasti-Cruz, Alejandro] Univ Autonoma Coahuila, Posgrad Biotecnol, Fac Ciencias Quim, Coahuila, Mexico. [Rodriguez-Acosta, Alexis] Cent Univ Venezuela, Inst Anat, Caracas, Venezuela. [Lazcano, David] Univ Autonoma Nuevo Leon, Fac Ciencias Biol, Lab Herpetol, Nuevo Leon, Mexico. [Eliza Sanchez, Elda] Texas A&M Univ, Dept Chem, Kingsville, TX 78363 USA. RP Sanchez, EE (reprint author), Texas A&M Univ, Natl Nat Toxins Res Ctr, Kingsville, TX 78363 USA.; Sanchez, EE (reprint author), Texas A&M Univ, Dept Chem, Kingsville, TX 78363 USA. EM elda.sanchez@tamuk.edu FU NIH-ORIP/BMRG, Viper Resource Grant [s 8P40OD01960-10, 3P40OD01096-10S1]; Department of Chemistry at Texas A&M University-Kingsville, Kingsville, Texas, USA; CDCH/Universidad Central de Venezuela [PG: 09-8760-2013/1] FX Funding for the project was provided by NIH-ORIP/BMRG, Viper Resource Grant #s 8P40OD01960-10 and 3P40OD01096-10S1 (NNTRC, Texas A&M University-Kingsville); the Department of Chemistry at Texas A&M University-Kingsville, Kingsville, Texas, USA and CDCH/Universidad Central de Venezuela PG: 09-8760-2013/1. We want to thank the NNTRC personnel for their assistance. We would also like to thank TAMUK campus housing for providing accommodations for visiting scientists. NR 30 TC 1 Z9 1 U1 2 U2 2 PU UNIV ZULIA, FACULTAD CIENCIAS VETERINARIAS PI MARACAIBO PA UNIVERSIDAD DEL ZULIA, MARACAIBO, VENEZUELA SN 0798-2259 J9 REV CIENT-FAC CIEN V JI Rev. Cient.-Fac. Cienc. Vet. PD MAR-APR PY 2016 VL 26 IS 2 BP 86 EP 94 PG 9 WC Veterinary Sciences SC Veterinary Sciences GA DQ6TD UT WOS:000379337200005 ER PT J AU Weinstock, T Kidambi, P Channick, CL Michaud, GC Broaddus, C Makani, SS Wiener, RS Wilson, KC Thomson, CC AF Weinstock, Tanya Kidambi, Pranav Channick, Colleen L. Michaud, Gaetane C. Broaddus, Courtney Makani, Samir S. Wiener, Renda Soylemez Wilson, Kevin C. Thomson, Carey C. TI Implementation of Lung Cancer Screening Programs with Low-Dose Computed Tomography in Clinical Practice SO ANNALS OF THE AMERICAN THORACIC SOCIETY LA English DT Article C1 [Weinstock, Tanya; Thomson, Carey C.] Mt Auburn Hosp, Div Pulm Dis, Cambridge, MA USA. [Weinstock, Tanya; Thomson, Carey C.] Mt Auburn Hosp, Div Crit Care Med, Cambridge, MA USA. [Weinstock, Tanya; Thomson, Carey C.] Harvard Med Sch, Boston, MA USA. [Kidambi, Pranav] Mt Auburn Hosp, Dept Med, Cambridge, MA USA. [Channick, Colleen L.] Massachusetts Gen Hosp, Div Pulm Crit Care & Sleep Med, Boston, MA 02114 USA. [Michaud, Gaetane C.] NYU, Div Pulm & Crit Care Med, New York, NY USA. [Broaddus, Courtney] San Francisco Gen Hosp, Div Pulm & Crit Care Med, San Francisco, CA 94110 USA. [Makani, Samir S.] Univ Calif San Diego, Div Pulm & Crit Care Med, San Diego, CA 92103 USA. [Wiener, Renda Soylemez; Wilson, Kevin C.] Boston Univ, Div Pulm & Crit Care Med, Boston, MA 02215 USA. [Wiener, Renda Soylemez] Edith Nourse Rogers Mem Vet Hosp, Ctr Healthcare Org & Implementat Res, Bedford, MA USA. RP Weinstock, T (reprint author), Mt Auburn Hosp, Pulm & Crit Care, Cambridge, MA 02138 USA. EM tweinsto@mah.harvard.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1546-3222 EI 2325-6621 J9 ANN AM THORAC SOC JI Ann. Am. Thoracic Society PD MAR PY 2016 VL 13 IS 3 BP 425 EP 427 DI 10.1513/AnnalsATS.201512-804CME PG 3 WC Respiratory System SC Respiratory System GA DQ4IR UT WOS:000379168000021 PM 26963353 ER PT J AU van der Sluis, IM Vrooman, LM Pieters, R Baruchel, A Escherich, G Goulden, N Mondelaers, V de Toledo, JS Rizzari, C Silverman, LB Whitlock, JA AF van der Sluis, Inge M. Vrooman, Lynda M. Pieters, Rob Baruchel, Andre Escherich, Gabriele Goulden, Nicholas Mondelaers, Veerle Sanchez de Toledo, Jose Rizzari, Carmelo Silverman, Lewis B. Whitlock, James A. TI Consensus expert recommendations for identification and management of asparaginase hypersensitivity and silent inactivation SO HAEMATOLOGICA LA English DT Article ID ACUTE LYMPHOBLASTIC-LEUKEMIA; ESCHERICHIA-COLI ASPARAGINASE; ERWINIA ASPARAGINASE; POLYETHYLENE-GLYCOL; CHILDREN; ANTIBODIES; CHILDHOOD; PHARMACOKINETICS; THERAPY; PHARMACODYNAMICS AB L-asparaginase is an integral component of therapy for acute lymphoblastic leukemia. However, asparaginase-related complications, including the development of hypersensitivity reactions, can limit its use in individual patients. Of considerable concern in the setting of clinical allergy is the development of neutralizing antibodies and associated asparaginase inactivity. Also problematic in the use of asparaginase is the potential for the development of silent inactivation, with the formation of neutralizing antibodies and reduced asparaginase activity in the absence of a clinically evident allergic reaction. Here we present guidelines for the identification and management of clinical hypersensitivity and silent inactivation with Escherichia coli- and Erwinia chrysanthemi- derived asparaginase preparations. These guidelines were developed by a consensus panel of experts following a review of the available published data. We provide a consensus of expert opinions on the role of serum asparaginase level assessment, indications for switching asparaginase preparation, and monitoring after change in asparaginase preparation. C1 [van der Sluis, Inge M.] Sophia Childrens Univ Hosp, Erasmus Med Ctr, Dept Pediat Hematol Oncol, Rotterdam, Netherlands. [Vrooman, Lynda M.; Silverman, Lewis B.] Boston Childrens Hosp, Dept Pediat Oncol, Dana Farber Canc Inst, Div Hematol Oncol, Boston, MA 02115 USA. [Pieters, Rob] Princess Maxima Ctr Pediat Oncol, Utrecht, Netherlands. [Baruchel, Andre] Hop Robert Debre, Dept Pediat Hematol, Paris, France. [Baruchel, Andre] Univ Paris Diderot, Paris, France. [Escherich, Gabriele] Univ Med Ctr Hamburg Eppendorf, Clin Paediat Hematol & Oncol, Hamburg, Germany. [Goulden, Nicholas] Great Ormond St Hosp Sick Children, London, England. [Mondelaers, Veerle] Ghent Univ Hosp, Pediat Hematol Oncol & Stem Cell Transplantat, Ghent, Belgium. [Sanchez de Toledo, Jose] Univ Hosp Vall Hebron, Dept Pediat Hematol Oncol, Barcelona, Spain. [Rizzari, Carmelo] Univ Milano Bicocca, Hosp S Gerardo, Dept Pediat, Pediat Hematol Oncol Unit, Monza, Italy. [Whitlock, James A.] Univ Toronto, Div Haematol Oncol, Hosp Sick Children, Toronto, ON M5S 1A1, Canada. [Whitlock, James A.] Univ Toronto, Dept Paediat, Toronto, ON M5S 1A1, Canada. RP van der Sluis, IM (reprint author), Sophia Childrens Univ Hosp, Erasmus Med Ctr, Dept Pediat Hematol Oncol, Rotterdam, Netherlands.; Vrooman, LM (reprint author), Boston Childrens Hosp, Dept Pediat Oncol, Dana Farber Canc Inst, Div Hematol Oncol, Boston, MA 02115 USA. EM i.vandersluis@erasmusmc.nl; lynda_vrooman@dfci.harvard.edu NR 38 TC 4 Z9 4 U1 0 U2 1 PU FERRATA STORTI FOUNDATION PI PAVIA PA VIA GIUSEPPE BELLI 4, 27100 PAVIA, ITALY SN 0390-6078 J9 HAEMATOLOGICA JI Haematologica PD MAR PY 2016 VL 101 IS 3 BP 279 EP 285 DI 10.3324/haematol.2015.137380 PG 7 WC Hematology SC Hematology GA DQ7MY UT WOS:000379392800019 PM 26928249 ER PT J AU Sorvillo, N Hartholt, RB Bloem, E Sedek, M ten Brinke, A van der Zwaan, C van Alphen, FP Meijer, AB Voorberg, J AF Sorvillo, Nicoletta Hartholt, Robin B. Bloem, Esther Sedek, Magdalena ten Brinke, Anja van der Zwaan, Carmen van Alphen, Floris P. Meijer, Alexander B. Voorberg, Jan TI von Willebrand factor binds to the surface of dendritic cells and modulates peptide presentation of factor VIII SO HAEMATOLOGICA LA English DT Article ID COAGULATION-FACTOR-VIII; SEVERE HEMOPHILIA-A; INHIBITOR DEVELOPMENT; C1 DOMAIN; MONOCLONAL-ANTIBODIES; RISK-FACTORS; IN-VITRO; CLASS-II; CLEARANCE; RECEPTOR AB It has been proposed that von Willebrand factor might affect factor VIII immunogenicity by reducing factor VIII uptake by antigen presenting cells. Here we investigate the interaction of recombinant von Willebrand factor with immature monocyte-derived dendritic cells using flow cytometry and confocal microscopy. Surprisingly, von Willebrand factor was not internalized by immature dendritic cells, but remained bound to the cell surface. As von Willebrand factor reduces the uptake of factor VIII, we investigated the repertoire of factor VIII presented peptides when in complex with von Willebrand factor. Interestingly, factor VIII-derived peptides were still abundantly presented on major histocompatibility complex class II molecules, even though a reduction of factor VIII uptake by immature dendritic cells was observed. Inspection of peptide profiles from 5 different donors showed that different core factor VIII peptide sequences were presented upon incubation with factor VIII/von Willebrand factor complex when compared to factor VIII alone. No von Willebrand factor peptides were detected when immature dendritic cells were pulsed with different concentrations of von Willebrand factor, confirming lack of von Willebrand factor endocytosis. Several von Willebrand factor derived peptides were recovered when cells were pulsed with von Willebrand factor/factor VIII complex, suggesting that factor VIII promotes endocytosis of small amounts of von Willebrand factor by immature dendritic cells. Taken together, our results establish that von Willebrand factor is poorly internalized by immature dendritic cells. We also show that von Willebrand factor modulates the internalization and presentation of factor VIII-derived peptides on major histocompatibility complex class II. C1 [Sorvillo, Nicoletta; Hartholt, Robin B.; Bloem, Esther; Sedek, Magdalena; van der Zwaan, Carmen; van Alphen, Floris P.; Voorberg, Jan] Sanquin AMC Landsteiner Lab, Dept Plasma Prot, Amsterdam, Netherlands. [Sorvillo, Nicoletta] Harvard Med Sch, Program Cellular & Mol Med, Boston Childrens Hosp, Boston, MA USA. [ten Brinke, Anja] Sanquin AMC Landsteiner Lab, Dept Immune Pathol, Amsterdam, Netherlands. [Meijer, Alexander B.] Sanquin Blood Supply Fdn, Dept Plasma Prot, Amsterdam, Netherlands. [Meijer, Alexander B.] Univ Utrecht, Utrecht Inst Pharmaceut Sci, Dept Pharmaceut, NL-3508 TC Utrecht, Netherlands. RP Voorberg, J (reprint author), Sanquin AMC Landsteiner Lab, Dept Plasma Prot, Amsterdam, Netherlands. EM j.voorberg@sanquin.nl FU Sanquin; Landsteiner Foundation for Blood Transfusion Research (LSBR) FX This work was supported by Sanquin and Landsteiner Foundation for Blood Transfusion Research (LSBR). NR 40 TC 5 Z9 5 U1 0 U2 1 PU FERRATA STORTI FOUNDATION PI PAVIA PA VIA GIUSEPPE BELLI 4, 27100 PAVIA, ITALY SN 0390-6078 J9 HAEMATOLOGICA JI Haematologica PD MAR PY 2016 VL 101 IS 3 BP 309 EP 318 DI 10.3324/haematol.2015.137067 PG 10 WC Hematology SC Hematology GA DQ7MY UT WOS:000379392800022 PM 26635035 ER PT J AU de Rooij, MFM Kuil, A Kraan, W Kersten, MJ Treon, SP Pals, ST Spaargaren, M AF de Rooij, Martin F. M. Kuil, Annemieke Kraan, Willem Kersten, Marie Jose Treon, Steven P. Pals, Steven T. Spaargaren, Marcel TI Ibrutinib and idelalisib target B cell receptor- but not CXCL12/CXCR4-controlled integrin-mediated adhesion in Waldenstrom macroglobulinemia SO HAEMATOLOGICA LA English DT Letter DE adhesion; BCR; CXCR4; kinase inhibitors; Waldenstrom macroglobulinemia ID CHRONIC LYMPHOCYTIC-LEUKEMIA; BRUTON TYROSINE KINASE; INHIBITOR IBRUTINIB; LYMPHOMA; PCI-32765; MUTATION; THERAPY; MCL; BTK C1 [de Rooij, Martin F. M.; Kuil, Annemieke; Kraan, Willem; Pals, Steven T.; Spaargaren, Marcel] Univ Amsterdam, Acad Med Ctr, Dept Pathol, NL-1012 WX Amsterdam, Netherlands. [Kersten, Marie Jose] Univ Amsterdam, Acad Med Ctr, Dept Hematol, NL-1012 WX Amsterdam, Netherlands. [Kersten, Marie Jose; Pals, Steven T.; Spaargaren, Marcel] LYMMCARE, Lymphoma & Myeloma Ctr Amsterdam, Amsterdam, Netherlands. [Treon, Steven P.] Dana Farber Canc Inst, Bing Ctr Waldenstroms Macroglobulinemia, Boston, MA 02115 USA. RP Spaargaren, M (reprint author), Univ Amsterdam, Acad Med Ctr, Dept Pathol, NL-1012 WX Amsterdam, Netherlands.; Spaargaren, M (reprint author), LYMMCARE, Lymphoma & Myeloma Ctr Amsterdam, Amsterdam, Netherlands. EM marcel.spaargaren@amc.uva.nl NR 15 TC 5 Z9 5 U1 0 U2 1 PU FERRATA STORTI FOUNDATION PI PAVIA PA VIA GIUSEPPE BELLI 4, 27100 PAVIA, ITALY SN 0390-6078 J9 HAEMATOLOGICA JI Haematologica PD MAR PY 2016 VL 101 IS 3 BP E111 EP E115 DI 10.3324/haematol.2015.137265 PG 5 WC Hematology SC Hematology GA DQ7MY UT WOS:000379392800010 PM 26635033 ER PT J AU Wong, CA Ostapovich, G Kramer-Golinkoff, E Griffis, H Asch, DA Merchant, RM AF Wong, Charlene A. Ostapovich, Gabrielle Kramer-Golinkoff, Emily Griffis, Heather Asch, David A. Merchant, Raina M. TI How U.S. children's hospitals use social media: A mixed methods study SO HEALTHCARE-THE JOURNAL OF DELIVERY SCIENCE AND INNOVATION LA English DT Article ID HEALTH RESEARCH; CARE; INFORMATION; FACEBOOK; TWITTER; YOUTUBE; SITES AB Background: Social media provide new channels for hospitals to engage with communities, a goal of increasing importance as non-profit hospitals face stricter definitions of community benefit under the Affordable Care Act. We describe the variability in social media presence among US children's hospitals and the distribution of their Facebook content curation. Methods: Social media data from freestanding children's hospitals were extracted from September November 2013. Social media adoption was reviewed for each hospital-generated Facebook, Twitter, YouTube, Google + and Pinterest platform. Facebook page (number of Likes) and Twitter account (number of followers) engagement were examined by hospital characteristics. Facebook posts from each hospital over a 6-week period were thematically characterized. Results: We reviewed 5 social media platforms attributed to 45 children's hospitals and 2004 associated Facebook posts. All hospitals maintained Facebook and Twitter accounts and most used YouTube (82%), Google+ (53%) and Pinterest (69%). Larger hospitals were more often high performers for Facebook (67% versus 10%, p < 0.01) and Twitter (75% versus 17%, p < 0.05) engagement than small hospitals. The most common Facebook post-themes were hospital promotion 35% (706), education and information 35% (694), community partnership or benefit 24% (474), fundraising 21% (426), and narratives 12% (241). Of health education posts, 73% (509) provided pediatric health supervision and anticipatory guidance. Conclusions: Social media adoption by US children's hospitals was widespread. Implications: Beyond its traditional marketing role, social media can serve as a conduit for health education, engagement with communities, including community benefit. (C) 2015 Elsevier Inc. All rights reserved. C1 [Wong, Charlene A.; Asch, David A.; Merchant, Raina M.] Univ Penn, Robert Wood Johnson Fdn, Clin Scholars Program, 1303 Blockley Hall,423 Guardian Dr, Philadelphia, PA 19104 USA. [Wong, Charlene A.; Ostapovich, Gabrielle; Kramer-Golinkoff, Emily; Griffis, Heather; Asch, David A.; Merchant, Raina M.] Univ Penn, Penn Med Social Media & Hlth Innovat Lab, Penn Med Ctr Hlth Care Innovat, Philadelphia, PA 19104 USA. [Asch, David A.; Merchant, Raina M.] Univ Penn, Div Gen Internal Med, Philadelphia, PA 19104 USA. [Asch, David A.] Philadelphia Vet Affairs Med Ctr, Ctr Hlth Equ Res & Promot, Philadelphia, PA USA. RP Wong, CA (reprint author), Univ Penn, Robert Wood Johnson Fdn, Clin Scholars Program, 1303 Blockley Hall,423 Guardian Dr, Philadelphia, PA 19104 USA. EM charwong@upenn.edu NR 30 TC 0 Z9 0 U1 5 U2 8 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 2213-0764 EI 2213-0772 J9 HEALTHCARE JI HealthCare PD MAR PY 2016 VL 4 IS 1 BP 15 EP 21 DI 10.1016/j.hjdsi.2015.12.004 PG 7 WC Health Care Sciences & Services SC Health Care Sciences & Services GA DQ5LK UT WOS:000379246500006 PM 27001094 ER PT J AU Fryer, AK Friedberg, MW Thompson, RW Singer, SJ AF Fryer, Ashley-Kay Friedberg, Mark W. Thompson, Ryan W. Singer, Sara J. TI Achieving care integration from the patients' perspective: Results from a care management program SO HEALTHCARE-THE JOURNAL OF DELIVERY SCIENCE AND INNOVATION LA English DT Article ID CENTERED MEDICAL HOME; PSYCHOMETRIC PROPERTIES; CONSUMER ASSESSMENT; ASSOCIATION; PROVIDERS; DELIVERY; QUALITY; SYSTEMS; SAVINGS C1 [Fryer, Ashley-Kay] Harvard Univ, PhD Program Hlth Policy, Cambridge, MA 02138 USA. [Friedberg, Mark W.] Harvard Med Sch, Dept Med, Brigham & Womens Hosp, RAND Corp,Div Gen Med, Boston, MA 02115 USA. [Thompson, Ryan W.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Med, Boston, MA 02115 USA. [Singer, Sara J.] Harvard Med Sch, Massachusetts Gen Hosp, Harvard TH Chan Sch Publ Hlth, Dept Hlth Policy & Management,Dept Med,Mongan Ins, Boston, MA 02115 USA. RP Fryer, AK (reprint author), Harvard Univ, PhD Program Hlth Policy, Cambridge, MA 02138 USA. EM afryer@hbs.edu; ssinger@hsph.harvard.edu NR 26 TC 1 Z9 1 U1 1 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 2213-0764 EI 2213-0772 J9 HEALTHCARE JI HealthCare PD MAR PY 2016 VL 4 IS 1 BP 36 EP 44 DI 10.1016/j.hjdsi.2015.12.006 PG 9 WC Health Care Sciences & Services SC Health Care Sciences & Services GA DQ5LK UT WOS:000379246500009 PM 27001097 ER PT J AU Mota, N Tsai, J Kirwin, PD Harpaz-Rotem, I Krystal, JH Southwick, SM Pietrzak, RH AF Mota, Natalie Tsai, Jack Kirwin, Paul D. Harpaz-Rotem, Ilan Krystal, John H. Southwick, Steven M. Pietrzak, Robert H. TI Late-Life Exacerbation of PTSD Symptoms in US Veterans: Results From the National Health and Resilience in Veterans Study SO JOURNAL OF CLINICAL PSYCHIATRY LA English DT Article ID POSTTRAUMATIC-STRESS-DISORDER; INTERNATIONAL NEUROPSYCHIATRIC INTERVIEW; OLDER-ADULTS; CASE SERIES; DSM-IV; TRAUMA; EXPOSURE; ONSET; INTERVENTIONS; TRAJECTORIES AB Objective: More than 60% of US military veterans are 55 years or older. Although several case studies have suggested that older age is associated with a higher likelihood of reactivated or delayed-onset posttraumatic stress disorder (PTSD) symptoms in veterans, population-based data on the prevalence and determinants of this phenomenon are lacking. Method: Using data from the National Health and Resilience in Veterans Study (NHRVS: Wave 1 = October 2011-December 2011; Wave 2 = September 2013), a nationally representative, cohort study of US veterans, we evaluated the prevalence and determinants of exacerbated PTSD symptoms in 1,441 veterans 55 years or older using a DSM-IV-based measure in 2011 and a DSM-5-based measure in 2013. Veterans whose worst trauma occurred at least 5 years prior to Wave 2 of the NHRVS (mean = 28.6 years) and who reported a clinically significant increase (ie, >= 0.5 standard deviation [SD]; mean = 1.27, SD = 0.78) in PTSD symptoms from Wave 1 (lifetime) to Wave 2 (past-month) were identified as having exacerbated PTSD symptoms. Results: Results revealed that 9.9% of older US veterans experienced exacerbated PTSD symptoms an average of nearly 3 decades after their worst trauma. A multivariable logistic regression model indicated that greater self-reported cognitive difficulties at Wave 1 independently predicted exacerbated PTSD symptoms at Wave 2. Post hoc analysis revealed that this association was driven by greater severity of executive dysfunction (adjusted odds ratio range, 1.27-3.22). Conclusions: Approximately 1 in 10 older US veterans experiences a clinically significant exacerbation of PTSD symptoms in late life. Executive dysfunction may contribute to risk for exacerbated PTSD symptoms. These results suggest that exacerbated PTSD symptoms are prevalent in US veterans and highlight potential targets for identifying veterans at risk for this phenomenon. (C) Copyright 2016 Physicians Postgraduate Press, Inc. C1 [Mota, Natalie; Tsai, Jack; Kirwin, Paul D.; Harpaz-Rotem, Ilan; Krystal, John H.; Southwick, Steven M.; Pietrzak, Robert H.] Yale Univ, Sch Med, Dept Psychiat, New Haven, CT USA. [Mota, Natalie; Kirwin, Paul D.; Harpaz-Rotem, Ilan; Krystal, John H.; Southwick, Steven M.; Pietrzak, Robert H.] US Dept Vet Affairs, Natl Ctr Posttraumat Stress Disorder, Clin Neurosci Div, West Haven, CT USA. [Tsai, Jack] US Dept Vet Affairs, New England Mental Illness Res Educ & Clin Ctr, West Haven, CT USA. [Mota, Natalie] Univ Manitoba, Dept Clin Hlth Psychol, Winnipeg, MB, Canada. [Mota, Natalie] Yale Univ, Natl Ctr Posttraumat Stress Disorder, New Haven, CT 06520 USA. RP Mota, N (reprint author), 817 Bannatyne Ave, Winnipeg, MB R3E 0W2, Canada. EM natalie.mota@umanitoba.ca FU US Department of Veterans Affairs National Center for Posttraumatic Stress Disorder FX The National Health and Resilience in Veterans Study (NHRVS) was funded by the US Department of Veterans Affairs National Center for Posttraumatic Stress Disorder. NR 40 TC 0 Z9 0 U1 2 U2 3 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 MAR PY 2016 VL 77 IS 3 BP 348 EP 354 DI 10.4088/JCP.15m10101 PG 7 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA DQ5LC UT WOS:000379245700015 PM 27046308 ER PT J AU Roberson, AM Castro, VM Cagan, A Perlis, RH AF Roberson, Ashlee M. Castro, Victor M. Cagan, Andrew Perlis, Roy H. TI Antidepressant Nonadherence in Routine Clinical Settings Determined From Discarded Blood Samples SO JOURNAL OF CLINICAL PSYCHIATRY LA English DT Article ID LIQUID-CHROMATOGRAPHY; FLUORESCENCE DETECTION; ADHERENCE; PLASMA; CARE; METABOLITES; MEDICATION; ENTERPRISE; DEPRESSION; RECORDS AB Objective: Antidepressant nonadherence is common and represents a potentially modifiable risk factor for treatment nonresponse. We used a novel approach based on discarded blood samples from routine clinical blood draws to assess treatment nonadherence in a general clinical population. Method: Individuals diagnosed with or without major depressive disorder (using ICD-9) and prescribed sertraline, citalopram, bupropion, or venlafaxine in January 2014 were identified by querying the electronic health record of 2 academic medical centers. Discarded blood samples from routine blood draws for 109 individuals within 14-90 days of treatment initiation were anonymized and then assessed for detectable serum antidepressant levels. Results: Overall, 17% of samples lacked detectable levels of the index antidepressant. Individuals with public versus private insurance were more likely to have undetectable antidepressant levels (.2 1 = 5.07, P = .02) as were those receiving shorter-term (<90 days) prescriptions (.2 1 = 4.03, P = .05). Conclusions: In general, electronic prescribing data provided a reasonable proxy for actual antidepressant use. Additionally, up to 1 in 5 individuals prescribed an antidepressant may not be adherent, suggesting the need for further efforts to reduce treatment nonadherence. (C) Copyright 2015 Physicians Postgraduate Press, Inc. C1 [Roberson, Ashlee M.; Castro, Victor M.; Cagan, Andrew; Perlis, Roy H.] Massachusetts Gen Hosp, Dept Psychiat, Ctr Expt Drugs & Diagnost, Boston, MA 02114 USA. [Castro, Victor M.; Cagan, Andrew] Partners HealthCare Syst, Partners Res Informat Syst & Comp, Boston, MA USA. RP Perlis, RH (reprint author), MGH, Simches Res Bldg,185 Cambridge St,6th Fl, Boston, MA 02114 USA. EM rperlis@partners.org NR 20 TC 1 Z9 1 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 MAR PY 2016 VL 77 IS 3 BP 359 EP + DI 10.4088/JCP.14m09612 PG 6 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA DQ5LC UT WOS:000379245700016 PM 26613178 ER PT J AU Durgam, S Earley, W Guo, H Li, D Nemeth, G Laszlovszky, I Fava, M Montgomery, SA AF Durgam, Suresh Earley, Willie Guo, Hua Li, Dayong Nemeth, Gyorgy Laszlovszky, Istvan Fava, Maurizio Montgomery, Stuart A. TI Efficacy and Safety of Adjunctive Cariprazine in Inadequate Responders to Antidepressants: A Randomized, Double-Blind, Placebo-Controlled Study in Adult Patients With Major Depressive Disorder SO JOURNAL OF CLINICAL PSYCHIATRY LA English DT Article ID TREATMENT-RESISTANT DEPRESSION; EXTENDED-RELEASE QUETIAPINE; RATING-SCALE; ACUTE MANIA; I DISORDER; OPEN-LABEL; PHASE-III; AUGMENTATION; MULTICENTER; ANTIPSYCHOTICS AB Background: Cariprazine is an atypical antipsychotic currently under investigation as adjunctive therapy in patients with major depressive disorder (MDD) who have inadequate response to standard antidepressant therapy. Method: A randomized, double-blind, placebo-controlled, flexible-dose study was conducted from December 2011 to December 2013 in adults who met DSM-IV-TR criteria for MDD and had an inadequate antidepressant response. Eligible patients were randomized to 8-week adjunctive treatment with placebo (n = 269), cariprazine 1-2 mg/d (n = 274), or cariprazine 2-4.5 mg/d (n = 276). The primary efficacy parameter was change from baseline to week 8 in Montgomery-Asberg Depression Rating Scale (MADRS) total score; P values were adjusted for multiple comparisons. Safety assessments included adverse events, clinical laboratory tests, vital signs, electrocardiograms (ECGs), and suicidality. Results: Compared with placebo, reduction in MADRS total score at week 8 was significantly greater with adjunctive cariprazine 2-4.5 mg/d (least squares mean difference [LSMD] = -2.2; adjusted P =.0114), but not with cariprazine 1-2 mg/d (LSMD = -0.9; adjusted P =.2404). Significant LSMDs for MADRS total score change were detected at all earlier study visits (weeks 2, 4, 6) in the 2-to 4.5-mg/d group and at weeks 2 and 4 in the 1to 2-mg/d group (all P values < .05). Treatment-emergent adverse events reported in = 10% of patients in either cariprazine dosage group were akathisia (22.3%), insomnia (13.6%), and nausea (12.8%) (all in 2-to 4.5-mg/d group). Mean changes in metabolic parameters, vital signs, and ECG parameters were generally similar between groups. No suicide-related adverse events were reported. Discussion: These results show that adjunctive cariprazine 2-4.5 mg/d was effective and generally well tolerated in adults with MDD who had inadequate responses to standard antidepressants. Further clinical studies to confirm these results are warranted. (C) Copyright 2016 Physicians Postgraduate Press, Inc. C1 [Durgam, Suresh; Earley, Willie; Guo, Hua; Li, Dayong] Forest Res Inst, Jersey City, NJ USA. [Nemeth, Gyorgy; Laszlovszky, Istvan] Gedeon Richter Plc, Budapest, Hungary. [Fava, Maurizio] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Montgomery, Stuart A.] Univ London, Imperial Coll Sch Sci & Med, London, England. RP Durgam, S (reprint author), Harborside Financial Ctr, Clin Dev, Forest Res Inst, Jersey City, NJ 07311 USA. EM suresh.durgam@actavis.com FU Forest Laboratories, LLC (Jersey City, New Jersey), an Allergan affiliate; Gedeon Richter Plc (Budapest, Hungary) FX Supported by funding from Forest Laboratories, LLC (Jersey City, New Jersey), an Allergan affiliate and Gedeon Richter Plc (Budapest, Hungary). NR 41 TC 4 Z9 4 U1 1 U2 1 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 MAR PY 2016 VL 77 IS 3 BP 371 EP + DI 10.4088/JCP.15m10070 PG 10 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA DQ5LC UT WOS:000379245700018 PM 27046309 ER PT J AU Dekel, S Solomon, Z Ein-Dor, T AF Dekel, Sharon Solomon, Zahava Ein-Dor, Tsachi TI PTSD Symptoms Lead to Modification in the Memory of the Trauma: A Prospective Study of Former Prisoners of War SO JOURNAL OF CLINICAL PSYCHIATRY LA English DT Article ID POSTTRAUMATIC-STRESS-DISORDER; CONSISTENCY; EXPOSURE; RECONSOLIDATION; EVENTS; RETRIEVAL; VETERANS; AMYGDALA; MODEL AB Objective: With the growing interest in the role of trauma memory in posttraumatic stress disorder (PTSD), this prospective study examined long-term changes in memory and the bidirectional relationship between symptoms of PTSD and trauma memory. Method: A sample of Israeli former prisoners of the 1973 Yom Kippur War (N = 103) was assessed in 1991 and in 2008. Participants' PTSD symptom clusters, measured by the PTSD Inventory, and recollections of subjective and objective exposure during captivity, measured by a self-report questionnaire, were assessed at both times. Data on prewar and postwar negative life events and psychotherapy were also collected. Results: Repeated-measures analysis revealed that participants' recollections were increasingly negative over time (P < .001). Applying an autoregressive cross-lagged modeling strategy showed that the PTSD symptoms of hyperarousal facilitated subsequent amplifications in their recollections (P < .01). Conclusions: These findings challenge the accuracy of reports of traumatic experiences and show that PTSD symptoms, in part, lead to the formation of more negative recollections over time. The findings suggest that the original memory is repeatedly updated under the influence of the individual's emotional state. The findings are discussed in the context of the reconsolidation theory of memory. (C) Copyright 2016 Physicians Postgraduate Press, Inc. C1 [Dekel, Sharon] Massachusetts Gen Hosp, Dept Psychiat, Charlestown, MA USA. [Dekel, Sharon] Harvard Med Sch, Dept Psychiat, Boston, MA USA. [Solomon, Zahava] Tel Aviv Univ, Bob Shapell Sch Social Work, IL-69978 Tel Aviv, Israel. [Ein-Dor, Tsachi] Interdisciplinary Ctr Herzliya, Sch Psychol, Herzliyya, Israel. RP Dekel, S (reprint author), Massachusetts Gen Hosp East, PTSD Res Lab, 120 Second Ave, Charlestown, MA 02129 USA. EM dekel.sharon@gmail.com FU NARSAD FX The funding source, NARSAD, had no role in the design, conduct, or reporting of study findings. NR 30 TC 2 Z9 2 U1 6 U2 12 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 MAR PY 2016 VL 77 IS 3 BP E290 EP E296 DI 10.4088/JCP.14m09114 PG 7 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA DQ5LC UT WOS:000379245700003 PM 26796992 ER PT J AU Thorndike, AN Achtyes, ED Cather, C Pratt, S Pachas, GN Hoeppner, SS Evins, AE AF Thorndike, Anne N. Achtyes, Eric D. Cather, Corinne Pratt, Sarah Pachas, Gladys N. Hoeppner, Susanne S. Evins, A. Eden TI Weight Gain and 10-Year Cardiovascular Risk With Sustained Tobacco Abstinence in Smokers With Serious Mental Illness: A Subgroup Analysis of a Randomized Trial SO JOURNAL OF CLINICAL PSYCHIATRY LA English DT Article ID CATIE SCHIZOPHRENIA TRIAL; SMOKING-CESSATION; BIPOLAR DISORDER; DOUBLE-BLIND; BASE-LINE; SCHIZOAFFECTIVE DISORDER; NICOTINE DEPENDENCE; METABOLIC SYNDROME; DIABETES-MELLITUS; EXCESS MORTALITY AB Objective: People with serious mental illness die earlier than those without mental illness, largely from cardiovascular disease due to high rates of smoking and obesity. The objective of this study was to determine whether the metabolic effects of postcessation weight gain among smokers with serious mental illness attenuated the cardiovascular benefit of tobacco abstinence. Method: A subgroup analysis was conducted of 65 outpatient smokers with DSM-IV diagnosis of schizophrenia, schizoaffective disorder, or bipolar disorder from 10 community mental health centers in 6 states who enrolled between March 2008-April 2012 and completed a trial of varenicline for tobacco abstinence. The intervention included a 12-week open-label phase with varenicline followed by a 40-week randomized, placebo-controlled phase in 87 participants who achieved 12-week abstinence. Main outcome measures were smoking status and change from baseline in weight and 10-year Framingham cardiovascular risk score at end of intervention (week 52). Results: At week 52, 65 participants completed follow-up (33 abstinent; 32 relapsed). At baseline, the 2 groups did not differ in body mass index (mean = 31 kg/m(2)), blood pressure, serum glucose, or diagnoses of diabetes (31%) and hypertension (34%). Abstinent participants were older and had a higher mean baseline Framingham risk score (14.2% vs 10.3%, P = .002). At week 52, abstinent participants gained more weight than relapsed participants (4.8 vs 1.2 kg, P = .048) and, as a result of quitting smoking, had a greater reduction in Framingham risk score (-7.6% vs 0.0%, P < .001). There was no effect of study drug assignment on weight or Framingham risk score. Conclusions: Sustained tobacco abstinence reduced 10-year cardiovascular risk in outpatients with serious mental illness despite significant postcessation weight gain and high prevalence of obesity, diabetes, and hypertension. (C) Copyright 2016 Physicians Postgraduate Press, Inc. C1 [Thorndike, Anne N.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Thorndike, Anne N.; Cather, Corinne; Pachas, Gladys N.; Hoeppner, Susanne S.; Evins, A. Eden] Harvard Med Sch, Boston, MA USA. [Achtyes, Eric D.] Cherry Hlth, Grand Rapids, MI USA. [Achtyes, Eric D.] Michigan State Univ, Coll Human Med, Grand Rapids, MI USA. [Cather, Corinne; Pachas, Gladys N.; Hoeppner, Susanne S.; Evins, A. Eden] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Pratt, Sarah] Dartmouth Coll, Geisel Sch Med, Hanover, NH USA. RP Thorndike, AN (reprint author), Massachusetts Gen Hosp, 50 Staniford St,9th Fl, Boston, MA 02114 USA. EM athorndike@partners.org OI Achtyes, Eric/0000-0001-8939-1535 FU National Institute on Drug Abuse [R01 DA021245, K24 DA030443]; Pfizer FX This study was funded by grant R01 DA021245 by National Institute on Drug Abuse with supplemental financial and material support from an investigator-initiated award from Pfizer for study medications and project funding. Drs Evins and Hoeppner were supported by grant K24 DA030443 from the National Institute on Drug Abuse. NR 61 TC 2 Z9 2 U1 5 U2 5 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 MAR PY 2016 VL 77 IS 3 BP E320 EP E326 DI 10.4088/JCP.15m10074 PG 7 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA DQ5LC UT WOS:000379245700008 PM 27046320 ER PT J AU Kronenberg, HM AF Kronenberg, Henry M. TI Bone and Mineral Metabolism: Where Are We, Where Are We Going, and How Will We Get There? SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID SKELETAL STEM-CELL; RECEPTOR; MARROW AB Context: Advances in diagnosing and treating metabolic bone diseases will require ways to assess cellular signaling within human bones, ideally noninvasively. Only then will we be able to fully harness the increased molecular understanding of bone that derives from human genetics and model organisms, primarily rodents. New hormones regulating mineral ion homeostasis surely remain to be discovered, probably through advances in the study of human genetic disease. C1 [Kronenberg, Henry M.] Massachusetts Gen Hosp, Endocrine Unit, 50 Blossom St,Thier 1101, Boston, MA 02114 USA. [Kronenberg, Henry M.] Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Kronenberg, HM (reprint author), Massachusetts Gen Hosp, Endocrine Unit, 50 Blossom St,Thier 1101, Boston, MA 02114 USA. EM hkronenberg@partners.org FU National Institutes of Health [DK011794] FX This work was supported by National Institutes of Health Grant DK011794. NR 13 TC 0 Z9 0 U1 2 U2 2 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 MAR PY 2016 VL 101 IS 3 BP 795 EP 798 DI 10.1210/jc.2015-3607 PG 4 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DP9JA UT WOS:000378811300005 PM 26908104 ER PT J AU Chavarro, JE Minguez-Alarcon, L Chiu, YH Gaskins, AJ Souter, I Williams, PL Calafat, AM Hauser, R AF Chavarro, Jorge E. Minguez-Alarcon, Lidia Chiu, Yu-Han Gaskins, Audrey J. Souter, Irene Williams, Paige L. Calafat, Antonia M. Hauser, Russ CA EARTH Study Team TI Soy Intake Modifies the Relation Between Urinary Bisphenol A Concentrations and Pregnancy Outcomes Among Women Undergoing Assisted Reproduction SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID FOOD-FREQUENCY QUESTIONNAIRE; ESTROGEN-RECEPTOR-ALPHA; SEMEN QUALITY; US ADULTS; IN-VITRO; INTRAUTERINE IMPLANTATION; NEONATAL EXPOSURE; FERTILIZED OVA; GENISTEIN; ISOFLAVONES AB Context: Experimental data in rodents suggest that the adverse reproductive health effects of bisphenol A (BPA) can be modified by intake of soy phytoestrogens. Whether the same is true in humans is not known. Objective: The purpose of this study was to evaluate whether soy consumption modifies the relation between urinary BPA levels and infertility treatment outcomes among women undergoing assisted reproduction. Setting: The study was conducted in a fertility center in a teaching hospital. Design: We evaluated 239 women enrolled between 2007 and 2012 in the Environment and Reproductive Health (EARTH) Study, a prospective cohort study, who underwent 347 in vitro fertilization (IVF) cycles. Participants completed a baseline questionnaire and provided up to 2 urine samples in each treatment cycle before oocyte retrieval. IVF outcomes were abstracted from electronic medical records. We used generalized linear mixed models with interaction terms to evaluate whether the association between urinary BPA concentrations and IVF outcomes was modified by soy intake. Main Outcome Measure: Live birth rates per initiated treatment cycle were measured. Results: Soy food consumption modified the association of urinary BPA concentration with live birth rates (P for interaction = .01). Among women who did not consume soy foods, the adjusted live birth rates per initiated cycle in increasing quartiles of cycle-specific urinary BPA concentrations were 54%, 35%, 31%, and 17% (P for trend = .03). The corresponding live birth rates among women reporting pretreatment consumption of soy foods were 38%, 42%, 47%, and 49% (P for trend = 0.35). A similar pattern was found for implantation (P for interaction = .02) and clinical pregnancy rates (P for interaction = .03) per initiated cycle, where urinary BPA was inversely related to these outcomes among women not consuming soy foods but unrelated to them among soy consumers. Conclusion: Soy food intake may protect against the adverse reproductive effects of BPA. As these findings represent the first report suggesting a potential interaction between soy and BPA in humans, they should be further evaluated in other populations. C1 [Chavarro, Jorge E.; Chiu, Yu-Han; Gaskins, Audrey J.] Harvard Univ, TH Chan Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Chavarro, Jorge E.; Gaskins, Audrey J.; Hauser, Russ] Harvard Univ, TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Minguez-Alarcon, Lidia; Hauser, Russ] Harvard Univ, TH Chan Sch Publ Hlth, Dept Environm Hlth, Boston, MA 02115 USA. [Williams, Paige L.] Harvard Univ, TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Chavarro, Jorge E.] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA. [Chavarro, Jorge E.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Souter, Irene; Hauser, Russ] Massachusetts Gen Hosp, Vincent Obstet & Gynecol, Boston, MA 02114 USA. [Souter, Irene; Hauser, Russ] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Calafat, Antonia M.] Ctr Dis Control & Prevent, Natl Ctr Environm Hlth, Atlanta, GA 30329 USA. RP Chavarro, JE (reprint author), Harvard Univ, Sch Publ Hlth Nutr, 665 Huntington Ave, Boston, MA 02115 USA. EM jchavarr@hsph.harvard.edu FU National Institutes of Health [R01ES022955, R01ES009718, R01ES000002, T32DK007703-16, P30DK46200] FX This work was supported by the National Institutes of Health (grants R01ES022955, R01ES009718, R01ES000002, T32DK007703-16, and P30DK46200). The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention. Use of trade names and commercial sources is for identification only and does not constitute endorsement by the US Department of Health and Human Services or the CDC. NR 51 TC 4 Z9 4 U1 7 U2 8 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 MAR PY 2016 VL 101 IS 3 BP 1082 EP 1090 DI 10.1210/jc.2015-3473 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DP9JA UT WOS:000378811300039 PM 26815879 ER PT J AU Makimura, H Stanley, TL Suresh, C de Sousa-Coelho, AL Frontera, WR Syu, S Braun, LR Looby, SE Feldpausch, MN Torriani, M Lee, H Patti, ME Grinspoon, SK AF Makimura, Hideo Stanley, Takara L. Suresh, Caroline de Sousa-Coelho, Ana Luisa Frontera, Walter R. Syu, Stephanie Braun, Laurie R. Looby, Sara E. Feldpausch, Meghan N. Torriani, Martin Lee, Hang Patti, Mary-Elizabeth Grinspoon, Steven K. TI Metabolic Effects of Long-Term Reduction in Free Fatty Acids With Acipimox in Obesity: A Randomized Trial SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID INDUCED INSULIN-RESISTANCE; PHOSPHATIDYLINOSITOL 3-KINASE ACTIVITY; MAGNETIC-RESONANCE-SPECTROSCOPY; HOMEOSTASIS MODEL ASSESSMENT; TYPE-2 DIABETIC-PATIENTS; HUMAN SKELETAL-MUSCLE; PHOSPHOCREATINE RECOVERY; MITOCHONDRIAL-FUNCTION; SUSTAINED REDUCTION; OXIDATIVE CAPACITY AB Context: Increased circulating free fatty acids (FFAs) have been proposed to contribute to insulin resistance in obesity. Short-term studies have investigated the effects of acipimox, an inhibitor of hormone-sensitive lipase, on glucose homeostasis, but longer-term studies have not been performed. Objective: To test the hypothesis that long-term treatment with acipimox would reduce FFA and improve insulin sensitivity among nondiabetic, insulin-resistant, obese subjects. Design, Setting, Patients, and Intervention: At an academic medical center, 39 obese men and women were randomized to acipimox 250 mg thrice-daily vs identical placebo for 6 months. Main Outcome Measures: Plasma lipids, insulin sensitivity, adiponectin, and mitochondrial function via assessment of the rate of post-exercise phosphocreatine recovery on P-31-magnetic resonance spectroscopy as well as muscle mitochondrial density and relevant muscle gene expression. Results: Fasting glucose decreased significantly in acipimox-treated individuals (effect size, -6 mg/dL; P = .02), in parallel with trends for reduced fasting insulin (effect size, -6.8 mu U/mL; P = .07) and HOMA-IR (effect size, -1.96; P = .06), and significantly increased adiponectin (effect size, +668 ng/mL; P = .02). Acipimox did not affect insulin-stimulated glucose uptake, as assessed by euglycemic, hyper-insulinemic clamp. Effects on muscle mitochondrial function and density and on relevant gene expression were not seen. Conclusion: These data shed light on the long-term effects of FFA reduction on insulin sensitivity, other metabolic parameters, and muscle mitochondrial function in obesity. Reduced FFA achieved by acipimox improved fasting measures of glucose homeostasis, lipids, and adiponectin but had no effect on mitochondrial function, mitochondrial density, or muscle insulin sensitivity. C1 [Makimura, Hideo; Stanley, Takara L.; Suresh, Caroline; Syu, Stephanie; Braun, Laurie R.; Looby, Sara E.; Feldpausch, Meghan N.; Grinspoon, Steven K.] Massachusetts Gen Hosp, Program Nutr Metab, 55 Fruit St,LON 207, Boston, MA 02114 USA. [Makimura, Hideo; Stanley, Takara L.; Suresh, Caroline; Syu, Stephanie; Braun, Laurie R.; Looby, Sara E.; Feldpausch, Meghan N.; Grinspoon, Steven K.] Massachusetts Gen Hosp, Neuroendocrine Unit, 55 Fruit St,LON 207, Boston, MA 02114 USA. [Makimura, Hideo; Stanley, Takara L.; de Sousa-Coelho, Ana Luisa; Braun, Laurie R.; Looby, Sara E.; Torriani, Martin; Lee, Hang; Patti, Mary-Elizabeth; Grinspoon, Steven K.] Harvard Univ, Sch Med, 55 Fruit St,LON 207, Boston, MA 02115 USA. [Stanley, Takara L.; Braun, Laurie R.] Massachusetts Gen Hosp, Pediat Endocrine Unit, Boston, MA 02114 USA. [de Sousa-Coelho, Ana Luisa; Patti, Mary-Elizabeth] Joslin Diabet Ctr, Div Res, 1 Joslin Pl, Boston, MA 02215 USA. [Frontera, Walter R.] Vanderbilt Univ, Med Ctr, Dept Phys Med & Rehabil, Nashville, TN 37212 USA. [Frontera, Walter R.] Harvard Univ, Dept Phys Med & Rehabil, Sch Med, Spaulding Rehabil Hosp, Boston, MA 02114 USA. [Frontera, Walter R.] Univ Puerto Rico, Sch Med, Dept Physiol, San Juan, PR 00936 USA. [Torriani, Martin] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Lee, Hang] Massachusetts Gen Hosp, MGH Biostat Ctr, Boston, MA 02114 USA. [Lee, Hang] Harvard Med Ctr, Boston, MA 02114 USA. RP Grinspoon, SK (reprint author), Massachusetts Gen Hosp, Program Nutr Metab, 55 Fruit St,LON 207, Boston, MA 02114 USA.; Grinspoon, SK (reprint author), Massachusetts Gen Hosp, Neuroendocrine Unit, 55 Fruit St,LON 207, Boston, MA 02114 USA.; Grinspoon, SK (reprint author), Harvard Univ, Sch Med, 55 Fruit St,LON 207, Boston, MA 02115 USA. EM sgrinspoon@partners.org FU American Diabetes Association [1-12-CT-47]; National Institutes of Health [1UL1RR025758-04, 8UL1TR000170-05, K23DK087857, K23DK089910, P30DK036836, P30DK040561]; Harvard Clinical and Translational Science Center; National Center for Research Resources FX This work was supported by Clinical/Translational Research Grant 1-12-CT-47 from the American Diabetes Association (to H.M.). The project was also supported by the National Institutes of Health Grants 1UL1RR025758-04 and 8UL1TR000170-05, Harvard Clinical and Translational Science Center, and the National Center for Research Resources. Further support was provided by the National Institutes of Health Grants K23DK087857 (to H.M.), K23DK089910 (to T.L.S.), P30DK036836 (to M.-E. P.), and P30DK040561 (to S.K.G.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health. NR 57 TC 1 Z9 1 U1 4 U2 4 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 MAR PY 2016 VL 101 IS 3 BP 1123 EP 1133 DI 10.1210/jc.2015-3696 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DP9JA UT WOS:000378811300044 PM 26691888 ER PT J AU Torriani, M Srinivasa, S Fitch, KV Thomou, T Wong, K Petrow, E Kahn, CR Cypess, AM Grinspoon, SK AF Torriani, Martin Srinivasa, Suman Fitch, Kathleen V. Thomou, Thomas Wong, Kimberly Petrow, Eva Kahn, C. Ronald Cypess, Aaron M. Grinspoon, Steven K. TI Dysfunctional Subcutaneous Fat With Reduced Dicer and Brown Adipose Tissue Gene Expression in HIV-Infected Patients SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID BEIGE ADIPOCYTES; LIPODYSTROPHY; DIFFERENTIATION; ADIPOGENESIS AB Context: HIV patients are at an increased risk for cardiometabolic disease secondary to depot-specific alterations in adipose function, but mechanisms remain poorly understood. Objective: The endoribonuclease Dicer has been linked to the modulation of brown and white adipocyte differentiation. We previously demonstrated that Dicer knockout mice undergo transformation of brown adipose tissue to white adipose tissue and develop a lipodystrophic phenotype. We hypothesized reduced Dicer and brown adipose tissue gene expression from nonlipomatous sc fat among HIV patients with a lipodystrophic phenotype. Design: Eighteen HIV (nine with and without lipodystrophic changes in fat distribution, characterized by excess dorsocervical adipose tissue [DCAT]) and nine non-HIV subjects underwent punch biopsy of abdominal sc fat to determine expression of Dicer and other adipose-related genes. Results: HIV subjects with long-duration antiretroviral use demonstrated excess DCAT vs non-HIV subjects (9.8 +/- 1.0 vs 6.6 +/- 0.8 cm(2), P = .02) with similar body mass index. Dicer expression was decreased in abdominal sc fat of HIV vs non-HIV (4.88 [1.91, 11.93] vs 17.69 [10.72, 47.91], P = .01), aswerePPAR alpha, ZIC1, PRDM16, DIO2, and HSP60 (all P <= .03). Moreover, the expression of Dicer (2.49 [0.02, 4.88] vs 11.20 [4.83, 21.45], P = .006), brown fat (PPAR alpha [P = .002], ZIC1 [P = .004], LHX8 [P = .03], PRDM16 [P = .0008], PAT2 [P = .008], P2RX5 [P = .02]), beige fat (TMEM26 [P = .004], CD137 [P = .008]), and other genes (DIO2 [P = .002], leptin [P = .003], HSP60 [P = .0004]) was further decreased in abdominal sc fat comparing HIV subjects with vs without excess DCAT. Down-regulation of Dicer in the abdominal sc fat correlated with the down-regulation of all brown and beige fat genes (all P <= .01). Conclusion: Our results demonstrate dysfunctional sc adipose tissue marked by reduced Dicer in relationship to the down-regulation of brown and beige fat-related genes in lipodystrophic HIV patients and may provide a novel mechanism for metabolic dysregulation. A strategy to increase browning of white adipose tissue may improve cardiometabolic health in HIV. C1 [Torriani, Martin; Srinivasa, Suman; Fitch, Kathleen V.; Wong, Kimberly; Petrow, Eva; Grinspoon, Steven K.] Massachusetts Gen Hosp, Program Nutr Metab, 55 Fruit St,LON207, Boston, MA 02114 USA. [Torriani, Martin] Massachusetts Gen Hosp, Div Musculoskeletal Imaging & Intervent, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. [Thomou, Thomas; Kahn, C. Ronald; Cypess, Aaron M.] Joslin Diabet Ctr, Sect Integrat Physiol & Metab, Boston, MA 02215 USA. Harvard Univ, Sch Med, Boston, MA 02215 USA. [Cypess, Aaron M.] NIDDK, Translat Physiol Sect, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD 20892 USA. RP Grinspoon, SK (reprint author), Massachusetts Gen Hosp, Program Nutr Metab, 55 Fruit St,LON207, Boston, MA 02114 USA. EM sgrinspoon@mgh.harvard.edu FU National Institutes of Health from the National Center for Research Resources [1UL1RR025758, 2P30AI060354, K23DK081604, M01RR01066, UL1TR001102]; National Center for Advancing Translational Sciences; Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases; [P30DK40561] FX This work was supported by the National Institutes of Health Grants 1UL1RR025758, 2P30AI060354 (to M.T.), K23DK081604 (to A.M.C.), M01RR01066, 1UL1RR025758, and UL1TR001102 (to the Harvard Catalyst/Harvard Clinical and Translational Science Center) from the National Center for Research Resources and National Center for Advancing Translational Sciences, and Grant P30DK40561, a pilot and feasibility grant to the Nutrition and Obesity Research Center at Harvard University, and the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases. NR 28 TC 3 Z9 4 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 MAR PY 2016 VL 101 IS 3 BP 1225 EP 1234 DI 10.1210/jc.2015-3993 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DP9JA UT WOS:000378811300056 PM 26756119 ER PT J AU George, B Denney, T Gupta, H Dell'Italia, L Aban, I AF George, Brandon Denney, Thomas, Jr. Gupta, Himanshu Dell'Italia, Louis Aban, Inmaculada TI APPLYING A SPATIOTEMPORAL MODEL FOR LONGITUDINAL CARDIAC IMAGING DATA SO ANNALS OF APPLIED STATISTICS LA English DT Article DE Spatiotemporal; imaging; correlation; separable; summary measures ID ISOLATED MITRAL REGURGITATION; CARDIOCYTE; BLOCKADE AB Longitudinal imaging studies have both spatial and temporal correlation among the multiple outcome measurements from a subject. Statistical methods of analysis must properly account for this autocorrelation. In this work we discuss how a linear model with a separable parametric correlation structure could be used to analyze data from such a study. The goal of this paper is to provide an easily understood description of how such a model works and discuss how it can be applied to real data. Model assumptions are discussed and the process of selecting a working correlation structure is thoroughly discussed. The steps necessitating collaboration between statistical and scientific investigators have been highlighted, as have considerations for missing data or uneven follow-up. The results from a completed longitudinal cardiac imaging study were considered for illustration purposes. The data comes from a clinical trial for medical therapy for patients with mitral regurgitation, with repeated measurements taken at sixteen locations from the left ventricle to measure disease progression. The spatiotemporal correlation model was compared to previously used summary measures to demonstrate improved power as well as increased flexibility in the use of time- and space- varying predictors. C1 [George, Brandon; Aban, Inmaculada] Univ Alabama Birmingham, Dept Biostat, 1720 2nd Ave S, Birmingham, AL 35233 USA. [Denney, Thomas, Jr.] Auburn Univ, Dept Elect & Comp Engn, Broun Hall,341 War Eagle Way, Auburn, AL 36849 USA. [Gupta, Himanshu; Dell'Italia, Louis] Univ Alabama Birmingham, Dept Med, 1808 7th Ave S, Birmingham, AL 35294 USA. [Gupta, Himanshu; Dell'Italia, Louis] Birmingham Vet Affairs Med Ctr, 700 South 19th St, Birmingham, AL 35233 USA. RP George, B (reprint author), Univ Alabama Birmingham, Dept Biostat, 1720 2nd Ave S, Birmingham, AL 35233 USA. EM brgeorge@uab.edu; caban@uab.edu FU NHLBI [T32HL079888]; National Institutes of Health Specialized Center of Clinically Oriented Research in Cardiac Dysfunction [P50-HL077100] FX Predoctoral funding was provided by NHLBI T32HL079888. The UAB SCCOR study was supported by National Institutes of Health Specialized Center of Clinically Oriented Research in Cardiac Dysfunction P50-HL077100. NR 31 TC 0 Z9 0 U1 0 U2 0 PU INST MATHEMATICAL STATISTICS PI CLEVELAND PA 3163 SOMERSET DR, CLEVELAND, OH 44122 USA SN 1932-6157 J9 ANN APPL STAT JI Ann. Appl. Stat. PD MAR PY 2016 VL 10 IS 1 BP 527 EP 548 DI 10.1214/16-AOAS911 PG 22 WC Statistics & Probability SC Mathematics GA DO9OU UT WOS:000378116900022 PM 27087884 ER PT J AU Charles, M Durham-Fowler, J Malone, JC AF Charles, Marilyn Durham-Fowler, Jennifer Malone, Johanna C. TI Factors discriminating creative engagement on an unstructured task: Creativity and the Rorschach SO BULLETIN OF THE MENNINGER CLINIC LA English DT Article ID EGO IMPAIRMENT INDEX AB In an attempt to find variables that would discriminate between creativity and psychopathology on the Rorschach, Rorschach data from two groups were compared. The first group was an inpatient sample of creative individuals who also carried a diagnosis of psychosis. The second was a group of creative writers. Both groups were engaged in intensive psychoanalytic psychotherapy. Comparing the most creative versus the least creative of the protocols in each group showed that more creative engagement was characterized by a higher response rate and greater and more idisosyncratic elaboration. Differences also emerged between groups: Whereas the inpatient sample relied more heavily on ideational coping, the writers relied more heavily on affective resources. C1 [Charles, Marilyn] Austen Riggs Ctr Inc, 25 Main St,POB 962, Stockbridge, MA 01262 USA. [Durham-Fowler, Jennifer] Boston Univ, Boston, MA 02215 USA. [Malone, Johanna C.] Massachusetts Gen Hosp, Cambridge, MA USA. [Malone, Johanna C.] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. RP Charles, M (reprint author), Austen Riggs Ctr Inc, 25 Main St,POB 962, Stockbridge, MA 01262 USA. EM mcharlesphd@gmail.com NR 49 TC 0 Z9 0 U1 1 U2 2 PU GUILFORD PUBLICATIONS INC PI NEW YORK PA 370 SEVENTH AVE, SUITE 1200, NEW YORK, NY 10001-1020 USA SN 0025-9284 EI 1943-2828 J9 B MENNINGER CLIN JI Bull. Menninger Clin. PD SPR PY 2016 VL 80 IS 2 BP 97 EP 130 PG 34 WC Psychiatry; Psychology, Psychoanalysis SC Psychiatry; Psychology GA DO9VD UT WOS:000378135200001 PM 27294585 ER PT J AU Jani, S Johnson, RS Banu, S Shah, A AF Jani, Suni Johnson, R. Scott Banu, Sophia Shah, Asim TI Cross-cultural bias in the diagnosis of borderline personality disorder SO BULLETIN OF THE MENNINGER CLINIC LA English DT Article ID PSYCHIATRIC EMERGENCIES; ETHNICITY; OUTPATIENTS; CHINA AB Borderline personality disorder (BPD) is an internationally recognized disorder, although it is slightly varied in its nosology in the International Classification of Diseases, 10th Revision (ICD-10), the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5), and the Chinese Classification of Mental Disorders (CCMD). While it is recognized by genetic and neurobiological patterns, instability of affect, impaired interpersonal relationships, and unstable sense of self, its manifestation is extremely varied based on environmental factors, particularly culture. Several studies of the manifestation of BPD between and across countries, particularly in immigrant populations, identify variations in symptom prevalence based on culture. These findings reveal a need for more unified dimensional-based categorization of BPD to reduce cross-cultural bias and improve identification. C1 [Jani, Suni] Harvard Univ, Massachusetts Gen Hosp, Sch Med, McLean Hosp,Child & Adolescent Psychiat, Boston, MA USA. [Johnson, R. Scott] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Forens Psychiat, Boston, MA 02114 USA. [Banu, Sophia; Shah, Asim] Baylor Coll Med, Menninger Dept Psychiat & Behav Sci, Psychiat, Houston, TX 77030 USA. RP Jani, S (reprint author), 55 Fruit St,Yawkey Ctr Outpatient Care 6A, Boston, MA 02114 USA. EM sjani@mgh.harvard.edu NR 38 TC 0 Z9 0 U1 10 U2 10 PU GUILFORD PUBLICATIONS INC PI NEW YORK PA 370 SEVENTH AVE, SUITE 1200, NEW YORK, NY 10001-1020 USA SN 0025-9284 EI 1943-2828 J9 B MENNINGER CLIN JI Bull. Menninger Clin. PD SPR PY 2016 VL 80 IS 2 BP 146 EP 165 PG 20 WC Psychiatry; Psychology, Psychoanalysis SC Psychiatry; Psychology GA DO9VD UT WOS:000378135200003 PM 27294587 ER PT J AU Novais, EA Baumal, CR Sarraf, D Freund, KB Duker, JS AF Novais, Eduardo A. Baumal, Caroline R. Sarraf, David Freund, K. Bailey Duker, Jay S. TI Multimodal Imaging in Retinal Disease: A Consensus Definition SO OPHTHALMIC SURGERY LASERS & IMAGING RETINA LA English DT Editorial Material ID OPTICAL COHERENCE TOMOGRAPHY; OCCULT MACULAR DYSTROPHY; CHOROIDAL NEOVASCULARIZATION; ANGIOGRAPHY; DEGENERATION; FUTURE C1 [Novais, Eduardo A.; Baumal, Caroline R.; Duker, Jay S.] Tufts Med Ctr, New England Eye Ctr, 260 Tremont St,Biewend Bldg,9-11th Floor, Boston, MA 02116 USA. [Novais, Eduardo A.] Univ Fed Sao Paulo, Sch Med, Sao Paulo, Brazil. [Sarraf, David] Univ Calif Los Angeles, Stein Eye Inst, Los Angeles, CA USA. [Sarraf, David] Greater Los Angeles VA Healthcare Ctr, Los Angeles, CA USA. [Freund, K. Bailey] Vitreous Retina Macula Consultants New York, New York, NY USA. [Freund, K. Bailey] NYU, Sch Med, Dept Ophthalmol, New York, NY USA. RP Duker, JS (reprint author), Tufts Med Ctr, New England Eye Ctr, 260 Tremont St,Biewend Bldg,9-11th Floor, Boston, MA 02116 USA. EM jduker@tuftsmedicalcenter.org OI Freund, K. Bailey/0000-0002-7888-9773 NR 34 TC 1 Z9 1 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 MAR PY 2016 VL 47 IS 3 BP 201 EP + DI 10.3928/23258160-20160229-01 PG 6 WC Ophthalmology; Surgery SC Ophthalmology; Surgery GA DP9VF UT WOS:000378844900001 PM 26985792 ER PT J AU Harriff, MJ Karamooz, E Burr, A Grant, WF Canfield, ET Sorensen, ML Moita, LF Lewinsohn, DM AF Harriff, Melanie J. Karamooz, Elham Burr, Ansen Grant, Wilmon F. Canfield, Elizabeth T. Sorensen, Michelle L. Moita, Luis F. Lewinsohn, David M. TI Endosomal MR1 Trafficking Plays a Key Role in Presentation of Mycobacterium tuberculosis Ligands to MAIT Cells SO PLOS PATHOGENS LA English DT Article ID INVARIANT T-CELLS; MHC CLASS-I; CD1 ANTIGEN PRESENTATION; ENDOPLASMIC-RETICULUM; BACTERIAL-INFECTION; SYNTAXIN 18; Q-SNARE; RECEPTOR; PATHWAY; INVOLVEMENT AB Mucosal-Associated Invariant T (MAIT) cells, present in high frequency in airway and other mucosal tissues, have Th1 effector capacity positioning them to play a critical role in the early immune response to intracellular pathogens, including Mycobacterium tuberculosis (Mtb). MR1 is a highly conserved Class I-like molecule that presents vitamin B metabolites to MAIT cells. The mechanisms for loading these ubiquitous small molecules are likely to be tightly regulated to prevent inappropriate MAIT cell activation. To define the intracellular localization of MR1, we analyzed the distribution of an MR1-GFP fusion protein in antigen presenting cells. We found that MR1 localized to endosomes and was translocated to the cell surface upon addition of 6-formyl pterin (6-FP). To understand the mechanisms by which MR1 antigens are presented, we used a lentiviral shRNA screen to identify trafficking molecules that are required for the presentation of Mtb antigen to HLA-diverse T cells. We identified Stx18, VAMP4, and Rab6 as trafficking molecules regulating MR1-dependent MAIT cell recognition of Mtb-infected cells. Stx18 but not VAMP4 or Rab6 knockdown also resulted in decreased 6-FP-dependent surface translocation of MR1 suggesting distinct pathways for loading of exogenous ligands and intracellular mycobacterially-derived ligands. We postulate that endosome-mediated trafficking of MR1 allows for selective sampling of the intracellular environment. C1 [Harriff, Melanie J.; Karamooz, Elham; Burr, Ansen; Sorensen, Michelle L.; Lewinsohn, David M.] Portland VA Med Ctr, Portland, OR 97239 USA. [Harriff, Melanie J.; Karamooz, Elham; Grant, Wilmon F.; Canfield, Elizabeth T.; Lewinsohn, David M.] Oregon Hlth & Sci Univ, Pulm & Crit Care Med, Portland, OR 97201 USA. [Moita, Luis F.] Inst Gulbenkian Ciencias, Oeiras, Portugal. [Lewinsohn, David M.] Oregon Hlth & Sci Univ, Mol Microbiol & Immunol, Portland, OR 97201 USA. RP Harriff, MJ (reprint author), Portland VA Med Ctr, Portland, OR 97239 USA.; Harriff, MJ (reprint author), Oregon Hlth & Sci Univ, Pulm & Crit Care Med, Portland, OR 97201 USA. EM harriffm@ohsu.edu; lewinsod@ohsu.edu OI Moita, Luis/0000-0003-0707-315X FU Career Development Award from the U.S. Department of Veterans Affairs Clinical Sciences Research and Development Program [IK2 CX000538]; U.S. Department of Veterans Affairs Biomedical Laboratory Research and Development Program [I01 BX000533]; American Lung Association [RT-350058] FX This work was supported in part by Career Development Award #IK2 CX000538 from the U.S. Department of Veterans Affairs Clinical Sciences Research and Development Program (MJH) and in part by Merit Award #I01 BX000533 from the U.S. Department of Veterans Affairs Biomedical Laboratory Research and Development Program (DML). EK also received support from the American Lung Association (RT-350058). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 34 TC 2 Z9 2 U1 4 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7366 EI 1553-7374 J9 PLOS PATHOG JI PLoS Pathog. PD MAR PY 2016 VL 12 IS 3 AR e1005524 DI 10.1371/journal.ppat.1005524 PG 19 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA DP0CH UT WOS:000378154800039 PM 27031111 ER PT J AU Kiselinova, M De Spiegelaere, W Buzon, MJ Malatinkova, E Lichterfeld, M Vandekerckhove, L AF Kiselinova, Maja De Spiegelaere, Ward Buzon, Maria Jose Malatinkova, Eva Lichterfeld, Mathias Vandekerckhove, Linos TI y Integrated and Total HIV-1 DNA Predict Ex Vivo Viral Outgrowth SO PLOS PATHOGENS LA English DT Article ID HOST RESTRICTION FACTORS; CD4(+) T-CELLS; ANTIRETROVIRAL THERAPY; LATENT RESERVOIR; COMBINATION THERAPY; PROVIRAL DNA; PCR DATA; INFECTION; PERSISTENCE; CURE AB The persistence of a reservoir of latently infected CD4 T cells remains one of the major obstacles to cure HIV. Numerous strategies are being explored to eliminate this reservoir. To translate these efforts into clinical trials, there is a strong need for validated biomarkers that can monitor the reservoir over time in vivo. A comprehensive study was designed to evaluate and compare potential HIV-1 reservoir biomarkers. A cohort of 25 patients, treated with suppressive antiretroviral therapy was sampled at three time points, with median of 2.5 years (IQR: 2.4-2.6) between time point 1 and 2; and median of 31 days (IQR: 28-36) between time point 2 and 3. Patients were median of 6 years (IQR: 3-12) on ART, and plasma viral load (<50 copies/ml) was suppressed for median of 4 years (IQR: 2-8). Total HIV-1 DNA, unspliced (us) and multiply spliced HIV-1 RNA, and 2LTR circles were quantified by digital PCR in peripheral blood, at 3 time points. At the second time point, a viral outgrowth assay (VOA) was performed, and integrated HIV-1 DNA and relative mRNA expression levels of HIV-1 restriction factors were quantified. No significant change was found for long-and short-term dynamics of all HIV-1 markers tested in peripheral blood. Integrated HIV-1 DNA was associated with total HIV-1 DNA (p<0.001, R-2=0.85), us HIV-1 RNA (p = 0.029, R-2=0.40), and VOA (p = 0.041, R-2=0.44). Replication-competent virus was detected in 80% of patients by the VOA and it correlated with total HIV-1 DNA (p = 0.039, R-2=0.54). The mean quantification difference between Alu-PCR and VOA was 2.88 log(10), and 2.23 log10 between total HIV-1 DNA and VOA. The levels of us HIV-1 RNA were inversely correlated with mRNA levels of several HIV-1 restriction factors (TRIM5 alpha, SAMHD1, MX2, SLFN11, pSIP1). Our study reveals important correlations between the viral outgrowth and total and integrated HIV-1 DNA measures, suggesting that the total pool of HIV-1 DNA may predict the size of the replication-competent virus in ART suppressed patients. C1 [Kiselinova, Maja; De Spiegelaere, Ward; Malatinkova, Eva; Vandekerckhove, Linos] Univ Ghent, Dept Internal Med, HIV Translat Res Unit HTRU, B-9000 Ghent, Belgium. [Kiselinova, Maja; De Spiegelaere, Ward; Malatinkova, Eva; Vandekerckhove, Linos] Ghent Univ Hosp, Ghent, Belgium. [Kiselinova, Maja; Buzon, Maria Jose; Lichterfeld, Mathias] Ragon Inst MGH MIT & Harvard, Boston, MA USA. [Buzon, Maria Jose; 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 Vandekerckhove, L (reprint author), Univ Ghent, Dept Internal Med, HIV Translat Res Unit HTRU, B-9000 Ghent, Belgium.; Vandekerckhove, L (reprint author), Ghent Univ Hosp, Ghent, Belgium. EM Linos.Vandekerckhove@ugent.be FU NIAID NIH HHS [R21 AI106468, AI098487, AI106468] NR 45 TC 8 Z9 9 U1 2 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7366 EI 1553-7374 J9 PLOS PATHOG JI PLoS Pathog. PD MAR PY 2016 VL 12 IS 3 AR e1005472 DI 10.1371/journal.ppat.1005472 PG 17 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA DP0CH UT WOS:000378154800015 PM 26938995 ER PT J AU Zinner, DE Pham-Kanter, G Campbell, EG AF Zinner, Darren E. Pham-Kanter, Genevieve Campbell, Eric G. TI The Changing Nature of Scientific Sharing and Withholding in Academic Life Sciences Research: Trends From National Surveys in 2000 and 2013 SO ACADEMIC MEDICINE LA English DT Article ID ACCESS AB Purpose Since 2000, federal funders and many journals have established policies requiring more open sharing of data and materials post-publication, primarily through online supplements and thirdparty repositories. This study examined changes in sharing and withholding practices among academic life scientists, particularly geneticists, between 2000 and 2013. Method In 2000 and 2013, the authors surveyed separate samples of 3,000 academic life scientists at the 100 U.S. universities receiving the most National Institutes of Health funding. Respondents were asked to estimate the number of requests for information, data, and materials they made to and received from other academic researchers in the past three years. They were also asked about potential consequences of sharing and withholding. Results Response rates were 63.9% (1,849/2,893) in 2000 and 40.8% (1,165/2,853) in 2013. Proportions of faculty in 2000 and 2013 who received, denied, made, or were denied at least one request were not statistically different. However, the total volume of requests received from or made to other scientists dropped substantially (19.4 received in 2000 versus 10.8 in 2013, P < .001; 8.4 made in 2000 versus 6.6 in 2013, P < .001). Faculty in 2013 also made an average of 8.4 requests to third-party repositories. Researchers in 2013 were less likely to report sharing resulted in new research or collaborations. Conclusions The results show a dramatic shift in sharing mechanisms, away from a peer-to-peer sharing model toward one based on central repositories. This may increase efficiency, but collaborations may suffer if personal communication among scientists is deemphasized. C1 [Zinner, Darren E.] Brandeis Univ, Heller Sch Social Policy & Management, Schneider Inst Hlth Policy, Waltham, MA 02453 USA. [Pham-Kanter, Genevieve] Drexel Univ, Sch Publ Hlth, Dept Hlth Management & Policy, Philadelphia, PA 19104 USA. [Pham-Kanter, Genevieve] Harvard Univ, Edmond J Safra Ctr Eth, Cambridge, MA 02138 USA. [Campbell, Eric G.] Massachusetts Gen Hosp, Mongan Inst Hlth Policy, Med, Boston, MA 02114 USA. [Campbell, Eric G.] Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Zinner, DE (reprint author), Brandeis Univ, 415 South St,MS035, Waltham, MA 02453 USA. EM dzinner@brandeis.edu FU National Human Genome Research Institute of the National Institutes of Health [5R01HG01789, 5R01HG006281] FX Both the 2000 and 2013 studies were funded by the National Human Genome Research Institute of the National Institutes of Health, grant numbers 5R01HG01789 and 5R01HG006281, respectively. NR 16 TC 2 Z9 2 U1 5 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1040-2446 EI 1938-808X J9 ACAD MED JI Acad. Med. PD MAR PY 2016 VL 91 IS 3 BP 433 EP 440 DI 10.1097/ACM.0000000000001028 PG 8 WC Education, Scientific Disciplines; Health Care Sciences & Services SC Education & Educational Research; Health Care Sciences & Services GA DO2KA UT WOS:000377607500042 PM 26675188 ER PT J AU Coutinho, JF Fernandesl, SV Soares, JM Maia, L Goncalves, OF Sampaio, A AF Coutinho, Joana Fernandes Fernandesl, Sara Veiga Soares, Jose Miguel Maia, Liliana Goncalves, Oscar Filipe Sampaio, Adriana TI Default mode network dissociation in depressive and anxiety states SO BRAIN IMAGING AND BEHAVIOR LA English DT Article DE Default mode network; Anterior-posterior dissociation; Depressive states; Anxiety states ID ANTERIOR CINGULATE CORTEX; INDEPENDENT COMPONENT ANALYSIS; MAJOR DEPRESSION; FUNCTIONAL CONNECTIVITY; AUTOBIOGRAPHICAL MEMORY; BRAIN ACTIVITY; COGNITIVE CONTROL; SELF; DISORDER; FMRI AB The resting state brain networks, particularly the Default Mode Network (DMN), have been found to be altered in several psychopathological conditions such as depression and anxiety. In this study we hypothesized that cortical areas of the DMN, particularly the anterior regions - medial prefrontal cortex and anterior cingulate cortex - would show an increased functional connectivity associated with both anxiety and depression. Twenty-four healthy participants were assessed using Hamilton Depression and Anxiety Rating Scales and completed a resting-state functional magnetic resonance imaging scan. Multiple regression was performed in order to identify which areas of the DMN were associated with anxiety and depression scores. We found that the functional connectivity of the anterior portions of DMN, involved in self-referential and emotional processes, was positively correlated with anxiety and depression scores, whereas posterior areas of the DMN, involved in episodic memory and perceptual processing were negatively correlated with anxiety and depression scores. The dissociation between anterior and posterior cortical midline regions, raises the possibility of a functional specialization within the DMN in terms of self-referential tasks and contributes to the understanding of the cognitive and affective alterations in depressive and anxiety states. C1 [Coutinho, Joana Fernandes; Fernandesl, Sara Veiga; Maia, Liliana; Goncalves, Oscar Filipe; Sampaio, Adriana] Univ Minho, Sch Psychol, CIPsi, Neuropsychophysiol Lab, Braga, Portugal. [Soares, Jose Miguel] Univ Minho, Life & Hlth Sci Res Inst, Braga, Portugal. [Soares, Jose Miguel] Univ Minho, ICVS PT Govt Associate Lab 3Bs, Braga, Portugal. [Goncalves, Oscar Filipe] Northeastern Univ, Bouve Coll Hlth Sci, Dept Counseling & Appl Educ Psychol, Boston, MA 02115 USA. [Goncalves, Oscar Filipe] Spaulding Rehabil Hosp, Dept Phys Med & Rehabil, Spaulding Neuromodulat Ctr, Boston, MA USA. [Goncalves, Oscar Filipe] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. RP Coutinho, JF (reprint author), Univ Minho, Sch Psychol, CIPsi, Neuropsychophysiol Lab, Braga, Portugal. EM joanafpc@gmail.com RI Sampaio, Adriana/C-8361-2011; Goncalves, Oscar/G-5278-2010; OI Sampaio, Adriana/0000-0001-7347-1282; Goncalves, Oscar/0000-0003-2735-9155; Soares, Jose Miguel/0000-0001-6558-4973; Coutinho, Joana/0000-0002-1562-0099 FU Portuguese Foundation for Science and Technology (FCT) [PIC/IC/83290/2007]; FEDER (POFC - COMPETE); FCT [SFRH/BPD/75014/2010]; Bial Foundation [87/12]; Competitive Factors Operational Programme-COMPETE-; national funds from the Portuguese Foundation for Science and Technology [PTDC/PSI-PCL/115316/2009] FX This research was funded by the Portuguese Foundation for Science and Technology (FCT): PIC/IC/83290/2007, which is supported by FEDER (POFC - COMPETE). Joana Coutinho was funded by a FCT postdoctoral grant (number: SFRH/BPD/75014/2010)- POPH program and Bial Foundation (grant number 87/12); Liliana Maia is supported by the Competitive Factors Operational Programme-COMPETE-, by national funds from the Portuguese Foundation for Science and Technology (grant PTDC/PSI-PCL/115316/2009). NR 80 TC 9 Z9 10 U1 4 U2 8 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1931-7557 EI 1931-7565 J9 BRAIN IMAGING BEHAV JI Brain Imaging Behav. PD MAR PY 2016 VL 10 IS 1 BP 147 EP 157 DI 10.1007/s11682-015-9375-7 PG 11 WC Neuroimaging SC Neurosciences & Neurology GA DO5NJ UT WOS:000377829500016 PM 25804311 ER PT J AU Eicher, JD Montgomery, AM Akshoomoff, N Amaral, DG Bloss, CS Libiger, O Schork, NJ Darst, BF Casey, BJ Chang, LD Ernst, T Frazier, J Kaufmann, WE Keating, B Kenet, T Kennedy, D Mostofsky, S Murray, SS Sowell, ER Bartsch, H Kuperman, JM Brown, TT Hagler, DJ Dale, AM Jernigan, TL Gruen, JR AF Eicher, John D. Montgomery, Angela M. Akshoomoff, Natacha Amaral, David G. Bloss, Cinnamon S. Libiger, Ondrej Schork, Nicholas J. Darst, Burcu F. Casey, B. J. Chang, Linda Ernst, Thomas Frazier, Jean Kaufmann, Walter E. Keating, Brian Kenet, Tal Kennedy, David Mostofsky, Stewart Murray, Sarah S. Sowell, Elizabeth R. Bartsch, Hauke Kuperman, Joshua M. Brown, Timothy T. Hagler, Donald J., Jr. Dale, Anders M. Jernigan, Terry L. Gruen, Jeffrey R. CA Pediat Imaging Neurocognition TI Dyslexia and language impairment associated genetic markers influence cortical thickness and white matter in typically developing children SO BRAIN IMAGING AND BEHAVIOR LA English DT Article DE Dyslexia; Language impairment; KIAA0319; DYX3; DYX2; Imaging-genetics ID QUANTITATIVE-TRAIT LOCUS; ALTERED BRAIN ACTIVATION; READING-DISABILITY; DEVELOPMENTAL DYSLEXIA; SUSCEPTIBILITY GENE; NEURONAL MIGRATION; CHROMOSOME 6P22; GRAY-MATTER; GENOME SCAN; DYX2 LOCUS AB Dyslexia and language impairment (LI) are complex traits with substantial genetic components. We recently completed an association scan of the DYX2 locus, where we observed associations of markers in DCDC2, KIAA0319, ACOT13, and FAM65B with reading-, language-, and IQ-related traits. Additionally, the effects of reading-associated DYX3 markers were recently characterized using structural neuroimaging techniques. Here, we assessed the neuroimaging implications of associated DYX2 and DYX3 markers, using cortical volume, cortical thickness, and fractional anisotropy. To accomplish this, we examined eight DYX2 and three DYX3 markers in 332 subjects in the Pediatrics Imaging Neurocognition Genetics study. Imaging-genetic associations were examined by multiple linear regression, testing for influence of genotype on neuroimaging. Markers in DYX2 genes KIAA0319 and FAM65B were associated with cortical thickness in the left orbitofrontal region and global fractional anisotropy, respectively. KIAA0319 and ACOT13 were suggestively associated with overall fractional anisotropy and left pars opercularis cortical thickness, respectively. DYX3 markers showed suggestive associations with cortical thickness and volume measures in temporal regions. Notably, we did not replicate association of DYX3 markers with hippocampal measures. In summary, we performed a neuroimaging follow-up of reading-, language-, and IQ-associated DYX2 and DYX3 markers. DYX2 associations with cortical thickness may reflect variations in their role in neuronal migration. Furthermore, our findings complement gene expression and imaging studies implicating DYX3 markers in temporal regions. These studies offer insight into where and how DYX2 and DYX3 risk variants may influence neuroimaging traits. Future studies should further connect the pathways to risk variants associated with neuroimaging/neurocognitive outcomes. C1 [Eicher, John D.; Gruen, Jeffrey R.] Yale Univ, Dept Genet, New Haven, CT 06520 USA. [Montgomery, Angela M.; Gruen, Jeffrey R.] Yale Univ, Dept Pediat, Sch Med, New Haven, CT 06520 USA. [Akshoomoff, Natacha; Brown, Timothy T.; Jernigan, Terry L.] Univ Calif San Diego, Ctr Human Dev, La Jolla, CA 92037 USA. [Akshoomoff, Natacha; Dale, Anders M.] Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92037 USA. [Amaral, David G.] Univ Calif Davis, Dept Psychiat & Behav Sci, Sacramento, CA 95817 USA. [Bloss, Cinnamon S.; Libiger, Ondrej; Schork, Nicholas J.; Darst, Burcu F.; Murray, Sarah S.] Scripps Translat Sci Inst, Scripps Genom Med, Scripps Hlth, La Jolla, CA 92037 USA. [Casey, B. J.] Weill Cornell Med Coll, Sackler Inst Dev Psychobiol, New York, NY 10065 USA. [Chang, Linda; Ernst, Thomas; Keating, Brian] Univ Hawaii, Dept Med, Queens Med Ctr, Honolulu, HI 96813 USA. [Frazier, Jean; Kennedy, David] Univ Massachusetts, Sch Med, Dept Psychiat, Worcester, MA 01655 USA. [Kaufmann, Walter E.; Mostofsky, Stewart] Kennedy Krieger Inst, 707 N Broadway, Baltimore, MD 21205 USA. [Kaufmann, Walter E.] Harvard Univ, Sch Med, Dept Neurol, Childrens Hosp Boston, Boston, MA 02115 USA. [Kenet, Tal] Massachusetts Gen Hosp, Dept Neurol, Charlestown, MA 02129 USA. [Kenet, Tal] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Sowell, Elizabeth R.] Univ So Calif, Dept Pediat, Los Angeles, CA 90027 USA. [Sowell, Elizabeth R.] Childrens Hosp Los Angeles, Dev Cognit Neuroimaging Lab, Los Angeles, CA 90027 USA. [Bartsch, Hauke; Kuperman, Joshua M.; Brown, Timothy T.; Hagler, Donald J., Jr.; Dale, Anders M.] Univ Calif San Diego, Multimodal Imaging Lab, La Jolla, CA 92037 USA. [Kuperman, Joshua M.; Brown, Timothy T.; Dale, Anders M.] Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92037 USA. [Hagler, Donald J., Jr.; Dale, Anders M.; Jernigan, Terry L.] Univ Calif San Diego, Radiol, La Jolla, CA 92037 USA. [Dale, Anders M.; Jernigan, Terry L.] Univ Calif San Diego, Cognit Sci, La Jolla, CA 92037 USA. [Gruen, Jeffrey R.] Yale Univ, Sch Med, Dept Invest, 333 Cedar St, New Haven, CT 06520 USA. [Gruen, Jeffrey R.] Yale Child Hlth Res Ctr, Dept Pediat Genet & Invest Med, 464 Congress Ave, New Haven, CT 06520 USA. RP Gruen, JR (reprint author), Yale Univ, Dept Genet, New Haven, CT 06520 USA.; Gruen, JR (reprint author), Yale Univ, Dept Pediat, Sch Med, New Haven, CT 06520 USA.; Gruen, JR (reprint author), Yale Univ, Sch Med, Dept Invest, 333 Cedar St, New Haven, CT 06520 USA.; Gruen, JR (reprint author), Yale Child Hlth Res Ctr, Dept Pediat Genet & Invest Med, 464 Congress Ave, New Haven, CT 06520 USA. FU National Institutes of Health [RC2DA029475, R01 NS043530, 2P50 HD 02780222, T32 HD07094, F31 DC012270]; National Institute on Drug Abuse; Eunice Kennedy Shriver National Institute of Child Health & Human Development; Manton Foundation FX Data collection and sharing for this project were funded by the PING Study (National Institutes of Health Grant RC2DA029475). PING is funded by the National Institute on Drug Abuse and the Eunice Kennedy Shriver National Institute of Child Health & Human Development. This research was specifically funded by the National Institutes of Health (Grant ref: R01 NS043530 and 2P50 HD 02780222 in support of J.R.G., T32 HD07094 awarded to A.M.M., and F31 DC012270 awarded to J.D.E.). In addition, J.D.E. and J.R.G received support from the Manton Foundation. NR 64 TC 1 Z9 1 U1 6 U2 7 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1931-7557 EI 1931-7565 J9 BRAIN IMAGING BEHAV JI Brain Imaging Behav. PD MAR PY 2016 VL 10 IS 1 BP 272 EP 282 DI 10.1007/s11682-015-9392-6 PG 11 WC Neuroimaging SC Neurosciences & Neurology GA DO5NJ UT WOS:000377829500028 PM 25953057 ER PT J AU Kochupurakkal, BS Iglehart, JD AF Kochupurakkal, Bose S. Iglehart, J. Dirk TI Identification of genes responsible for RelA-dependent proliferation arrest in human mammary epithelial cells conditionally expressing RelA SO GENOMICS DATA LA English DT Article ID MICROARRAY DATA AB The molecular mechanisms responsible for opposing oncogenic and tumor-suppressor activities of NF-kB are obscure. Semi-quantitative immunohistochemistry of primary breast tumors using antibodies to RelA, the pleiotropic NF-kB factor, and Ki67 revealed a negative correlation between RelA levels and Ki67-index among ER+/HER2 - tumors [1]. Similarly, expression of AURKA, a marker for proliferation, negatively correlates with expression of NFKBIA, a surrogate for RelA expression and activity, in ER+/HER2 - tumors analyzed by The Cancer Genome Atlas [2-4]. Furthermore, conditional expression of RelA using a Tetracycline-inducible system in Human Mammary Epithelial Cells (HRA cells) caused proliferation arrest while withdrawal of Doxycycline (Dox) and suppression of RelA expression in arrested cells restored cell cycle progression [1]. To identify genes responsible for the negative relationship between RelA levels and proliferation, we performed genome-wide gene expression analysis of HRA cells under the following conditions: RelA un-induced, No Dox (ND); Dox induced for 24 h; Dox induced for 72 h; Dox induced for 24 h then Dox withdrawn for 48 h. The expression data was submitted to Gene Expression Ominibus (GEO) and the accession number is GSE65040. Analysis of the data identified cross-talk between basal RelA activity and the Interferon pathway mediated by IRF1, a target of RelA [5]. Activation of the Interferon pathway lead to down-regulation of CDK4 expression resulting in RB1 hypo-phosphorylation and suppression of cell cycle progression. The tumor-suppressor activity of NF-kB, specifically RelA, may stem from cross-talk with the Interferon pathway. (c) 2015 The Authors. Published by Elsevier Inc. C1 [Kochupurakkal, Bose S.; Iglehart, J. Dirk] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA. [Iglehart, J. Dirk] Brigham & Womens Hosp, Dept Surg, 75 Francis St, Boston, MA 02115 USA. RP Kochupurakkal, BS; Iglehart, JD (reprint author), Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA. EM bose_kochupurakkal@dfci.harvard.edu; jiglehart@partners.org FU NCI NIH HHS [P50 CA089393] NR 10 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 2213-5960 J9 GENOM DATA JI Genom. Data PD MAR PY 2016 VL 7 BP 92 EP 93 DI 10.1016/j.gdata.2015.11.022 PG 2 WC Genetics & Heredity SC Genetics & Heredity GA DO4NY UT WOS:000377761100027 PM 26981373 ER PT J AU Agarwal, A O'Neil, K Kelly, A Keaty, M Whitehouse, C Kalinowski, B Orio, PF Martin, NE AF Agarwal, Ankit O'Neil, Kelly Kelly, Andrea Keaty, Maureen Whitehouse, Colleen Kalinowski, Barbara Orio, Peter F. Martin, Neil E. TI Implementing patient-reported outcome surveys as part of routine care: Lessons from an academic radiation oncology department. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT ASCO Quality Care Symposium CY FEB 26-27, 2016 CL Phoenix, AZ SP Amer Soc Clin Oncol C1 Boston Univ, Sch Med, Boston, MA 02118 USA. Brigham & Womens Dana Farber Canc Inst, Boston, MA USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. Brigham & Womens Hosp, Dana Farber Canc Inst, 75 Francis St, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAR 1 PY 2016 VL 34 IS 7 SU S MA 97 PG 1 WC Oncology SC Oncology GA DO9ME UT WOS:000378109900096 ER PT J AU Barysauskas, C Bundy, DG Gaur, AH Hord, JD Miller, MR Werner, EJ Winkle, C Billett, A AF Barysauskas, Constance Bundy, David G. Gaur, Aditya H. Hord, Jeffrey D. Miller, Marlene R. Werner, Eric J. Winkle, Cindi Billett, Amy TI Burden of bloodstream infections among ambulatory pediatric hematology/oncology patients with a central line SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT ASCO Quality Care Symposium CY FEB 26-27, 2016 CL Phoenix, AZ SP Amer Soc Clin Oncol C1 Dana Farber Canc Inst, Boston, MA 02115 USA. Johns Hopkins Univ, Pediat, Baltimore, MD USA. St Jude Childrens Res Hosp, Infect Dis, 332 N Lauderdale St, Memphis, TN 38105 USA. Akron Childrens Hosp, Akron, OH USA. Johns Hopkins Children, Pediat, Baltimore, MD USA. Childrens Hosp Kings Daughters, Pediat Hematol Oncol, Norfolk, VA USA. Eastern Virginia Med Sch, Pediat Hematol Oncol, Norfolk, VA 23501 USA. Univ Texas SW Med Ctr Dallas, Pediat, Dallas, TX 75390 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAR 1 PY 2016 VL 34 IS 7 SU S MA 262 PG 1 WC Oncology SC Oncology GA DO9ME UT WOS:000378109900252 ER PT J AU Bowhay-Carnes, EA Lee, S Datta, P AF Bowhay-Carnes, Elizabeth Ann Lee, Shuko Datta, Paromita TI Evaluation of leukocytosis: Benign or malignant. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT ASCO Quality Care Symposium CY FEB 26-27, 2016 CL Phoenix, AZ SP Amer Soc Clin Oncol C1 Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. South Texas Vet Hlth Care Syst, San Antonio, TX USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAR 1 PY 2016 VL 34 IS 7 SU S MA 245 PG 1 WC Oncology SC Oncology GA DO9ME UT WOS:000378109900236 ER PT J AU Brooks, G Dalby, CK Chaudary, S Jacobson, JO AF Brooks, Gabriel Dalby, Carole Kathleen Chaudary, Saira Jacobson, Joseph O. TI A pragmatic approach for measuring and monitoring hospitalizations in patients receiving chemotherapy for pancreatic cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT ASCO Quality Care Symposium CY FEB 26-27, 2016 CL Phoenix, AZ SP Amer Soc Clin Oncol C1 Dana Farber Canc Inst, Boston, MA 02115 USA. Dana Farber Canc Inst, Waban, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAR 1 PY 2016 VL 34 IS 7 SU S MA 278 PG 1 WC Oncology SC Oncology GA DO9ME UT WOS:000378109900268 ER PT J AU Brooks, G Stuver, SO Zhang, YC Gottsch, S Fraile, B McNiff, KK Dodek, A Jacobson, JO AF Brooks, Gabriel Stuver, Sherri Oliver Zhang, Yichen Gottsch, Stephanie Fraile, Belen McNiff, Kristen K. Dodek, Anton Jacobson, Joseph O. TI Characteristics associated with in-hospital death in commercially insured decedent SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT ASCO Quality Care Symposium CY FEB 26-27, 2016 CL Phoenix, AZ SP Amer Soc Clin Oncol C1 Dana Farber Canc Inst, Boston, MA 02115 USA. Blue Cross & Blue Shield Massachusetts, Boston, MA USA. Dana Farber Canc Inst, Waban, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAR 1 PY 2016 VL 34 IS 7 SU S MA 35 PG 1 WC Oncology SC Oncology GA DO9ME UT WOS:000378109900035 ER PT J AU Carter, BW Erasmus, JJ Truong, M Munden, RF Shepard, JAO Clarke, RK Steele, JR AF Carter, Brett W. Erasmus, Jeremy J. Truong, Mylene Munden, Reginald F. Shepard, Jo-Anne O. Clarke, Ryan Kristopher Steele, Joseph Rodgers TI Quality and value of subspecialty reinterpretation of outside thoracic CT scans of patients referred to a tertiary cancer center SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT ASCO Quality Care Symposium CY FEB 26-27, 2016 CL Phoenix, AZ SP Amer Soc Clin Oncol C1 Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. Houston Methodist Hosp, Phys Org, Houston, TX USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAR 1 PY 2016 VL 34 IS 7 SU S MA 265 PG 1 WC Oncology SC Oncology GA DO9ME UT WOS:000378109900255 ER PT J AU Clarke, CA Baker, LC Malin, J Parker, J Holliday-Hanson, M Fong, N Teleki, S Lang, L O'Sullivan, M AF Clarke, Christina A. Baker, Laurence C. Malin, Jennifer Parker, Joseph Holliday-Hanson, Merry Fong, Niya Teleki, Stephanie Lang, Lance O'Sullivan, Maryann TI Creating an online resource providing hospital cancer surgery volumes in California. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT ASCO Quality Care Symposium CY FEB 26-27, 2016 CL Phoenix, AZ SP Amer Soc Clin Oncol C1 Canc Prevent Inst Calif, Fremont, CA USA. Stanford Univ, Palo Alto, CA 94304 USA. VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. Calif Off Statewide Hlth Planning & Dev, Sacramento, CA USA. Calif HealthCare Fndtn, Oakland, CA USA. Calif Qual Collaborat, Berkeley, CA USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAR 1 PY 2016 VL 34 IS 7 SU S MA 172 PG 1 WC Oncology SC Oncology GA DO9ME UT WOS:000378109900168 ER PT J AU Close, S Emmert, A Soiffer, R Alyea, E Antin, JH Glotzbecker, B AF Close, Sara Emmert, Amy Soiffer, Robert Alyea, Edwin Antin, Joseph Harry Glotzbecker, Brett TI An interactive video-based approach to diet education for patients posthematopoietic stem cell transplantation. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT ASCO Quality Care Symposium CY FEB 26-27, 2016 CL Phoenix, AZ SP Amer Soc Clin Oncol C1 [Close, Sara; Emmert, Amy; Soiffer, Robert; Alyea, Edwin; Antin, Joseph Harry; Glotzbecker, Brett] Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAR 1 PY 2016 VL 34 IS 7 SU S MA 183 PG 1 WC Oncology SC Oncology GA DO9ME UT WOS:000378109900179 ER PT J AU Flaherty, S Horvath, K Stahl, PJ AF Flaherty, Stephen Horvath, Kathleen Stahl, Patricia Jahoda TI Learning from and engaging patients/families during the implementation of a new medical record system. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT ASCO Quality Care Symposium CY FEB 26-27, 2016 CL Phoenix, AZ SP Amer Soc Clin Oncol C1 [Flaherty, Stephen; Horvath, Kathleen; Stahl, Patricia Jahoda] Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAR 1 PY 2016 VL 34 IS 7 SU S MA 66 PG 1 WC Oncology SC Oncology GA DO9ME UT WOS:000378109900065 ER PT J AU Kostka, J Zerillo, JA Kruse, A Sinclair, NF Patrick, M McGovern, L Fuller, F O'Neil, K Hixon, N Weeks, K Johnson, BE Krop, IE Savoie, J Daftary, F Constantine, M Kaddis, MS Rossi, HA Tahir, N Norden, AD AF Kostka, Judith Zerillo, Jessica A. Kruse, Andrea Sinclair, Natalie Faye Patrick, Maureen McGovern, Lauren Fuller, Frances O'Neil, Kelly Hixon, Nicole Weeks, Kristie Johnson, Bruce E. Krop, Ian E. Savoie, Jen Daftary, Farah Constantine, Michael Kaddis, Mona S. Rossi, Humberto A. Tahir, Naeem Norden, Andrew David TI Clinical trial enrollment expansion to the community. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT ASCO Quality Care Symposium CY FEB 26-27, 2016 CL Phoenix, AZ SP Amer Soc Clin Oncol C1 Dana Farber Canc Inst, Boston, MA 02115 USA. Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. Dana Farber Canc Inst, Milford, MA USA. Milford Reg Med Ctr, Brigham & Womens Canc Ctr, Dana Farber Canc Inst, Milford, MA USA. Milford Reg Medcl Ctr, Dana Farber Canc Inst, Holliston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAR 1 PY 2016 VL 34 IS 7 SU S MA 112 PG 1 WC Oncology SC Oncology GA DO9ME UT WOS:000378109900111 ER PT J AU Lennes, IT Eusebio, J Bohlen, N Ruddy, M Ryan, DP AF Lennes, Inga Tolin Eusebio, Justin Bohlen, Nie Ruddy, Margaret Ryan, David P. TI Characterization of unplanned 30-day medical oncology readmissions after discharge at an academic medical center with a comprehensive cancer center SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT ASCO Quality Care Symposium CY FEB 26-27, 2016 CL Phoenix, AZ SP Amer Soc Clin Oncol C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAR 1 PY 2016 VL 34 IS 7 SU S MA 269 PG 1 WC Oncology SC Oncology GA DO9ME UT WOS:000378109900259 ER PT J AU Marmarelis, M Shulman, LN Jacobson, JO Norden, AD AF Marmarelis, Melina Shulman, Lawrence N. Jacobson, Joseph O. Norden, Andrew David TI Molecular testing for colorectal and lung cancer at an academic cancer center satellite site: Opportunities for improvement. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT ASCO Quality Care Symposium CY FEB 26-27, 2016 CL Phoenix, AZ SP Amer Soc Clin Oncol C1 Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA. Dana Farber Canc Inst, Waban, MA USA. Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAR 1 PY 2016 VL 34 IS 7 SU S MA 229 PG 1 WC Oncology SC Oncology GA DO9ME UT WOS:000378109900222 ER PT J AU Zerillo, JA Santacroce, E Zimmerman, MA Freeman, M Greenberg, TL Nguyen, P Chi, SN Bandopadhayay, P Lane, S Szabatura, A Houlahan, K Billett, A AF Zerillo, Jessica A. Santacroce, Erin Zimmerman, Mary Ann Freeman, Melissa Greenberg, Teresa Lau Nguyen, Phuong Chi, Susan N. Bandopadhayay, Pratiti Lane, Sharon Szabatura, Audrea Houlahan, Kathleen Billett, Amy TI Building a new process: Nursing verification of pediatric oral chemotherapy. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT ASCO Quality Care Symposium CY FEB 26-27, 2016 CL Phoenix, AZ SP Amer Soc Clin Oncol C1 [Zerillo, Jessica A.; Santacroce, Erin; Zimmerman, Mary Ann; Freeman, Melissa; Greenberg, Teresa Lau; Nguyen, Phuong; Chi, Susan N.; Bandopadhayay, Pratiti; Lane, Sharon; Szabatura, Audrea; Houlahan, Kathleen; Billett, Amy] Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAR 1 PY 2016 VL 34 IS 7 SU S MA 199 PG 1 WC Oncology SC Oncology GA DO9ME UT WOS:000378109900195 ER PT J AU Fink, A Hassan, MA Okan, NA Sheffer, M Camejo, A Saeij, JPJ Kasper, DL AF Fink, Avner Hassan, Musa A. Okan, Nihal A. Sheffer, Michal Camejo, Ana Saeij, Jeroen P. J. Kasper, Dennis L. TI Early Interactions of Murine Macrophages with Francisella tularensis Map to Mouse Chromosome 19 SO MBIO LA English DT Article ID LIVE VACCINE STRAIN; MONONUCLEAR PHAGOCYTES; AIM2 INFLAMMASOME; DENDRITIC CELLS; HOST-RESISTANCE; INFECTION; RECEPTOR; MICE; IDENTIFICATION; TULAREMIA AB Differences among individuals in susceptibility to infectious diseases can be modulated by host genetics. Much of the research in this field has aimed to identify loci within the host genome that are associated with these differences. In mice, A/J (AJ) and C57BL/6J (B6) mice show differential susceptibilities to various pathogens, including the intracellular pathogen Francisella tularensis. Because macrophages are the main initial target during F. tularensis infection, we explored early interactions of macrophages from these two mouse strains with F. tularensis as well as the genetic factors underlying these interactions. Our results indicate that bacterial interactions with bone marrow-derived macrophages (BMDMs) during early stages of infection are different in the AJ and B6 strains. During these early stages, bacteria are more numerous in B6 than in AJ macrophages and display differences in trafficking and early transcriptional response within these macrophages. To determine the genetic basis for these differences, we infected BMDMs isolated from recombinant inbred (RI) mice derived from reciprocal crosses between AJ and B6, and we followed early bacterial counts within these macrophages. Quantitative trait locus (QTL) analysis revealed a locus on chromosome 19 that is associated with early differences in bacterial counts in AJ versus B6 macrophages. QTL analysis of published data that measured the differential susceptibilities of the same RI mice to an in vivo challenge with F. tularensis confirmed the F. tularensis susceptibility QTL on chromosome 19. Overall, our results show that early interactions of macrophages with F. tularensis are dependent on the macrophage genetic background. IMPORTANCE Francisella tularensis is a highly pathogenic bacterium with a very low infectious dose in humans. Some mechanisms of bacterial virulence have been elucidated, but the host genetic factors that contribute to host resistance or susceptibility are largely unknown. In this work, we have undertaken a genetic approach to assess what these factors are in mice. Analyzing early interactions of macrophages with the bacteria as well as data on overall susceptibility to infection revealed a locus on chromosome 19 that is associated with both phenotypes. In addition, our work revealed differences in the early macrophage response between macrophages with different genetic backgrounds. Overall, this work suggests some intriguing links between in vitro and in vivo infection models and should aid in further elucidating the genetic circuits behind the host response to Francisella tularensis infection. C1 [Fink, Avner; Okan, Nihal A.; Kasper, Dennis L.] Harvard Univ, Sch Med, Dept Microbiol & Immunobiol, Boston, MA 02115 USA. [Hassan, Musa A.; Camejo, Ana; Saeij, Jeroen P. J.] MIT, Dept Biol, Cambridge, MA USA. [Hassan, Musa A.] Univ Glasgow, Wellcome Trust Ctr Mol Parasitol, Glasgow, Lanark, Scotland. [Sheffer, Michal] Harvard Univ, Sch Med, Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. [Saeij, Jeroen P. J.] Univ Calif Davis, Dept Pathol Microbiol & Immunol, Davis, CA 95616 USA. RP Kasper, DL (reprint author), Harvard Univ, Sch Med, Dept Microbiol & Immunobiol, Boston, MA 02115 USA. EM dennis_kasper@hms.harvard.edu FU HHS \ NIH \ National Institute of Allergy and Infectious Diseases (NIAID) [AI057159]; Wellcome Trust Massachusetts Institute of Technology FX This work, including the efforts of Avner Fink, Musa A. Hassan, Nihal A. Okan, Michal Sheffer, Ana Camejo, Jeroen P.J. Saeij, and Dennis L. Kasper, was funded by HHS vertical bar NIH vertical bar National Institute of Allergy and Infectious Diseases (NIAID) (AI057159).; Wellcome Trust Massachusetts Institute of Technology (http://www.wellcome.ac.uk) Postdoctoralt Fellowship and Recruitment Enhancement was awarded to Musa A. Hassan. NR 49 TC 1 Z9 1 U1 0 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 2150-7511 J9 MBIO JI mBio PD MAR-APR PY 2016 VL 7 IS 2 AR e02243 DI 10.1128/mBio.02243-15 PG 11 WC Microbiology SC Microbiology GA DO4QT UT WOS:000377768700034 PM 26980837 ER PT J AU Rogers, WB Shih, WM Manoharan, VN AF Rogers, W. Benjamin Shih, William M. Manoharan, Vinothan N. TI Using DNA to program the self-assembly of colloidal nanoparticles and microparticles SO NATURE REVIEWS MATERIALS LA English DT Review ID NUCLEIC-ACID; STRAND-DISPLACEMENT; BLOCK-COPOLYMERS; COATED COLLOIDS; PLASMONIC NANOCLUSTERS; PATCHY PARTICLES; BUILDING-BLOCKS; RATIONAL DESIGN; SHAPE CONTROL; WEB SERVER AB DNA is not just the stuff of our genetic code; it is also a means to design self-assembling materials. Grafting DNA onto nano-and microparticles can, in principle, 'program' them with information that tells them exactly how to self-assemble. Although fully programmable assembly has not yet been realized, the groundwork has been laid: with an understanding of how specific interparticle attractions arise from DNA hybridization, we can now make systems that reliably assemble in and out of equilibrium. We discuss these advances, and the design rules that will allow us to control - and ultimately program - the assembly of new materials. C1 [Rogers, W. Benjamin; Manoharan, Vinothan N.] Harvard Univ, Harvard John A Paulson Sch Engn & Appl Sci, Cambridge, MA 02138 USA. [Rogers, W. Benjamin] Brandeis Univ, Martin A Fisher Sch Phys, Waltham, MA 02453 USA. [Shih, William M.] Harvard Univ, Wyss Inst Biol Inspired Engn, Boston, MA 02115 USA. [Shih, William M.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Shih, William M.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Manoharan, Vinothan N.] Harvard Univ, Dept Phys, Cambridge, MA 02138 USA. RP Rogers, WB (reprint author), Harvard Univ, Harvard John A Paulson Sch Engn & Appl Sci, Cambridge, MA 02138 USA.; Rogers, WB (reprint author), Brandeis Univ, Martin A Fisher Sch Phys, Waltham, MA 02453 USA. EM wrogers@brandeis.edu; william.shih@wyss.harvard.edu; vnm@seas.harvard.edu RI Rogers, William/L-8941-2016 OI Rogers, William/0000-0001-8587-8215 NR 148 TC 17 Z9 18 U1 38 U2 67 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2058-8437 J9 NAT REV MATER JI Nat. Rev. Mater. PD MAR PY 2016 VL 1 IS 3 AR 16008 DI 10.1038/natrevmats.2016.8 PG 14 WC Materials Science, Multidisciplinary SC Materials Science GA DO3GK UT WOS:000377668700004 ER PT J AU Bicket, MC Simmons, C Zheng, Y AF Bicket, Mark C. Simmons, Courtney Zheng, Yi TI The Best-Laid Plans of "Back Mice" and Men: A Case Report and Literature Review of Episacroiliac Lipoma SO PAIN PHYSICIAN LA English DT Review DE Low back pain; back mice; back mouse; episacroiliac lipoma; lumbar subcutaneous nodules; multifidus triangle syndrome; subcutaneous fatty nodes; case report; review ID CREST PAIN SYNDROME; MOUSE; NODULES AB Background: Back mice, or episacroiliac lipoma, represent a potentially treatable cause of low back pain that may be under-recognized in clinical practice. Despite being well characterized based on clinical history and physical examination findings, implementation of appropriate treatment may be delayed or missed based on a lack of familiarity with the diagnosis. Objectives: In this case report and literature review, we describe a 47-year-old woman with history of persistent low back pain who presented with a pain exacerbation consistent with a back mouse. The history, epidemiology, clinical characteristics, differential diagnosis, potential mechanisms for pain, and treatment options for back mice were then reviewed. Study Design: Case report and literature review. Setting: Academic university-based pain management center. Results: Studies included one randomized clinical trial, 4 cross-sectional studies, 8 case reports or series, and 16 other publications prior to 1967. Limitations: A single case report. Conclusions: Firm, rubbery, mobile nodules that are located in characteristic regions of the sacroiliac, posterior superior iliac, and the lumbar paraspinal regions may represent fatty tissue that has herniated through fascial layers. When painful, these back mice may be confused with other causes of low back pain. In particular, the presence of point tenderness may mimic myofascial pain, and reports of radicular pain may imitate herniated nucleus pulposus. However, back mice may be distinguished from other entities based on findings from the history and physical examination such as absence of neurological deficit. Treatment consisting of injection of local anesthetic into the nodule with or without corticosteroid followed by repeated, direct needling has been reported to relieve pain in many case reports. The one clinical trial comparing injection of local anesthetic to normal saline, which did not include repeated needling, found only mild and transient benefit in the treatment group. C1 [Bicket, Mark C.] Johns Hopkins Univ, Baltimore, MD USA. [Simmons, Courtney; Zheng, Yi] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Bicket, MC (reprint author), Johns Hopkins Univ, Baltimore, MD USA.; Bicket, MC (reprint author), 600 N Wolfe St, Baltimore, MD 21287 USA. EM Mark.bicket@gmail.com NR 35 TC 0 Z9 0 U1 0 U2 0 PU AM SOC INTERVENTIONAL PAIN PHYSICIANS PI PADUCAH PA 81 LAKEVIEW DR, PADUCAH, KY 42001 USA SN 1533-3159 J9 PAIN PHYSICIAN JI Pain Physician PD MAR PY 2016 VL 19 IS 3 BP 181 EP 188 PG 8 WC Anesthesiology; Clinical Neurology SC Anesthesiology; Neurosciences & Neurology GA DO4RP UT WOS:000377771100024 PM 27008292 ER PT J AU Manchikanti, L Knezevic, NN Boswell, MV Kaye, AD Hirsch, JA AF Manchikanti, Laxmaiah Knezevic, Nebojsa Nick Boswell, Mark V. Kaye, Alan D. Hirsch, Joshua A. TI Epidural Injections for Lumbar Radiculopathy and Spinal Stenosis: A Comparative Systematic Review and Meta-Analysis SO PAIN PHYSICIAN LA English DT Review DE Epidural injections; epidural steroids; lumbar radiculopathy; spinal stenosis; lidocaine; steroids; bupivacaine ID LOW-BACK-PAIN; RANDOMIZED-CONTROLLED-TRIAL; CLINICALLY IMPORTANT DIFFERENCE; CONFLICT-OF-INTEREST; ACTIVE-CONTROL TRIAL; DOUBLE-BLIND TRIAL; 2-YEAR FOLLOW-UP; EXTRADURAL CORTICOSTEROID INJECTION; INTERVERTEBRAL DISC HERNIATION; OUTCOMES RESEARCH-INSTITUTE AB Background: The prevalence of chronic low back pain and related disability is rapidly increasing as are the myriad treatments, including epidural injections. Even though epidural injections are one of the most commonly performed procedures in managing low back and lower extremity pain, starting in 1901 with local anesthetic alone, conflicting recommendations have been provided, despite the extensive literature. Recently Chou et al performed a technology assessment review for Agency for Healthcare Research and Quality (AHRQ) part of which was published in Annals of Internal Medicine showing lack of effectiveness of epidural steroid injections in managing lumbar radiculopathy and spinal stenosis. In contrast, multiple other publications have supported the efficacy and use of epidural injections. Purpose: To assess the efficacy of 3 categories of epidural injections for lumbar and spinal stenosis: performed with saline with steroids, local anesthetic alone, or steroids with local anesthetic and separate facts from opinions. Data Sources: PubMed, Cochrane Library, US National Guideline Clearinghouse, prior systematic reviews, and reference lists. The literature search was performed through August 2015. Study Selection: Randomized trials, either placebo or active control, of epidural injections for lumbar radiculopathy and spinal stenosis. Data Extraction: Data extraction and methodological quality assessment were performed utilizing Cochrane review methodologic quality assessment and Interventional Pain Management Techniques - Quality Appraisal of Reliability and Risk of Bias Assessment (IPM-QRB). Evidence was summarized utilizing principles of best evidence synthesis. Data Synthesis: Thirty-nine randomized controlled trials met inclusion criteria. There were 9 placebo-controlled trials evaluating epidural corticosteroid injections, either with sodium chloride solution or bupivacaine, compared to placebo injections. There were 12 studies comparing local anesthetic alone to local anesthetic with steroid. Results A meta-analysis of 5 studies utilizing sodium chloride or bupivacaine with steroid showed a lack of efficacy. A comparison of lidocaine to lidocaine with steroids in 7 studies showed significant effectiveness from baseline to long-term follow-up periods. Meta-analysis showed a similar effectiveness for pain and function without non-inferiority of lidocaine compared to lidocaine with steroid at 3 months and 12 months. Limitations: The review was restricted to the data available with at least 3 months of follow-up, which excluded some studies. The inclusion criteria were restricted to English language studies. Conclusion: Epidural corticosteroid injections for radiculopathy or spinal stenosis with sodium chloride solution or bupivacaine were shown to be ineffective. Lidocaine alone or lidocaine in conjunction with steroids were significantly effective. C1 [Manchikanti, Laxmaiah] Ctr Paducah, Pain Management, Paducah, KY USA. [Manchikanti, Laxmaiah] Univ Louisville, Louisville, KY 40292 USA. [Knezevic, Nebojsa Nick] Chicago Anesthesia Pain Specialists, Illinois Mason Med Ctr, Chicago, IL USA. [Knezevic, Nebojsa Nick] Univ Illinois, Chicago, IL USA. [Boswell, Mark V.] Univ Louisville, Dept Anesthesiol & Perioperat Med, Louisville, KY 40292 USA. [Kaye, Alan D.] LSU Hlth Sci Ctr, New Orleans, LA USA. [Hirsch, Joshua A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Hirsch, Joshua A.] Harvard Univ, Sch Med, Boston, MA USA. [Kaye, Alan D.] Depomed Inc, Newark, CA USA. [Hirsch, Joshua A.] Medtronic, Fridley, MI USA. RP Manchikanti, L (reprint author), 2831 Lone Oak Rd, Paducah, KY 42003 USA. EM drlm@thepainmd.com NR 165 TC 9 Z9 9 U1 0 U2 3 PU AM SOC INTERVENTIONAL PAIN PHYSICIANS PI PADUCAH PA 81 LAKEVIEW DR, PADUCAH, KY 42001 USA SN 1533-3159 J9 PAIN PHYSICIAN JI Pain Physician PD MAR PY 2016 VL 19 IS 3 BP E365 EP E409 PG 45 WC Anesthesiology; Clinical Neurology SC Anesthesiology; Neurosciences & Neurology GA DO4RP UT WOS:000377771100001 PM 27008296 ER PT J AU Kaplan, MS Huguet, N McFarland, BH Caetano, R Conner, KR Nolte, KB Giesbrecht, N AF Kaplan, Mark S. Huguet, Nathalie McFarland, Bentson H. Caetano, Raul Conner, Kenneth R. Nolte, Kurt B. Giesbrecht, Norman TI Heavy Alcohol Use Among Suicide Decedents: Differences in Risk Across Racial-Ethnic Groups SO PSYCHIATRIC SERVICES LA English DT Editorial Material ID UNITED-STATES C1 [Kaplan, Mark S.] Univ Calif Los Angeles, Luskin Sch Publ Affairs, Los Angeles, CA 90095 USA. [Huguet, Nathalie; McFarland, Bentson H.] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Caetano, Raul] Pacific Inst Res & Evaluat, Oakland, CA USA. [Conner, Kenneth R.] US Dept Vet Affairs, VISN Ctr Excellence Suicide Prevent 2, Canandaigua, NY USA. [Conner, Kenneth R.] Univ Rochester, Med Ctr, Rochester, NY 14642 USA. [Nolte, Kurt B.] Univ New Mexico, Albuquerque, NM 87131 USA. [Giesbrecht, Norman] Ctr Addict & Mental Hlth, Toronto, ON, Canada. RP Kaplan, MS (reprint author), Univ Calif Los Angeles, Luskin Sch Publ Affairs, Los Angeles, CA 90095 USA. EM kaplanm@luskin.ucla.edu FU National Institute on Alcohol Abuse and Alcoholism [R01-AA020063] FX This research was supported by the National Institute on Alcohol Abuse and Alcoholism (grant R01-AA020063). NR 2 TC 2 Z9 2 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 MAR PY 2016 VL 67 IS 3 BP 258 EP 258 DI 10.1176/appi.ps.201500494 PG 1 WC Health Policy & Services; Public, Environmental & Occupational Health; Psychiatry SC Health Care Sciences & Services; Public, Environmental & Occupational Health; Psychiatry GA DO4TI UT WOS:000377776600002 PM 26725300 ER PT J AU Goyal, M Derdeyn, CP Fiorella, D Ross, J Schaefer, P Tarr, R Willson, MC Bartlett, E Wintermark, M Kallmes, D AF Goyal, Mayank Derdeyn, Colin P. Fiorella, David Ross, Jeffrey Schaefer, Pamela Tarr, Robert Willson, Morgan C. Bartlett, Eric Wintermark, Max Kallmes, David TI Recent Endovascular Trials: Implications for Radiology Departments, Radiology Residency, and Neuroradiology Fellowship Training at Comprehensive Stroke Centers SO RADIOLOGY LA English DT Editorial Material ID ACUTE ISCHEMIC-STROKE; THROMBECTOMY; GUIDELINES; MANAGEMENT; THERAPY; UPDATE; TIME C1 [Goyal, Mayank; Willson, Morgan C.] Univ Calgary, Dept Radiol & Clin Neurosci, Calgary, AB, Canada. [Derdeyn, Colin P.] Washington Univ, Sch Med, Neuroradiol Sect, Mallinckrodt Inst Radiol, St Louis, MO USA. [Fiorella, David] SUNY Stony Brook, Dept Neurosurg, Stony Brook, NY USA. [Ross, Jeffrey] Mayo Clin, Dept Radiol, Neuroradiol Div, Scottsdale, AZ USA. [Schaefer, Pamela] Massachusetts Gen Hosp, Dept Radiol, Div Neuroradiol, Boston, MA USA. [Tarr, Robert] Case Western Reserve Univ, Dept Radiol, Univ Hosp Case Med Ctr, Cleveland, OH 44106 USA. [Bartlett, Eric] Univ Toronto, Dept Radiol, Toronto, ON M5S 1A1, Canada. [Wintermark, Max] Stanford Univ, Dept Radiol, Neuroradiol Sect, Stanford, CA 94305 USA. [Kallmes, David] Mayo Clin, Dept Radiol & Neurosurg, Rochester, MN USA. RP Goyal, M (reprint author), Seaman Family MR Res Ctr, Dept Radiol, 1403-29th St NW, Calgary, AB T2N 2T9, Canada. EM mgoyal@ucalgary.ca OI Derdeyn, Colin/0000-0002-5932-2683 NR 14 TC 1 Z9 1 U1 0 U2 3 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 MAR PY 2016 VL 278 IS 3 BP 642 EP 645 DI 10.1148/radiol.2015151965 PG 4 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DO3TC UT WOS:000377703400002 PM 26885731 ER PT J AU Catalano, OA Gee, MS Nicolai, E Selvaggi, F Pellino, G Cuocolo, A Luongo, A Catalano, M Rosen, BR Gervais, D Vangel, MG Soricelli, A Salvatore, M AF Catalano, Onofrio A. Gee, Michael S. Nicolai, Emanuele Selvaggi, Francesco Pellino, Gianluca Cuocolo, Alberto Luongo, Angelo Catalano, Marco Rosen, Bruce R. Gervais, Debra Vangel, Mark G. Soricelli, Andrea Salvatore, Marco TI Evaluation of Quantitative PET/MR Enterography Biomarkers for Discrimination of Inflammatory Strictures from Fibrotic Strictures in Crohn Disease SO RADIOLOGY LA English DT Article ID INTESTINAL FIBROSIS; MR ENTEROGRAPHY; CT ENTEROGRAPHY; IBD AB Purpose: To retrospectively evaluate positron emission tomography (PET)/magnetic resonance (MR) enterography for the differentiation of fibrotic strictures from inflammatory strictures in patients with Crohn disease. Materials and Methods: This HIPAA-compliant retrospective study was approved by the institutional review board. Patients gave their written informed consent for study enrollment. PET/MR enterography images were evaluated in 19 patients with Crohn disease who had strictures that underwent surgical resection with pathologic confirmation. Two radiologists and a nuclear medicine physician in consensus evaluated the following bowel wall PET/MR enterography biomarkers: signal intensity (SI) on T2-weighted images, apparent diffusion coefficient (ADC), PET maximum standardized uptake value (SUVmax), SI on T2-weighted images x SUVmax, and ADC x SUVmax values at levels that corresponded to pathologic specimens. MR, PET, and hybrid PET/MR biomarkers were compared, and the performance for differentiation of inflammatory strictures from fibrotic strictures was assessed. Mixed-model regression analysis was used to compare the mean imaging parameters between groups; the P values were corrected for the five comparisons by using the Bonferroni method. Results: Three of the PET/MR enterography biomarkers, SUVmax, SI on T2-weighted images x SUVmax, and ADC x SUVmax, showed significant differences in the fibrosis group compared with the fibrosis with active inflammation group and the active inflammation only group. The best discriminator between fibrosis and active inflammation was the combined PET/MR enterography biomarker ADC x SUVmax cutoff of less than 3000, which was associated with accuracy, sensitivity, and specificity values of 0.71, 0.67, and 0.73, respectively. Conclusion: PET/MR enterography offers a potential noninvasive technique for the differentiation of purely fibrotic strictures from mixed or inflammatory strictures. A hybrid biomarker that incorporates both MR and PET information performed better for stricture evaluation than either modality alone. (C) RSNA, 2015 C1 [Catalano, Onofrio A.; Soricelli, Andrea] Univ Naples Parthenope, Dept Radiol, Via Acton 18, I-80113 Naples, NA, Italy. [Catalano, Onofrio A.; Gee, Michael S.; Gervais, Debra] Harvard Univ, Sch Med, Dept Radiol, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Nicolai, Emanuele; Salvatore, Marco] SDN IRCC, Dept Nucl Med, Naples, Italy. [Selvaggi, Francesco; Pellino, Gianluca] Univ Naples 2, Dept Surg, Naples, Italy. [Cuocolo, Alberto] Univ Naples Federico II, Dept Nucl Med, Naples, Italy. [Luongo, Angelo; Catalano, Marco] Univ Naples Federico II, Dept Radiol, Naples, Italy. [Rosen, Bruce R.; Vangel, Mark G.] Harvard Univ, Sch Med, Athinoula A Martinos Ctr Biomed Imaging, Dept Radiol,Massachusetts Gen Hosp, Charlestown, MA USA. [Vangel, Mark G.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, MGH Biostat Ctr, Charlestown, MA USA. RP Catalano, OA (reprint author), Univ Naples Parthenope, Dept Radiol, Via Acton 18, I-80113 Naples, NA, Italy.; Catalano, OA (reprint author), Harvard Univ, Sch Med, Dept Radiol, Massachusetts Gen Hosp, Boston, MA 02115 USA. EM onofriocatalano@yahoo.it RI Nicolai, Emanuele/K-6678-2016; soricelli, andrea/C-1133-2009; Salvatore, Marco/K-8083-2016; OI Nicolai, Emanuele/0000-0003-3171-368X; soricelli, andrea/0000-0001-7011-7667; Salvatore, Marco/0000-0001-9734-7702; Cuocolo, Alberto/0000-0003-3431-7658; Pellino, Gianluca/0000-0002-8322-6421 NR 14 TC 7 Z9 8 U1 0 U2 1 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 MAR PY 2016 VL 278 IS 3 BP 792 EP 800 DI 10.1148/radiol.2015150566 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DO3TC UT WOS:000377703400017 PM 26436860 ER PT J AU Pandharipande, PV Reisner, AT Binder, WD Zaheer, A Gunn, ML Linnau, KF Miller, CM Avery, LL Herring, MS Tramontano, AC Dowling, EC Abujudeh, HH Eisenberg, JD Halpern, EF Donelan, K Gazelle, GS AF Pandharipande, Pari V. Reisner, Andrew T. Binder, William D. Zaheer, Atif Gunn, Martin L. Linnau, Ken F. Miller, Chad M. Avery, Laura L. Herring, Maurice S. Tramontano, Angela C. Dowling, Emily C. Abujudeh, Hani H. Eisenberg, Jonathan D. Halpern, Elkan F. Donelan, Karen Gazelle, G. Scott TI CT in the Emergency Department: A Real-Time Study of Changes in Physician Decision Making SO RADIOLOGY LA English DT Article ID COMPUTED-TOMOGRAPHY; ABDOMINAL-PAIN; RADIATION-EXPOSURE; SUPPORT; TRENDS; RISK; MEDICINE; IMPACT; CANCER AB Purpose: To determine how physicians' diagnoses, diagnostic uncertainty, and management decisions are affected by the results of computed tomography (CT) in emergency department settings. Materials and Methods: This study was approved by the institutional review board and compliant with HIPAA. Data were collected between July 12, 2012, and January 13, 2014. The requirement to obtain patient consent was waived. In this prospective, four-center study, patients presenting to the emergency department who were referred for CT with abdominal pain, chest pain and/or dyspnea, or headache were identified. Physicians were surveyed before and after CT to determine the leading diagnosis, diagnostic confidence (on a scale of 0% to 100%), alternative "rule out" diagnosis, and management decisions. Primary measures were the proportion of patients for whom the leading diagnosis or admission decision changed and median changes in diagnostic confidence. Secondary measures addressed alternative diagnoses and return-to-care visits (eg, to emergency department) at 1-month follow-up. Regression analysis was used to identify associations between primary measures and site and participant characteristics. Results: Both surveys were completed for 1280 patients by 245 physicians. The leading diagnosis changed in 235 of 460 patients with abdominal pain (51%), 163 of 387 with chest pain and/or dyspnea (42%), and 103 of 433 with headache (24%). Pre-CT diagnostic confidence was inversely associated with the likelihood of a diagnostic change (P<.0001). Median changes in confidence were substantial (increases of 25%, 20%, and 13%, respectively, for patients with abdominal pain, chest pain and/or dyspnea, and headache; P<.0001); median post-CT confidence was high (95% for all three groups). CT helped confirm or exclude at least 95% of alternative diagnoses. Admission decisions changed in 116 of 457 patients with abdominal pain (25%), 72 of 387 with chest pain and/or dyspnea (19%), and 81 of 426 with headache (19%). During follow-up, 70 of 450 patients with abdominal pain (15%), 53 of 387 with chest pain and/or dyspnea (14%), and 49 of 433 with headache (11%) returned for the same indication. In general, changes in leading diagnosis, diagnostic confidence, and admission decisions were not well explained with site or participant characteristics. Conclusion: Physicians' diagnoses and admission decisions changed frequently after CT, and diagnostic uncertainty was alleviated. (C) RSNA, 2015 C1 [Pandharipande, Pari V.; Avery, Laura L.; Abujudeh, Hani H.; Halpern, Elkan F.; Gazelle, G. Scott] Massachusetts Gen Hosp, Dept Radiol, 101 Merrimac St,10th Floor, Boston, MA 02114 USA. [Pandharipande, Pari V.; Herring, Maurice S.; Tramontano, Angela C.; Dowling, Emily C.; Eisenberg, Jonathan D.; Halpern, Elkan F.; Gazelle, G. Scott] Massachusetts Gen Hosp, Inst Technol Assessment, 101 Merrimac St,10th Floor, Boston, MA 02114 USA. [Reisner, Andrew T.; Binder, William D.] Massachusetts Gen Hosp, Dept Emergency Med, 101 Merrimac St,10th Floor, Boston, MA 02114 USA. [Donelan, Karen] Massachusetts Gen Hosp, Dept Med, Mongan Inst Hlth Policy, 101 Merrimac St,10th Floor, Boston, MA 02114 USA. [Zaheer, Atif] Johns Hopkins Univ, Dept Radiol, Baltimore, MD USA. [Gunn, Martin L.; Linnau, Ken F.] Univ Washington, Dept Radiol, Seattle, WA 98195 USA. [Miller, Chad M.] Duke Univ, Med Ctr, Dept Radiol, Durham, NC 27710 USA. [Eisenberg, Jonathan D.] Univ Massachusetts, Sch Med, Worcester, MA USA. [Gazelle, G. Scott] Harvard Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA 02115 USA. [Binder, William D.] Brown Univ, Dept Emergency Med, Providence, RI 02912 USA. [Herring, Maurice S.] Univ Calif San Francisco, Dept Med, Hematol Oncol, San Francisco, CA USA. RP Pandharipande, PV (reprint author), Massachusetts Gen Hosp, Dept Radiol, 101 Merrimac St,10th Floor, Boston, MA 02114 USA. EM pari@mgh-ita.org FU National Electrical Manufacturers Association FX Supported by a grant from the National Electrical Manufacturers Association. NR 24 TC 8 Z9 8 U1 2 U2 3 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 MAR PY 2016 VL 278 IS 3 BP 812 EP 821 DI 10.1148/radiol.2015150473 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DO3TC UT WOS:000377703400019 PM 26402399 ER PT J AU Zhang, YN Seeburg, DP Pulli, B Wojtkiewicz, GR Bure, L Atkinson, W Schob, S Iwamoto, Y Ali, M Zhang, W Rodriguez, E Milewski, A Keliher, EJ Wang, CH Pan, YW Swirski, FK Chen, JW AF Zhang, Yinian Seeburg, Daniel P. Pulli, Benjamin Wojtkiewicz, Gregory R. Bure, Lionel Atkinson, Wendy Schob, Stefan Iwamoto, Yoshiko Ali, Muhammad Zhang, Wei Rodriguez, Elisenda Milewski, Andrew Keliher, Edmund J. Wang, Cuihua Pan, Yawen Swirski, Filip K. Chen, John W. TI Myeloperoxidase Nuclear Imaging for Epileptogenesis SO RADIOLOGY LA English DT Article ID TEMPORAL-LOBE EPILEPSY; ANTIEPILEPTIC DRUGS; OXIDATIVE MECHANISM; PILOCARPINE MODEL; MICE; INFLAMMATION; HIPPOCAMPUS; RATS; MATRIX-METALLOPROTEINASE-9; ATHEROSCLEROSIS AB Purpose: To determine if myeloperoxidase (MPO) is involved in epileptogenesis and if molecular nuclear imaging can be used to noninvasively map inflammatory changes in epileptogenesis. Materials and Methods: The animal and human studies were approved by the institutional review boards. Pilocarpine-induced epileptic mice were treated with 4-aminobenzoic acid hydrazide (n = 46), a specific irreversible MPO inhibitor, or saline (n = 42). Indium-111-bis-5-hydroxytryptamide-diethylenetriaminepentaacetate was used to image brain MPO activity (n = 6 in the 4-aminobenzoic acid hydrazide and saline groups; n = 5 in the sham group) by using single photon emission computed tomography/computed tomography. The role of MPO in the development of spontaneous recurrent seizures was assessed by means of clinical symptoms and biochemical and histopathologic data. Human brain specimens from a patient with epilepsy and a patient without epilepsy were stained for MPO. The Student t test, one-way analysis of variance, and Mann-Whitney and Kruskal-Wallis tests were used. Differences were regarded as significant if P was less than.05. Results: MPO and leukocytes increased in the brain during epileptogenesis (P<.05). Blocking MPO delayed spontaneous recurrent seizures (99.6 vs 142 hours, P =.016), ameliorated the severity of spontaneous recurrent seizures (P<.05), and inhibited mossy fiber sprouting (Timm index, 0.31 vs 0.03; P =.003). Matrix metalloproteinase activity was upregulated during epileptogenesis in an MPO-dependent manner (1.44 vs 0.94 U/mg, P =.049), suggesting that MPO acts upstream of matrix metalloproteinases. MPO activity was mapped during epileptogenesis in vivo in the hippocampal regions. Resected temporal lobe tissue from a human patient with refractory epilepsy but not the temporal lobe tissue from a patient without seizures demonstrated positive MPO immunostaining, suggesting high translational potential for this imaging technology. Conclusion: The findings of this study highlight an important role for MPO in epileptogenesis and show MPO to be a potential therapeutic target and imaging biomarker for epilepsy. (C) RSNA, 2015 C1 [Zhang, Yinian; Pan, Yawen] Lanzhou Univ, Hosp 2, Dept Neurosurg, Lanzhou 730000, Peoples R China. [Zhang, Yinian; Seeburg, Daniel P.; Pulli, Benjamin; Wojtkiewicz, Gregory R.; Bure, Lionel; Atkinson, Wendy; Schob, Stefan; Iwamoto, Yoshiko; Ali, Muhammad; Rodriguez, Elisenda; Milewski, Andrew; Keliher, Edmund J.; Wang, Cuihua; Swirski, Filip K.; Chen, John W.] Massachusetts Gen Hosp, Ctr Syst Biol, 185 Cambridge St, Boston, MA 02114 USA. [Zhang, Yinian; Seeburg, Daniel P.; Pulli, Benjamin; Wojtkiewicz, Gregory R.; Bure, Lionel; Atkinson, Wendy; Schob, Stefan; Iwamoto, Yoshiko; Ali, Muhammad; Rodriguez, Elisenda; Milewski, Andrew; Keliher, Edmund J.; Wang, Cuihua; Swirski, Filip K.; Chen, John W.] Massachusetts Gen Hosp, Dept Radiol, 185 Cambridge St, Boston, MA 02114 USA. [Zhang, Wei] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. [Seeburg, Daniel P.] Johns Hopkins Univ, Dept Radiol, Baltimore, MD USA. RP Chen, JW (reprint author), Massachusetts Gen Hosp, Ctr Syst Biol, 185 Cambridge St, Boston, MA 02114 USA.; Chen, JW (reprint author), Massachusetts Gen Hosp, Dept Radiol, 185 Cambridge St, Boston, MA 02114 USA. EM jwchen@mgh.harvard.edu FU National Institutes of Health [R01-NS070835, R01-NS072167] FX This research was supported by the National Institutes of Health (grants R01-NS070835 and R01-NS072167). NR 34 TC 0 Z9 2 U1 1 U2 2 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 MAR PY 2016 VL 278 IS 3 BP 822 EP 830 DI 10.1148/radiol.2015141922 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DO3TC UT WOS:000377703400020 PM 26397127 ER PT J AU Truini, A Tinelli, E Gerardi, MC Calistri, V Iannuccelli, C La Cesa, S Tarsitani, L Mainero, C Sarzi-Puttini, P Cruccu, G Caramia, F Di Franco, M AF Truini, A. Tinelli, E. Gerardi, M. C. Calistri, V. Iannuccelli, C. La Cesa, S. Tarsitani, L. Mainero, C. Sarzi-Puttini, P. Cruccu, G. Caramia, F. Di Franco, M. TI Abnormal resting state functional connectivity of the periaqueductal grey in patients with fibromyalgia SO CLINICAL AND EXPERIMENTAL RHEUMATOLOGY LA English DT Article DE fibromyalgia; magnetic resonance imaging; periaqueductal grey; endogenous pain modulatory system ID CHRONIC PAIN; CRITICAL DIGEST; SYMPTOMS; CRITERIA; GRAY; CLASSIFICATION; MODULATION; MECHANISMS; INTENSITY; SEVERITY AB Objective. Emerging evidence associates chronic pain syndrome, such as fibromyalgia, with endogenous pain modulatory system dysfunction, leading to an impaired descending pain inhibition. In this study, using resting state functional magnetic resonance imaging (fMRI), we aimed at seeking possible functional connectivity changes of the periaqueductal gray (PAG), a brainstem area that belongs to the endogenous pain modulatory system, in patients with fibromyalgia. Methods. In 20 patients with fibromyalgia and 15 healthy subjects, we investigated FAG functional connectivity using resting-state fMRI. We also analysed the correlation between clinical variables, such as pain severity, disease duration, and depressive personality traits with FAG functional connectivity. Results. Compared with control subjects, we identified that patients with fibromyalgia had an increased PAG connectivity with insula, anterior cingulate cortex, and anterior prefrontal cortex. The functional connectivity between PAG and the rostral ventral medulla, however, was not concordantly increased. FAG functional connectivity correlated with pain severity, disease duration, and the depressive personality trait rating. Conclusion. Our fMRI study showing abnormal resting state functional connectivity of the PAG suggests that patients with fibromyalgia have an endogenous pain modulatory system dysfitnction, possibly causing an impaired descending pain inhibition. This abnormal PAG functioning might underlaythe chronic pain these patients suffer from. C1 [Truini, A.; Tinelli, E.; Calistri, V.; La Cesa, S.; Tarsitani, L.; Cruccu, G.; Caramia, F.] Univ Roma La Sapienza, Dept Neurol & Psychiat, Rome, Italy. [Gerardi, M. C.; Iannuccelli, C.; Di Franco, M.] Univ Roma La Sapienza, Dept Internal Med & Med Specialties, Rheumatol Unit, Rome, Italy. [Sarzi-Puttini, P.] Luigi Sacco Univ Hosp, Rheumatol Unit, Via GB Grassi, I-20157 Milan, Italy. [Mainero, C.] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Boston, MA 02114 USA. [Mainero, C.] Harvard Univ, Sch Med, Boston, MA USA. RP Gerardi, MC (reprint author), Luigi Sacco Univ Hosp, Rheumatol Unit, Via GB Grassi, I-20157 Milan, Italy. EM mariachiara.gerardi@gmail.com NR 31 TC 2 Z9 2 U1 0 U2 0 PU CLINICAL & EXPER RHEUMATOLOGY PI PISA PA VIA SANTA MARIA 31, 56126 PISA, ITALY SN 0392-856X EI 1593-098X J9 CLIN EXP RHEUMATOL JI Clin. Exp. Rheumatol. PD MAR-APR PY 2016 VL 34 IS 2 SU 96 BP S129 EP S133 PG 5 WC Rheumatology SC Rheumatology GA DN7CT UT WOS:000377233600020 PM 27157397 ER PT J AU DeVita, VT Canellos, GP AF DeVita, Vincent T., Jr. Canellos, George P. TI Combination chemotherapy of solid tumors: an American-Italian collaboration: a celebration of the work of Gianni Bonadonna SO TUMORI LA English DT Review DE ABVD; C-MOPP; Diffuse large B cell lymphoma; Hodgkin's; Lymphoma; MOPP ID ADVANCED HODGKINS-DISEASE; BREAST-CANCER; LYMPHOMAS; MOPP; ABVD; ADRIAMYCIN AB This article highlights the important collaboration between the U.S. NCI in Bethesda, Maryland and the Istituto Tumori in Milan, Italy that had a major impact on the development of curative regimens for breast cancer, Hodgkin's disease and diffuse large B cell lymphoma. In addition to his contribution to developing new therapies, Gianni Bonadonna played an important role in bringing highly focused, disciplined, ethical clinical trials to the European continent. C1 [DeVita, Vincent T., Jr.] Yale Univ, Sch Med, Yale Canc Ctr, 333 Cedar St,POB 208028, New Haven, CT 06520 USA. [Canellos, George P.] Harvard Univ, Sch Med, Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. RP DeVita, VT (reprint author), Yale Univ, Sch Med, Yale Canc Ctr, 333 Cedar St,POB 208028, New Haven, CT 06520 USA. EM vincent.devita@yale.edu NR 20 TC 1 Z9 1 U1 1 U2 2 PU WICHTIG PUBLISHING PI MILAN PA 72/74 VIA FRIULI, 20135 MILAN, ITALY SN 0300-8916 EI 2038-2529 J9 TUMORI JI Tumori PD MAR-APR PY 2016 VL 102 IS 2 BP 124 EP 126 DI 10.5301/tj.5000492 PG 3 WC Oncology SC Oncology GA DO1MG UT WOS:000377541800002 PM 27002947 ER PT J AU Cavelti-Weder, C Li, WD Zumsteg, A Stemann-Andersen, M Zhang, YM Yamada, T Wang, M Lu, JQ Jermendy, A Bee, YM Bonner-Weir, S Weir, GC Zhou, Q AF Cavelti-Weder, Claudia Li, Weida Zumsteg, Adrian Stemann-Andersen, Marianne Zhang, Yuemei Yamada, Takatsugu Wang, Max Lu, Jiaqi Jermendy, Agnes Bee, Yong Mong Bonner-Weir, Susan Weir, Gordon C. Zhou, Qiao TI Hyperglycaemia attenuates in vivo reprogramming of pancreatic exocrine cells to beta cells in mice SO DIABETOLOGIA LA English DT Article DE Diabetes; Exocrine to beta cell reprogramming; Hyperglycaemia ID INSULIN-PRODUCING CELLS; EMBRYONIC-DEVELOPMENT; LINEAGE CONVERSION; PROGENITOR CELLS; RAT ISLETS; REGENERATION; GLUCOSE; EXPRESSION; SECRETION; ENDOCRINE AB Aims/hypothesis Reprogramming of pancreatic exocrine to insulin-producing cells by viral delivery of the genes encoding transcription factors neurogenin-3 (Ngn3), pancreas/duodenum homeobox protein 1 (Pdx1) and MafA is an efficient method for reversing diabetes in murine models. The variables that modulate reprogramming success are currently ill-defined. Methods Here, we assess the impact of glycaemia on in vivo reprogramming in a mouse model of streptozotocin-induced beta cell ablation, using subsequent islet transplantation or insulin pellet implantation for creation of groups with differing levels of glycaemia before viral delivery of transcription factors. Results We observed that hyperglycaemia significantly impaired reprogramming of exocrine to insulin-producing cells in their quantity, differentiation status and function. With hyperglycaemia, the reprogramming of acinar towards beta cells was less complete. Moreover, inflammatory tissue changes within the exocrine pancreas including macrophage accumulation were found, which may represent the tissue's response to clear the pancreas from insufficiently reprogrammed cells. Conclusions/interpretation Our findings shed light on normoglycaemia as a prerequisite for optimal reprogramming success in a diabetes model, which might be important in other tissue engineering approaches and disease models, potentially facilitating their translational applications. C1 [Cavelti-Weder, Claudia; Stemann-Andersen, Marianne; Yamada, Takatsugu; Jermendy, Agnes; Bee, Yong Mong; Bonner-Weir, Susan; Weir, Gordon C.] Harvard Univ, Joslin Diabet Ctr, Sect Islet Cell & Regenerat Biol, Boston, MA 02115 USA. [Li, Weida] Tongji Univ, Sch Life Sci & Technol, Shanghai East Hosp, Translat Med Ctr Stem Cell Therapy, Shanghai 200092, Peoples R China. [Li, Weida] Tongji Univ, Sch Life Sci & Technol, Shanghai East Hosp, Inst Regenerat Med, Shanghai 200092, Peoples R China. [Li, Weida; Zumsteg, Adrian; Zhang, Yuemei; Wang, Max; Lu, Jiaqi; Zhou, Qiao] Harvard Univ, Dept Stem Cell & Regenerat Biol, Sherman Fairchild 258C,7 Divin Ave, Cambridge, MA 02138 USA. RP Zhou, Q (reprint author), Harvard Univ, Dept Stem Cell & Regenerat Biol, Sherman Fairchild 258C,7 Divin Ave, Cambridge, MA 02138 USA. EM qiao_zhou@harvard.edu OI Bonner-Weir, Susan/0000-0003-4682-0656 FU JDRF; Hahnemann Hospital Foundation; National Institutes of Health NIH [R01 DK 066056, DK 093909, P30 DK036836]; Diabetes Research and Wellness Foundation; Swiss Science Foundation; Swiss Foundation for Grants in Biology and Medicine; Juvenile Diabetes Research Foundation; National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); Harvard Stem Cell Institute (HSCI) FX This study was supported by grants from the JDRF and the Hahnemann Hospital Foundation (GCW), and the National Institutes of Health NIH R01 DK 066056 and DK 093909 (SBW), P30 DK036836 (Joslin Diabetes Research Center and its Advanced Microscopy Core), as well as the Diabetes Research and Wellness Foundation. CCW and AZ are supported by postdoctoral fellowships from the Swiss Science Foundation and the Swiss Foundation for Grants in Biology and Medicine. WL is supported by a postdoctoral fellowship from the Juvenile Diabetes Research Foundation. QZ is supported by grants from The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and Harvard Stem Cell Institute (HSCI). NR 47 TC 5 Z9 5 U1 4 U2 7 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0012-186X EI 1432-0428 J9 DIABETOLOGIA JI Diabetologia PD MAR PY 2016 VL 59 IS 3 BP 522 EP 532 DI 10.1007/s00125-015-3838-7 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DN8BC UT WOS:000377302900015 PM 26693711 ER PT J AU Wang, CW Colas, RA Dalli, J Arnardottir, HH Nguyen, D Hasturk, H Chiang, N Van Dyke, TE Serhan, CN AF Wang, Chin-Wei Colas, Romain A. Dalli, Jesmond Arnardottir, Hildur H. Nguyen, Daniel Hasturk, Hatice Chiang, Nan Van Dyke, Thomas E. Serhan, Charles N. TI Maresin 1 Biosynthesis and Proresolving Anti-infective Functions with Human-Localized Aggressive Periodontitis Leukocytes SO INFECTION AND IMMUNITY LA English DT Article ID JUVENILE PERIODONTITIS; FUSOBACTERIUM-NUCLEATUM; LIPID MEDIATORS; ACTINOBACILLUS-ACTINOMYCETEMCOMITANS; INFLAMMATION; RESOLUTION; TISSUE; PATHOGENESIS; HOMEOSTASIS AB Localized aggressive periodontitis (LAP) is a distinct form of early-onset periodontitis linked to periodontal infection with uncontrolled inflammation and leukocyte-mediated tissue destruction. The resolution of inflammation is an active process orchestrated by specialized proresolving lipid mediators (SPMs). Since the level of the Maresin pathway marker 14-hydroxy-docosa-hexaenoic acid (14-HDHA) was lower in activated peripheral blood from LAP patients, we investigated the Maresin 1 (MaR1) biosynthetic pathway in these subjects and its role in regulating phagocyte functions. Macrophages from LAP patients had a lower level of expression of 12-lipoxygenase (similar to 30%) and reduced MaR1 (LAP versus healthy controls [HC], 87.8 +/- 50 pg/10(6) cells versus 239.1 +/- 32 pg/10(6) cells). Phagocytosis by LAP macrophages was reduced similar to 40% compared to that of HC, and killing of periodontal pathogens, including Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans, were similarly reduced. LAP neutrophils also displayed slower kinetics (similar to 30%) and decreased maximal phagocytosis (similar to 20% lower) with these pathogens than those of HC. The administration of MaR1 at 1 nM enhanced phagocytosis (31 to 65% increase), intracellular antimicrobial reactive oxygen species production (26 to 71% increase), bacterial killing of these periodontal pathogens (22 to 38% reduction of bacterial titers), and restored impairment of LAP phagocytes. Together, these results suggest that therapeutics targeting the Maresin pathway have clinical utility in treating LAP and other oral diseases associated with infection, inflammation, and altered phagocyte functions. C1 [Wang, Chin-Wei; Colas, Romain A.; Dalli, Jesmond; Arnardottir, Hildur H.; Chiang, Nan; Serhan, Charles N.] Brigham & Womens Hosp, Harvard Inst Med, Dept Anesthesiol Perioperat & Pain Med, Ctr Expt Therapeut & Reperfus Injury, 75 Francis St, Boston, MA 02115 USA. [Wang, Chin-Wei; Colas, Romain A.; Dalli, Jesmond; Arnardottir, Hildur H.; Chiang, Nan; Serhan, Charles N.] Harvard Univ, Sch Med, Boston, MA USA. [Wang, Chin-Wei; Van Dyke, Thomas E.; Serhan, Charles N.] Harvard Univ, Sch Dent Med, Div Periodontol, Dept Oral Med Infect & Immun, 188 Longwood Ave, Boston, MA 02115 USA. [Wang, Chin-Wei; Nguyen, Daniel; Hasturk, Hatice; Van Dyke, Thomas E.] Forsyth Inst, Dept Periodontol, Cambridge, MA USA. RP Serhan, CN (reprint author), Brigham & Womens Hosp, Harvard Inst Med, Dept Anesthesiol Perioperat & Pain Med, Ctr Expt Therapeut & Reperfus Injury, 75 Francis St, Boston, MA 02115 USA.; Serhan, CN (reprint author), Harvard Univ, Sch Med, Boston, MA USA.; Serhan, CN (reprint author), Harvard Univ, Sch Dent Med, Div Periodontol, Dept Oral Med Infect & Immun, 188 Longwood Ave, Boston, MA 02115 USA. EM cnserhan@zeus.bwh.harvard.edu OI Arnardottir, Hildur/0000-0002-5163-3946 FU HHS \ NIH \ National Institute of General Medical Sciences (NIGMS) [GM038765]; HHS \ NIH \ National Institute of Dental and Craniofacial Research (NIDCR) [DE018917, DE015566] FX HHS vertical bar NIH vertical bar National Institute of General Medical Sciences (NIGMS) provided funding to Charles N. Serhan under grant number GM038765. HHS vertical bar NIH vertical bar National Institute of Dental and Craniofacial Research (NIDCR) provided funding to Hatice Hasturk under grant number DE018917. HHS vertical bar NIH vertical bar National Institute of Dental and Craniofacial Research (NIDCR) provided funding to Thomas E. Van Dyke under grant number DE015566. NR 35 TC 1 Z9 1 U1 2 U2 2 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 MAR PY 2016 VL 84 IS 3 BP 658 EP 665 DI 10.1128/IAI.01131-15 PG 8 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA DN5JS UT WOS:000377103300005 PM 26667839 ER PT J AU Ho, MF Bongartz, T Liu, M Kalari, KR Goss, PE Shepherd, LE Goetz, MP Kubo, M Ingle, JN Wang, LW Weinshilboum, RM AF Ho, Ming-Fen Bongartz, Tim Liu, Mohan Kalari, Krishna R. Goss, Paul E. Shepherd, Lois E. Goetz, Matthew P. Kubo, Michiaki Ingle, James N. Wang, Liewei Weinshilboum, Richard M. TI Estrogen, SNP-Dependent Chemokine Expression and Selective Estrogen Receptor Modulator Regulation SO MOLECULAR ENDOCRINOLOGY LA English DT Article ID GENOME-WIDE ASSOCIATION; RHEUMATOID-ARTHRITIS; BREAST-CANCER; AROMATASE INHIBITORS; RESPONSE ELEMENTS; BINDING-SITES; CELLS; IDENTIFICATION; TRANSCRIPTION; SUSCEPTIBILITY AB We previously reported, on the basis of a genome-wide association study for aromatase inhibitor-induced musculoskeletal symptoms, that single-nucleotide polymorphisms (SNPs) near the T-cell leukemia/lymphoma 1A (TCL1A) gene were associated with aromatase inhibitor-induced musculoskeletal pain and with estradiol (E2)-induced TCL1A expression. Furthermore, variation in TCL1A expression influenced the downstream expression of proinflammatory cytokines and cytokine receptors. Specifically, the top hit genome-wide association study SNP, rs11849538, created a functional estrogen response element (ERE) that displayed estrogen receptor (ER) binding and increased E2 induction of TCL1A expression only for the variant SNP genotype. In the present study, we pursued mechanisms underlying the E2-SNP-dependent regulation of TCL1A expression and, in parallel, our subsequent observations that SNPs at a distance from EREs can regulate ER alpha binding and that ER antagonists can reverse phenotypes associated with those SNPs. Specifically, we performed a series of functional genomic studies using a large panel of lymphoblastoid cell lines with dense genomic data that demonstrated that TCL1A SNPs at a distance from EREs can modulate ER alpha binding and expression of TCL1A as well as the expression of downstream immune mediators. Furthermore, 4-hydroxytamoxifen or fulvestrant could reverse these SNP-genotype effects. Similar results were found for SNPs in the IL17A cytokine and CCR6 chemokine receptor genes. These observations greatly expand our previous results and support the existence of a novel molecular mechanism that contributes to the complex interplay between estrogens and immune systems. They also raise the possibility of the pharmacological manipulation of the expression of proinflammatory cytokines and chemokines in a SNP genotype-dependent fashion. C1 [Ho, Ming-Fen; Liu, Mohan; Wang, Liewei; Weinshilboum, Richard M.] Mayo Clin, Div Clin Pharmacol, 200 First St SW, Rochester, MN 55905 USA. [Ho, Ming-Fen; Bongartz, Tim] Mayo Clin, Dept Mol Pharmacol & Expt Therapeut, Div Rheumatol, 200 First St SW, Rochester, MN 55905 USA. [Kalari, Krishna R.] Mayo Clin, Dept Med, Div Biomed Stat & Informat, 200 First St SW, Rochester, MN 55905 USA. [Goetz, Matthew P.; Ingle, James N.] Mayo Clin, Dept Hlth Sci Res, 200 First St SW, Rochester, MN 55905 USA. [Goetz, Matthew P.; Ingle, James N.] Mayo Clin, Dept Oncol, Div Med Oncol, 200 First St SW, Rochester, MN 55905 USA. [Goss, Paul E.] Harvard Univ, Massachusetts Gen Hosp, Ctr Canc, Dept Med,Div Hematol Oncol, Boston, MA 02114 USA. [Shepherd, Lois E.] Natl Canc Inst Canada Clin Trials Grp, Kingston, ON K7L 3N6, Canada. [Kubo, Michiaki] RIKEN Ctr Integrat Med Sci, Yokohama, Kanagawa 2300045, Japan. RP Weinshilboum, RM (reprint author), Mayo Clin, 200 First St SW, Rochester, MN 55905 USA. EM weinshilboum.richard@mayo.edu FU National Institutes of Health [U19GM61388, P50CA116201, U10 CA77202, RO1 GM28157, RO1 CA138461, RO1 CA196648, 94203005]; Canadian Cancer Society [CCS 015469]; Biobank Japan Project; Ministry of Education, Culture, Sports, Science, and Technology (Japan); Avon Foundation (New York); Pfizer, Inc. FX This work was supported by National Institutes of Health Grants U19GM61388 (to The Pharmacogenomics Research Network), P50CA116201 (to The Mayo Clinic Breast Cancer Specialized Program of Research Excellence), U10 CA77202, RO1 GM28157, RO1 CA138461, RO1 CA196648, 94203005 (to The Mayo Clinic Rheumatoid Arthritis CDA, Montgomery Award); Grant CCS 015469 from the Canadian Cancer Society; and the Biobank Japan Project, funded by the Ministry of Education, Culture, Sports, Science, and Technology (Japan). P.E.G. is supported in part by the Avon Foundation (New York). The MA. 27 trial, from which the patient samples for the MA. 27 genome-wide association study were obtained, was supported in part by Pfizer, Inc. NR 42 TC 3 Z9 3 U1 1 U2 3 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0888-8809 J9 MOL ENDOCRINOL JI Mol. Endocrinol. PD MAR PY 2016 VL 30 IS 3 BP 382 EP 398 DI 10.1210/me.2015-1267 PG 17 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DN6SR UT WOS:000377206900011 PM 26866883 ER PT J AU Harrington, AT Black, JA Clarridge, JE AF Harrington, Amanda T. Black, Jennifer A. Clarridge, Jill E., III TI In Vitro Activity of Retapamulin and Antimicrobial Susceptibility Patterns in a Longitudinal Collection of Methicillin-Resistant Staphylococcus aureus Isolates from a Veterans Affairs Medical Center SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID MUPIROCIN RESISTANCE; COLONIZATION; DECOLONIZATION; PLEUROMUTILIN; EPIDEMIOLOGY; INHIBITION; INFECTION; OINTMENT AB Mupirocin is a topical antimicrobial used to decolonize patients who carry methicillin-resistant Staphylococcus aureus (MRSA), and the topical agent retapamulin may be a potential alternative therapy. The goal of this study was to determine the in vitro activity of retapamulin as well as a panel of 15 antimicrobial agents, including mupirocin, for 403 MRSA isolates collected longitudinally from a naive population at the Veterans Affairs Puget Sound Health Care System. The MICs for retapamulin had a unimodal distribution, ranging from 0.008 to 0.5 mu g/ml. One isolate had an MIC of > 16 mu g/ml, was also resistant to clindamycin and erythromycin, and was recovered from the nares of a patient undergoing hemodialysis. Twenty-four isolates (6%) and 11 isolates (3%) demonstrated low-level resistance (MICs of 8 to 64 mu g/ml) and high-level resistance (MICs of> 512 mu g/ml), respectively, to mupirocin. Isolates were recovered from 10 patients both before and after mupirocin therapy. Of those, isolates from 2 patients demonstrated MIC changes postmupirocin therapy; in both cases, however, strain typing demonstrated that the pre and postmupirocin strains were different. A total of 386 isolates (96%) had vancomycin MICs of <= 1.0 mu g/ml; 340 isolates (84%) were resistant to levofloxacin, 18 isolates (4.5%) were resistant to trimethoprim-sulfamethoxazole, and 135 isolates (33%) had elevated MICs of 4 mu g/ml for linezolid. The baseline levels of resistance were low for mupirocin (9%) and even lower for retapamulin (0.25%) Although the use of mupirocin is currently the standard therapy for decolonization practices, the activity of retapamulin warrants its consideration as an alternative therapy in MRSA decolonization regimens. C1 [Harrington, Amanda T.; Clarridge, Jill E., III] VA Puget Sound Hlth Care Syst, Seattle, WA USA. [Harrington, Amanda T.; Black, Jennifer A.; Clarridge, Jill E., III] Univ Washington, Seattle, WA 98195 USA. [Harrington, Amanda T.] Univ Illinois, Chicago, IL USA. RP Harrington, AT (reprint author), VA Puget Sound Hlth Care Syst, Seattle, WA USA.; Harrington, AT (reprint author), Univ Illinois, Chicago, IL USA. EM harria@uic.edu FU North Carolina GlaxoSmithKline Foundation FX North Carolina GlaxoSmithKline Foundation provided funding to Amanda T. Harrington. NR 24 TC 0 Z9 0 U1 1 U2 1 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 MAR PY 2016 VL 60 IS 3 BP 1298 EP 1303 DI 10.1128/AAC.01568-15 PG 6 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA DM6VM UT WOS:000376490800016 ER PT J AU Vinue, L Corcoran, MA Hooper, DC Jacoby, GA AF Vinue, Laura Corcoran, Marian A. Hooper, David C. Jacoby, George A. TI Mutations That Enhance the Ciprofloxacin Resistance of Escherichia coli with qnrA1 SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID MULTIPLE-ANTIBIOTIC RESISTANCE; MEDIATED QUINOLONE RESISTANCE; MULTIDRUG EFFLUX; 2-COMPONENT SYSTEM; PLASMID; EXPRESSION; GENES; MUTANTS; PROTEIN; RNA AB Plasmid-mediated qnr genes provide only a modest decrease in quinolone susceptibility but facilitate the selection of higher-level resistance. In Escherichia coli strain J53 without qnr, ciprofloxacin resistance often involves mutations in the GyrA subunit of DNA gyrase. Mutations in gyrA were absent, however, when 43 mutants with decreased ciprofloxacin susceptibility were selected from J53(pMG252) with qnrA1. Instead, in 13 mutants, individual and whole-genome sequencing identified mutations in marR and soxR associated with increased expression of marA and soxS and, through them, increased expression of the AcrAB pump, which effluxes quinolones. Nine mutants had increased expression of the MdtE efflux pump, and six demonstrated increased expression of the ydhE pump gene. Many efflux mutants also had increased resistance to novobiocin, another pump substrate, but other mutants were novobiocin hypersusceptible. Mutations in rfaD and rfaE in the pathway for inner core lipopolysaccharide (LPS) biosynthesis were identified in five such strains. Many of the pump and LPS mutants had decreased expression of OmpF, the major porin channel for ciprofloxacin entry. Three mutants had increased expression of qnrA that persisted when pMG252 from these strains was outcrossed. gyrA mutations were also rare when mutants with decreased ciprofloxacin susceptibility were selected from E. coli J53 with aac(6')-Ib-cr or qepA. We suggest that multiple genes conferring low-level resistance contribute to enhanced ciprofloxacin resistance selected from an E. coli strain carrying qnrA1, aac(6')-Ib-cr, or qepA because these determinants decrease the effective ciprofloxacin concentration and allow more common but lower-resistance mutations than those in gyrA to predominate. C1 [Vinue, Laura; Corcoran, Marian A.; Jacoby, George A.] Lahey Hosp & Med Ctr, Burlington, MA USA. [Vinue, Laura; Hooper, David C.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Jacoby, GA (reprint author), Lahey Hosp & Med Ctr, Burlington, MA USA. EM gajacoby50@gmail.com FU U.S. Public Health Service; National Institutes of Health; [R01 AI057576] FX U.S. Public Health Service, National Institutes of Health provided funding to David C. Hooper and George A. Jacoby under grant number R01 AI057576. NR 56 TC 6 Z9 6 U1 1 U2 1 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 MAR PY 2016 VL 60 IS 3 BP 1537 EP 1545 DI 10.1128/AAC.02167-15 PG 9 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA DM6VM UT WOS:000376490800046 PM 26711751 ER PT J AU Shields, RK Nguyen, MH Press, EG Cumbie, R Driscoll, E Pasculle, AW Clancy, CJ AF Shields, Ryan K. Nguyen, M. Hong Press, Ellen G. Cumbie, Richard Driscoll, Eileen Pasculle, A. William Clancy, Cornelius J. TI Rate of FKS Mutations among Consecutive Candida Isolates Causing Bloodstream Infection (vol 59, pg 7465, 2015) SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Correction C1 [Shields, Ryan K.; Nguyen, M. Hong; Press, Ellen G.; Clancy, Cornelius J.] Univ Pittsburgh, Dept Med, Pittsburgh, PA USA. [Shields, Ryan K.; Nguyen, M. Hong; Clancy, Cornelius J.] Univ Pittsburgh, Med Ctr, XDR Pathogen Lab, Pittsburgh, PA USA. [Cumbie, Richard; Driscoll, Eileen; Pasculle, A. William] Univ Pittsburgh, Dept Pathol, Pittsburgh, PA USA. [Clancy, Cornelius J.] VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. RP Shields, RK (reprint author), Univ Pittsburgh, Dept Med, Pittsburgh, PA USA.; Shields, RK (reprint author), Univ Pittsburgh, Med Ctr, XDR Pathogen Lab, Pittsburgh, PA USA. NR 1 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 MAR PY 2016 VL 60 IS 3 BP 1954 EP 1954 DI 10.1128/AAC.00183-16 PG 1 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA DM6VM UT WOS:000376490800110 PM 26921416 ER PT J AU Shelton, E Laharie, D Scott, F Mamtani, R Lewis, J Colombel, JF Ananthakrishnan, A AF Shelton, E. Laharie, D. Scott, F. Mamtani, R. Lewis, J. Colombel, J. -F. Ananthakrishnan, A. TI Cancer recurrence with immunosuppressive therapy in immune-mediated diseases: a systematic review and meta-analysis SO JOURNAL OF CROHNS & COLITIS LA English DT Meeting Abstract C1 [Shelton, E.; Ananthakrishnan, A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Laharie, D.] Univ Bordeaux, Bordeaux, France. [Scott, F.] Univ Penn, Philadelphia, PA 19104 USA. [Mamtani, R.; Lewis, J.] Univ Penn, Perelman Sch Med, Div Gastroenterol, Philadelphia, PA 19104 USA. [Colombel, J. -F.] Icahn Sch Med Mt Sinai, New York, NY 10029 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1873-9946 EI 1876-4479 J9 J CROHNS COLITIS JI J. Crohns Colitis PD MAR PY 2016 VL 10 SU 1 MA P335 BP S262 EP S263 PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA DJ8XF UT WOS:000374496600456 ER PT J AU Yao, JK Dougherty, GG Gautier, CH Haas, GL Condray, R Kasckow, JW Kisslinger, BL Gurklis, JA Messamore, E AF Yao, Jeffrey K. Dougherty, George G., Jr. Gautier, Clara H. Haas, Gretchen L. Condray, Ruth Kasckow, John W. Kisslinger, Benjamin L. Gurklis, John A. Messamore, Erik TI Prevalence and Specificity of the Abnormal Niacin Response: A Potential Endophenotype Marker in Schizophrenia SO SCHIZOPHRENIA BULLETIN LA English DT Article DE niacin-induced flush response; laser Doppler flowmeter; EC50; maximal blood flow; bipolar disorder; phospholipid-arachidonate-eicosanoid signaling ID SKIN FLUSH RESPONSE; NICOTINIC-ACID; ARACHIDONIC-ACID; FATTY-ACIDS; PHOSPHOLIPASE-A2 ACTIVITY; LANGERHANS CELLS; ABSENT RESPONSE; TOPICAL NIACIN; CHALLENGE TEST; PATHWAY AB The skin flush response to niacin is abnormally blunted among a subset of patients with schizophrenia (SZ), preferentially associates with SZ compared to other mental illnesses, occurs frequently in nonpsychotic members of SZ-affected families, appears heritable, and shows evidence of genetic association. The niacin response abnormality (NRA) may prove to be a useful SZ endophenotype. Using a laser Doppler flowmeter, we undertook this study to estimate the prevalence of NRA in SZ (n = 70), bipolar disorder (BP, n = 59), and healthy control (HC, n = 87) groups, and to estimate its specificity for the illness. From the dose-response curves, we calculated the concentration of methylnicotinate required to elicit a half-maximal blood flow (MBF) response (EC50 value) and MBF value for each subject. The median log(10) EC50 of the SZ was above the third quartile of log(10)EC(50) of either the HC or BP groups, whereas the MBF was significantly lower in the SZ than in the HC or BP groups. With a definition of NRA of having both EC50 above the ninetieth percentile of the control samples and MBF response below the sixtieth percentile for the control range, the NRA predicted SZ with 31% sensitivity and 97% specificity. Moreover, the NRA was not influenced by age, gender, race, and cigarette smoking. In summary, the NRA may define a SZ subtype with a clinically significant phospholipid signaling defect. Understanding its molecular origins may shed light on the pathophysiology of SZ and suggest new tools for its early diagnosis and treatment. C1 [Yao, Jeffrey K.; Dougherty, George G., Jr.; Gautier, Clara H.; Haas, Gretchen L.; Condray, Ruth; Kasckow, John W.; Kisslinger, Benjamin L.; Gurklis, John A.] VA Pittsburgh Healthcare Syst, Med Res Serv, Pittsburgh, PA 15240 USA. [Yao, Jeffrey K.; Dougherty, George G., Jr.; Haas, Gretchen L.; Kasckow, John W.] Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA USA. [Yao, Jeffrey K.] Univ Pittsburgh, Sch Pharm, Dept Pharmaceut Sci, Pittsburgh, PA 15261 USA. [Messamore, Erik] Univ Cincinnati, Dept Psychiat, Cincinnati, OH USA. [Messamore, Erik] Lindner Ctr Hope, Cincinnati, OH USA. RP Yao, JK (reprint author), VA Pittsburgh Healthcare Syst, B1-2E-140,Univ Dr C, Pittsburgh, PA 15240 USA. EM jkyao@pitt.edu FU Department of Veterans Affairs [1I01CX000110]; Senior Research Career Scientist Award; VA VISN4 Mental Illness Research, Education and Clinical Center (MIRECC); VA Pittsburgh Healthcare System FX This work was supported in part by Department of Veterans Affairs (Merit Reviews 1I01CX000110 and Senior Research Career Scientist Award to J K Y); VA VISN4 Mental Illness Research, Education and Clinical Center (MIRECC Director: D. Oslin; Associate Director: G. Haas); and the VA Pittsburgh Healthcare System. NR 36 TC 1 Z9 1 U1 4 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0586-7614 EI 1745-1701 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD MAR PY 2016 VL 42 IS 2 BP 369 EP 376 DI 10.1093/schbul/sbv130 PG 8 WC Psychiatry SC Psychiatry GA DM5PG UT WOS:000376401500014 PM 26371338 ER PT J AU Walton, E Hass, J Liu, JY Roffman, JL Bernardoni, F Roessner, V Kirsch, M Schackert, G Calhoun, V Ehrlich, S AF Walton, Esther Hass, Johanna Liu, Jingyu Roffman, Joshua L. Bernardoni, Fabio Roessner, Veit Kirsch, Matthias Schackert, Gabriele Calhoun, Vince Ehrlich, Stefan TI Correspondence of DNA Methylation Between Blood and Brain Tissue and Its Application to Schizophrenia Research SO SCHIZOPHRENIA BULLETIN LA English DT Article DE DNA methylation; cross-tissue; blood; brain; correlation; schizophrenia ID BIPOLAR DISORDER; SOCIAL MEMORY; GENE; VASOPRESSIN; PSYCHOSIS; PROMOTER; HYPERMETHYLATION; RECEPTOR; EXPOSURE; GENOME AB Given the difficulty of procuring human brain tissue, a key question in molecular psychiatry concerns the extent to which epigenetic signatures measured in more accessible tissues such as blood can serve as a surrogate marker for the brain. Here, we aimed (1) to investigate the blood-brain correspondence of DNA methylation using a within-subject design and (2) to identify changes in DNA methylation of brain-related biological pathways in schizophrenia. We obtained paired blood and temporal lobe biopsy samples simultaneously from 12 epilepsy patients during neurosurgical treatment. Using the Infinium 450K methylation array we calculated similarity of blood and brain DNA methylation for each individual separately. We applied our findings by performing gene set enrichment analyses (GSEA) of peripheral blood DNA methylation data (Infinium 27K) of 111 schizophrenia patients and 122 healthy controls and included only Cytosine-phosphate-Guanine (CpG) sites that were significantly correlated across tissues. Only 7.9% of CpG sites showed a statistically significant, large correlation between blood and brain tissue, a proportion that although small was significantly greater than predicted by chance. GSEA analysis of schizophrenia data revealed altered methylation profiles in pathways related to precursor metabolites and signaling peptides. Our findings indicate that most DNA methylation markers in peripheral blood do not reliably predict brain DNA methylation status. However, a subset of peripheral data may proxy methylation status of brain tissue. Restricting the analysis to these markers can identify meaningful epigenetic differences in schizophrenia and potentially other brain disorders. C1 [Walton, Esther; Hass, Johanna; Bernardoni, Fabio; Roessner, Veit; Ehrlich, Stefan] Tech Univ Dresden, Fac Med, Translat Dev Neurosci Sect, Dept Child & Adolescent Psychiat, Dresden, Germany. [Walton, Esther] Kings Coll London, Dept Psychol, Inst Psychol Psychiat & Neurosci, London WC2R 2LS, England. [Hass, Johanna] Univ Tubingen, Inst Trop Med, Tubingen, Germany. [Liu, Jingyu; Calhoun, Vince] Mind Res Network, Albuquerque, NM USA. [Roffman, Joshua L.; Ehrlich, Stefan] Massachusetts Gen Hosp, MGH MIT HMS Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Roffman, Joshua L.; Ehrlich, Stefan] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Kirsch, Matthias; Schackert, Gabriele] Tech Univ Dresden, Fac Med, Dept Neurosurg, Dresden, Germany. [Kirsch, Matthias] Tech Univ Dresden, DFG Res Ctr, Ctr Regenerat Therapies Dresden, Dresden, Germany. [Kirsch, Matthias] Tech Univ Dresden, Cluster Excellence, Dresden, Germany. [Calhoun, Vince] Univ New Mexico, Dept Elect & Comp Engn, Albuquerque, NM 87131 USA. RP Ehrlich, S (reprint author), Psychiat Neuroimaging Res Program, CNY Bldg 120,Suite 100, Charlestown, MA 02129 USA. EM transden.lab@uniklinikum-dresden.de OI Walton, Esther/0000-0002-0935-2200; Liu, Jingyu/0000-0002-1724-7523 FU National Institutes of Health [NIH/NCRR P41RR14075, K08 MH068540, NIH: 2P20GM103472-06]; Department of Energy [DE-FG02-99ER62764]; MIND Research Network, Morphometry BIRN [1U24, RR021382A]; Function BIRN [U24RR021992-01, NIH.NCRR MO1 RR025758-01]; National Institute of General Medical Sciences [NIGMS P20-GM103472]; National Institute of Biomedical Imaging and Bioengineering [NIBIB 2R01-EB000840]; National Association for Research in Schizophrenia and Affective Disorders (NARSAD); German Ministry for Education, Research and Technology (BMBF) [13N10777]; Friedrich-Ebert foundation FX This work was supported by the National Institutes of Health (NIH/NCRR P41RR14075, K08 MH068540, NIH: 2P20GM103472-06 to J.L.); the Department of Energy (DE-FG02-99ER62764); the MIND Research Network, Morphometry BIRN (1U24, RR021382A); Function BIRN (U24RR021992-01, NIH.NCRR MO1 RR025758-01); the National Institute of General Medical Sciences and the National Institute of Biomedical Imaging and Bioengineering (NIGMS P20-GM103472 & NIBIB 2R01-EB000840 to V.C.); the National Association for Research in Schizophrenia and Affective Disorders (NARSAD award to S.E.), the German Ministry for Education, Research and Technology (BMBF, A.Z. 13N10777), and the Friedrich-Ebert foundation (scholarship to E.W.). NR 54 TC 16 Z9 16 U1 8 U2 12 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0586-7614 EI 1745-1701 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD MAR PY 2016 VL 42 IS 2 BP 406 EP 414 DI 10.1093/schbul/sbv074 PG 9 WC Psychiatry SC Psychiatry GA DM5PG UT WOS:000376401500019 PM 26056378 ER PT J AU Chami, HA Vasan, RS Larson, MG Benjamin, EJ Mitchell, GF Gottlieb, DJ AF Chami, Hassan A. Vasan, Ramachandran S. Larson, Martin G. Benjamin, Emelia J. Mitchell, Gary F. Gottlieb, Daniel J. TI The association between sleep-disordered breathing and aortic stiffness in a community cohort SO SLEEP MEDICINE LA English DT Article DE Aortic stiffness; Sleep apnea; Epidemiology ID POSITIVE AIRWAY PRESSURE; PULSE-WAVE VELOCITY; CORONARY-HEART-DISEASE; ARTERIAL STIFFNESS; CARDIOVASCULAR-DISEASE; ENDOTHELIAL FUNCTION; BLOOD-PRESSURE; EARLY SIGNS; ALL-CAUSE; KAPPA-B AB Objective: Sleep-disordered breathing is associated with hypertension and cardiovascular disease. Increased aortic stiffness is one possible linking mechanism. We evaluated the association between sleep-disordered breathing and aortic stiffness in a community-based sample. Methods: Our community-based cross-sectional observational study included 381 participants from the Framingham Heart Study (55% women, mean age 58.0 S.D. = 9.4 years, 51% ethnic minorities). Polysomnographically derived apnea-hypopnea index and CT90% (cumulative % sleep time with oxyhemoglobin saturation <90%) quantified sleep-disordered breathing severity. Carotid-femoral pulse wave velocity, the gold-standard measure of aortic stiffness, was calculated using arterial applanation tonometry-derived waveforms and body surface measured transit distance. We assessed associations between sleep-disordered breathing and carotid-femoral pulse wave velocity using multivariable regression. We adjusted for age, sex, race, body mass index, diabetes, alcohol consumption, hormone replacement therapy, cholesterol/high-density lipoprotein, lipid-lowering therapy, anti-hypertensive medication, smoking, hypertension, and prevalent cardiovascular disease. Results: After multivariable adjustment, carotid-femoral pulse wave velocity was associated with both apnea-hypopnea index (beta = 0.03, 95% CI: 0.002-0.07, p = 0.04) and CT90% (beta = 0.05, 95% CI: 0.005-0.1, p = 0.03). The adjusted mean carotid-femoral pulse wave velocity was 9.43 (95% CI: 9.12-9.74), 9.76 (95% CI: 9.25-10.26), and 10.15 (95% CI: 9.37-10.92) m/s, respectively, in subjects with apnea-hypopnea index <5, 5-14.9, and = 15 events/h. Conclusions: In a community-based sample of middle aged and older men and women, sleep-disordered breathing was associated with increased carotid-femoral pulse wave velocity, a strong predictor of cardiovascular risk. (C) 2015 Elsevier B.V. All rights reserved. C1 [Chami, Hassan A.] Amer Univ Beirut, Dept Med, Beirut, Lebanon. [Chami, Hassan A.] Boston Univ, Sch Med, Ctr Pulm, Boston, MA 02118 USA. [Vasan, Ramachandran S.; Benjamin, Emelia J.] Boston Univ, Sch Med, Dept Med, Sect Cardiovasc Med, Boston, MA 02118 USA. [Vasan, Ramachandran S.; Benjamin, Emelia J.] Boston Univ, Sch Med, Dept Med, Sect Prevent Med, Boston, MA 02118 USA. [Vasan, Ramachandran S.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Larson, Martin G.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [Larson, Martin G.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Mitchell, Gary F.] Cardiovasc Engn Inc, Norwood, MA USA. [Gottlieb, Daniel J.] VA Boston Healthcare Syst, Boston, MA USA. [Gottlieb, Daniel J.] Harvard Univ, Brigham & Womens Hosp, Dept Med, Div Sleep Med,Med Sch, Boston, MA 02115 USA. [Gottlieb, Daniel J.] Harvard Univ, Brigham & Womens Hosp, Dept Neurol, Div Sleep Med,Med Sch, Boston, MA 02115 USA. RP Chami, HA (reprint author), Amer Univ Beirut, POB 11-0236, Beirut, Lebanon. EM hchami@aub.edu.lb OI Ramachandran, Vasan/0000-0001-7357-5970; Benjamin, Emelia/0000-0003-4076-2336 FU NHLBI, Framingham Heart Study, (NHLBI/NIH) [HHSN268201500001I, N01-HC-25195, 1RO1HL60040, 1RO1HL70100]; Boston University School of Medicine; SHHS [U01HL53940, U01HL53941, U01HL53938, U01HL53916, U01HL53934, U01HL53931, U01HL53937, U01HL64360, U01HL63463, U01HL63429]; [HL076784]; [G028321]; [HL070100]; [HL060040]; [HL080124]; [HL071039]; [HL077447]; [HL107385]; [2-K24-HL04334] FX This work was supported by the NHLBI, Framingham Heart Study, (NHLBI/NIH Contract HHSN268201500001I; N01-HC-25195) 1RO1HL60040, 1RO1HL70100 and the Boston University School of Medicine and by HL076784, G028321, HL070100, HL060040, HL080124, HL071039, HL077447, HL107385, and 2-K24-HL04334. It was also supported by the SHHS cooperative agreements U01HL53940 (University of Washington), U01HL53941 (Boston University), U01HL53938 (University of Arizona), U01HL53916 (University of California, Davis), U01HL53934 (University of Minnesota), U01HL53931 (New York University), U01HL53937 and U01HL64360 (Johns Hopkins University), U01HL63463 (Case Western Reserve University), and U01HL63429 (Missouri Breaks Research). NR 48 TC 2 Z9 2 U1 5 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1389-9457 EI 1878-5506 J9 SLEEP MED JI Sleep Med. PD MAR PY 2016 VL 19 BP 69 EP 74 DI 10.1016/j.sleep.2015.11.009 PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA DM7EH UT WOS:000376518600012 PM 27198950 ER PT J AU Shirvani, M Motiei-Langroudi, R Sadeghian, H AF Shirvani, Manochehr Motiei-Langroudi, Rouzbeh Sadeghian, Homa TI Outcome of Microscopic Transsphenoidal Surgery in Cushing Disease: A Case Series of 96 Patients SO WORLD NEUROSURGERY LA English DT Article DE Cushing disease; Outcome; Recurrence; Remission; Transsphenoidal surgery ID TERM-FOLLOW-UP; SINGLE-CENTER; PITUITARY-ADENOMAS; REMISSION; CRITERIA; EXPERIENCE; CHILDREN; CURE; MACROADENOMAS; MICROSURGERY AB OBJECTIVE: To analyze the results of transsphenoidal surgery in patients with Cushing disease and outcome. METHOD: Retrospective analysis of the records of 96 patients with Cushing disease from 1997 to 2012. RESULTS: There were 73 females and 23 males, with a mean follow-up of 44 months (range, 3-13 years). The sex ratio was significantly different in children and teenagers versus adults. Magnetic resonance imaging showed microadenoroa, roacroadenoma, and no adenoma in 66, 18, and 12 patients, respectively, There was no surgical mortality. Early remission (normal 24-hour urinary free cortisol and basal serum cortisol <5 mu g/dL) was achieved in 94.8%. Regression analysis showed that only tumor size, cavernous sinus extension, and tumor consistency influenced remission. Recurrence was seen in 21.9%. Regression analysis showed that age, preoperative basal cortisol levels, and follow-up duration influenced recurrence. Correlation analysis showed that there was a significant negative correlation between patient age and the follow-up period. After detection of recurrence, 17 patients underwent repeat transsphenoidal surgery that resulted in remission in 12 patients (70,6%). The other 5 patients were referred for gamma knife radiosurgery or bilateral adrenalectomy. CONCLUSIONS: Transsphenoidal surgery is a safe and highly efficient procedure in the treatment of Cushing disease, Macroadenomas, cavernous sinus invasion, and harder tumor consistencies, however, are associated with lower remission rates (higher disease persistence) and younger age, higher preoperative cortisol levels, and longer follow-up periods are associated with higher recurrence. C1 [Shirvani, Manochehr; Motiei-Langroudi, Rouzbeh] Shahid Beheshti Univ Med Sci, Shohada Tajrish Hosp, Dept Neurosurg, Tehran, Iran. [Shirvani, Manochehr] Tehran Clin Hosp, Tehran, Iran. [Sadeghian, Homa] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Neurovasc Res Lab,Dept Radiol, Charlestown, MA USA. RP Shirvani, M (reprint author), Shahid Beheshti Univ Med Sci, Shohada Tajrish Hosp, Dept Neurosurg, Tehran, Iran.; Shirvani, M (reprint author), Tehran Clin Hosp, Tehran, Iran. EM dmshirvani@gmail.com NR 34 TC 0 Z9 0 U1 3 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1878-8750 EI 1878-8769 J9 WORLD NEUROSURG JI World Neurosurg. PD MAR PY 2016 VL 87 BP 170 EP 175 DI 10.1016/j.wneu.2015.11.046 PG 6 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA DI3HR UT WOS:000373390200024 PM 26704208 ER PT J AU Bekesi, N Kochevar, IE Marcos, S AF Bekesi, Nandor Kochevar, Irene E. Marcos, Susana TI Corneal Biomechanical Response Following Collagen Cross-Linking With Rose Bengal-Green Light and Riboflavin-UVA SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article DE corneal biomechanics; computational modeling; Scheimpflug photography ID ULTRAVIOLET-A; INFLATION TESTS; AIR-PUFF; KERATOCONUS; DEFORMATION; SCLERA AB PURPOSE. To compare the biomechanical corneal response of two different corneal cross-linking (CXL) treatments, rose bengal-green light (RGX) and riboflavin-UVA (UVX), using noninvasive imaging. METHODS. A total of 12 enucleated rabbit eyes were treated with RGX and 12 with UVX. Corneal dynamic deformation to an air puff was measured by high speed Scheimpflug imaging (Corvis ST) before and after treatment. The spatial and temporal deformation profiles were evaluated at constant intraocular pressure of 15 mm Hg, and several deformation parameterswere estimated. The deformation profiles were modeled numerically using finite element analysis, and the hyperelastic corneal material parameters were obtained by inverse modeling technique. RESULTS. The corneal deformation amplitude decreased significantly after both CXL methods. The material parameters obtained from inverse modeling were consistent with corneal stiffening after both RGX and UVX. Within the treated corneal volume, we found that the elasticity decreased by a factor of 11 after RGX and by a factor of 6.25 after UVX. CONCLUSIONS. The deformation of UVX-treated corneas was smaller than the RGX-treated corneas. However, the reconstructed corneal mechanical parameters reveal that RGX produced in fact larger stiffening of the treated region (100-mu m depth) than UVX (137-mu m depth). Rose bengal-green light stiffens the cornea effectively, with shorter treatment times and shallower treated areas. Dynamic air puff deformation imaging coupled with mechanical simulations is a useful tool to characterize corneal biomechanical properties, assess different treatments, and possibly help optimize the treatment protocols. C1 [Bekesi, Nandor; Marcos, Susana] CSIC, Inst Opt, 121 Serrano, E-28006 Madrid, Spain. [Kochevar, Irene E.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Wellman Ctr Photomed, Boston, MA USA. RP Bekesi, N (reprint author), CSIC, Inst Opt, 121 Serrano, E-28006 Madrid, Spain. EM nandor.bekesi@io.cfmac.csic.es RI Bekesi, Nandor/A-6812-2010 OI Bekesi, Nandor/0000-0001-7532-9589 FU European Research Council under the European Union [294099]; Comunidad de Madrid; EU Marie Curie COFUND program (FP7/REA) [291820]; Spanish Government [FIS2014-56643-R] FX Supported by the European Research Council under the European Union's Seventh Framework Program ERC Advanced Grant agreement no. 294099; Comunidad de Madrid and EU Marie Curie COFUND program (FP7/2007-2013/REA 291820); and the Spanish Government Grant FIS2014-56643-R. NR 31 TC 4 Z9 4 U1 2 U2 3 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAR PY 2016 VL 57 IS 3 BP 992 EP 1001 DI 10.1167/iovs.15-18689 PG 10 WC Ophthalmology SC Ophthalmology GA DK4BE UT WOS:000374860600032 PM 26968733 ER PT J AU Iacovelli, J Rowe, GC Khadka, A Diaz-Aguilar, D Spencer, C Arany, Z Saint-Geniez, M AF Iacovelli, Jared Rowe, Glenn C. Khadka, Arogya Diaz-Aguilar, Daniel Spencer, Carrie Arany, Zoltan Saint-Geniez, Magali TI PGC-1 alpha Induces Human RPE Oxidative Metabolism and Antioxidant Capacity SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article DE retinal pigment epithelium; PGC-1; metabolism; oxidative stress; age-related macular degeneration ID RETINAL-PIGMENT EPITHELIUM; MACULAR DEGENERATION; SKELETAL-MUSCLE; TRANSCRIPTIONAL COACTIVATORS; MITOCHONDRIAL BIOGENESIS; CELL-DIFFERENTIATION; MOLECULAR REGULATION; PARKINSONS-DISEASE; PGC-1 COACTIVATORS; AGE AB PURPOSE. Oxidative stress and metabolic dysregulation of the RPE have been implicated in AMD; however, the molecular regulation of RPE metabolism remains unclear. The transcriptional coactivator, peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1 alpha) is a powerful mediator of mitochondrial function. This study examines the ability of PGC-1 alpha to regulate RPE metabolic program and oxidative stress response. METHODS. Primary human fetal RPE (hfRPE) and ARPE-19 were matured in vitro using standard culture conditions. Mitochondrial mass of RPE was measured using MitoTracker staining and citrate synthase activity. Expression of PGC-1 isoforms, RPE-specific genes, oxidative metabolism proteins, and antioxidant enzymes was analyzed by quantitative PCR and Western blot. Mitochondrial respiration and fatty-acid oxidation were monitored using the Seahorse extracellular flux analyzer. Expression of PGC-1 alpha was increased using adenoviral delivery. ARPE-19 were exposed to hydrogen peroxide to induce oxidative stress. Reactive oxygen species were measured by CM-H2DCFDA fluorescence. Cell death was analyzed by LDH release. RESULTS. Maturation of ARPE-19 and hfRPE was associated with significant increase in mitochondrial mass, expression of oxidative phosphorylation (OXPHOS) genes, and PGC-1 alpha gene expression. Overexpression of PGC-1 alpha increased expression of OXPHOS and fatty-acid b-oxidation genes, ultimately leading to the potent induction of mitochondrial respiration and fatty-acid oxidation. PGC-1 alpha gain of function also strongly induced numerous antioxidant genes and, importantly, protected RPE from oxidant-mediated cell death without altering RPE functions. CONCLUSIONS. This study provides important insights into the metabolic changes associated with RPE functional maturation and identifies PGC-1 alpha as a potent driver of RPE mitochondrial function and antioxidant capacity. C1 [Iacovelli, Jared; Khadka, Arogya; Spencer, Carrie; Saint-Geniez, Magali] Massachusetts Eye & Ear Infirm, Schepens Eye Res Inst, Boston, MA 02114 USA. [Iacovelli, Jared; Saint-Geniez, Magali] Harvard Univ, Sch Med, Dept Ophthalmol, Boston, MA USA. [Rowe, Glenn C.] Univ Alabama Birmingham, Div Cardiovasc Dis, Birmingham, AL 35294 USA. [Diaz-Aguilar, Daniel] Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Angiogenesis Lab, Boston, MA 02114 USA. [Arany, Zoltan] Univ Penn, Perelman Sch Med, Cardiovasc Inst, Philadelphia, PA 19104 USA. RP Saint-Geniez, M (reprint author), Schepens Eye Res Inst, 20 Staniford St, Boston, MA 02114 USA. EM magali_saintgeniez@meei.harvard.edu FU National Institutes of Health [1R01EY023682]; Research to Prevent Blindness; BrightFocus Foundation FX Supported by National Institutes of Health Grant 1R01EY023682 (ZA, MSG), a Research to Prevent Blindness Unrestricted Grant (MSG), and donations to the Macular Degeneration Research, a program of the BrightFocus Foundation (MSG). NR 71 TC 2 Z9 3 U1 1 U2 3 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAR PY 2016 VL 57 IS 3 BP 1038 EP 1051 DI 10.1167/iovs.15-17758 PG 14 WC Ophthalmology SC Ophthalmology GA DK4BE UT WOS:000374860600038 PM 26962700 ER PT J AU Annunziata, R Kheirkhah, A Aggarwal, S Cavalcanti, BM Hamrah, P Trucco, E AF Annunziata, Roberto Kheirkhah, Ahmad Aggarwal, Shruti Cavalcanti, Bernardo M. Hamrah, Pedram Trucco, Emanuele TI Two-Dimensional Plane for Multi-Scale Quantification of Corneal Subbasal Nerve Tortuosity SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article DE tortuosity plane; confocal microscopy; corneal subbasal nerve plexus ID VIVO-CONFOCAL-MICROSCOPY; RETINAL VESSEL TORTUOSITY; OCULAR SURFACE; INFECTIOUS KERATITIS; DIABETIC-RETINOPATHY; NEUROPATHY; IMAGES; MORPHOLOGY; FEATURES; DISEASE AB PURPOSE. To assess the performance of a novel system for automated tortuosity estimation and interpretation. METHODS. A supervised strategy (driven by observers' grading) was employed to automatically identify the combination of tortuosity measures (i.e., tortuosity representation) leading to the best agreement with the observers. We investigated 18 tortuosity measures including curvature and density of inflection points, computed at multiple spatial scales. To leverage tortuosity interpretation, we propose the tortuosity plane (TP) onto which each image is mapped. Experiments were carried out on 140 images of subbasal nerve plexus of the central cornea, covering four levels of tortuosity. Three experienced observers graded each image independently. RESULTS. The best tortuosity representation was the combination of mean curvature at spatial scales 2 and 5. These tortuosity measures were the axes of the proposed TP (interpretation). The system for tortuosity estimation revealed strong agreement with the observers on a global and per- level basis. The agreement with each observer (Spearman's correlation) was statistically significant (alpha(s) = 0.05, P < 0.0001) and higher than that of at least one of the other observers in two out of three cases (rho(OUR) = 0.7594 versus rho(Obs3) = 0.7225; rho(OUR =) 0.8880 versus rho(Obs1) = 0.8017, rho(Obs3) = 0.7315). Based on paired-sample t-tests, these improvements were significant (P < 0.001). CONCLUSIONS. Our automated system stratifies images by four tortuosity levels (discrete scale) matching or exceeding the accuracy of experienced observers. Of importance, the TP allows the assessment of tortuosity on a two-dimensional continuous scale, thus leading to a finer discrimination among images. C1 [Annunziata, Roberto; Trucco, Emanuele] Univ Dundee, Sch Sci & Engn Comp, Comp Vis & Image Proc Grp, Perth Rd, Dundee DD1 4HN, Scotland. [Kheirkhah, Ahmad; Aggarwal, Shruti; Cavalcanti, Bernardo M.; Hamrah, Pedram] Harvard Univ, Sch Med, Ocular Surface Imaging Ctr, Boston, MA USA. [Kheirkhah, Ahmad; Aggarwal, Shruti; Cavalcanti, Bernardo M.; Hamrah, Pedram] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Cornea & Refract Surg Serv,Dept Ophthalmol, Boston, MA USA. [Hamrah, Pedram] Tufts Univ, Sch Med, Boston Image Reading Ctr, Boston, MA 02111 USA. [Hamrah, Pedram] Tufts Univ, Sch Med, Cornea Serv, New England Eye Ctr,Tufts Med Ctr, Boston, MA 02111 USA. RP Trucco, E (reprint author), Univ Dundee, Sch Sci & Engn Comp, Comp Vis & Image Proc Grp, Perth Rd, Dundee DD1 4HN, Scotland. EM e.trucco@dundee.ac.uk FU European Union Marie Sklodowska-Curie Initial Training Network Retinal Vascular Modelling, Measurement And Diagnosis (REVAMMAD) [316990]; National Institutes of Health [NIH R01-EY022695]; Falk Medical Research Foundation; Massachusetts Eye and Ear Infirmary Foundation FX Supported by European Union Marie Sklodowska-Curie Initial Training Network Retinal Vascular Modelling, Measurement And Diagnosis (REVAMMAD), Project Number 316990 (RA, ET) and by the National Institutes of Health Grant NIH R01-EY022695 (PH), Falk Medical Research Foundation (PH), and Massachusetts Eye and Ear Infirmary Foundation (PH). The authors alone are responsible for the content and writing of this paper. NR 41 TC 2 Z9 2 U1 0 U2 6 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAR PY 2016 VL 57 IS 3 BP 1132 EP 1139 DI 10.1167/iovs.15-18513 PG 8 WC Ophthalmology SC Ophthalmology GA DK4BE UT WOS:000374860600049 PM 26975024 ER PT J AU Brown, MC AF Brown, M. Christian TI Recording and labeling at a site along the cochlea shows alignment of medial olivocochlear and auditory nerve tonotopic mappings SO JOURNAL OF NEUROPHYSIOLOGY LA English DT Article DE outer hair cell; efferent; afferent; characteristic frequency; cochlear amplifier ID GUINEA-PIG COCHLEA; HAIR-CELLS; RESPONSE PROPERTIES; 2-TONE SUPPRESSION; MAMMALIAN COCHLEA; BASILAR-MEMBRANE; EFFERENT NEURONS; ACOUSTIC INJURY; FREQUENCY MAP; CAT AB Medial olivocochlear (MOC) neurons provide an efferent innervation to outer hair cells (OHCs) of the cochlea, but their tonotopic mapping is incompletely known. In the present study of anesthetized guinea pigs, the MOC mapping was investigated using in vivo, extracellular recording, and labeling at a site along the cochlear course of the axons. The MOC axons enter the cochlea at its base and spiral apically, successively turning out to innervate OHCs according to their characteristic frequencies (CFs). Recordings made at a site in the cochlear basal turn yielded a distribution of MOC CFs with an upper limit, or "edge," due to usually absent higher-CF axons that presumably innervate more basal locations. The CFs at the edge, normalized across preparations, were equal to the CFs of the auditory nerve fibers (ANFs) at the recording sites (near 16 kHz). Corresponding anatomical data from extracellular injections showed spiraling MOC axons giving rise to an edge of labeling at the position of a narrow band of lab